CN116916891A - 自我复制rna和其用途 - Google Patents
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- CN116916891A CN116916891A CN202280011346.4A CN202280011346A CN116916891A CN 116916891 A CN116916891 A CN 116916891A CN 202280011346 A CN202280011346 A CN 202280011346A CN 116916891 A CN116916891 A CN 116916891A
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Abstract
本公开涉及一种编码来自严重急性呼吸道综合征冠状病毒2(SARS‑CoV‑2)的抗原的自我复制RNA以及其用途。
Description
序列表
本申请与电子形式的序列表一起提交。序列表的整体内容特此通过引用并入。
技术领域
本公开涉及一种编码来自严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)的抗原的自我复制RNA以及其用途。
背景技术
疫苗是预防此感染性疾病的关键健康干预措施。此大流行病见证了多种疫苗前所未有的发展,其中迄今已有200多种疫苗在开发中,30多种在临床试验中,并且多种在3期。已经开发的大多数疫苗试图唤起免疫系统识别SARS-COV-2刺突蛋白(或S蛋白),因为在仓鼠攻击模型中重组SARS-CoV蛋白的早期研究证明此方法有免疫原性和保护性。
然而,目前还没有批准的针对SARS-CoV-2的治疗性和/或预防性疫苗。因此,仍然需要开发针对SARS-CoV-2的特异性和高效疫苗。还期望此类疫苗可以以足够的量生产,特别是在大流行病期间,并且比目前用于制备流感疫苗的基于鸡蛋的技术更快。
发明内容
本公开基于发明人对针对严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)抗原的自我复制RNA的鉴定。
发明人的发现为一种针对SARS-CoV-2抗原的自我复制RNA提供了基础。发明人的发现还为一种针对SARS-CoV-2抗原的单顺反子自我复制RNA提供了基础。此外,发明人的发现为治疗或预防受试者的疾病或病症(例如,SARS-COV-2感染、COVID-19和/或急性呼吸窘迫综合征(ARDS))或延缓所述疾病或病症的进展的方法提供了基础。
因此,本公开提供了一种自我复制RNA,其包括与亚基因组(SG)启动子可操作地连接的编码抗原的核苷酸序列,其中所述抗原来自SARS-CoV-2。
本公开还提供了一种单顺反子自我复制RNA,其包括与SG启动子可操作地连接的编码抗原的核苷酸序列,其中所述抗原来自SARS-CoV-2。
在一个实例中,所述抗原是刺突(S)蛋白或核衣壳(N)蛋白。在一个实例中,所述抗原是来自SARS-CoV-2毒株2019-nCoV/USA-WA1/2020的SARS-CoV-2N蛋白或S蛋白。
在一个实例中,所述抗原是S蛋白。例如,所S蛋白由SEQ ID NO:1中所示的序列编码。
在另一个实例中,所述S蛋白是突变S蛋白。
在一个实例中,突变S蛋白包括受体结合结构域中的突变。例如,所述突变选自由以下组成的组:S438F、N439K、N440K、L441I、K444R、V445A、V445I、G446V、G446S、N450K、L452R、L452P、L455F、K458N、N460T、D467V、I468F、I468T、I468V、E471O、I472V、A475V、G476S、S477G、S477I、S477N、S477R、T478I、P479L、P479L、P479S、N481D、N481H、V483F、V483A、E484D、E484K、E484K、E484O、G485S、Y489H、Y489D、Y489F、Y489C、Y489N、F490L、F490S、P491R、Q493L、S494P、Y495N、T500N、N501S和Y505H、Y508H。在一个实例中,突变S蛋白包括受体结合结构域中的突变,所述突变选自由以下组成的组:N439K、N439L、L452R、S477N、T478I、V483A和E484D。
在一个实例中,突变S蛋白包括选自由以下组成的组的突变:P337S、F338L、F338C、G339D、E340K、V341I、A344S、T345S、R346K、A348S、A348T、W353R、N354D、N354K、N354S、S359N、D364Y、V367F、S373L、V382L、P384L、P384S、T385A、T393P、V395I、F400C、R403K、R403S、D405V、R408I、Q414E、Q414K、Q414P、Q414R、T415S、K417R、K417N、I418V、Y421S、Y423C、Y423F、Y423S、D427Y、R509K、V510L、V511E、V512L、L518I、H519O、A520S、A520V、P521R、P521S、A522P、A522S和D614G。
在一个实例中,突变S蛋白包括选自由以下组成的组的突变:L18F、D80A、T95I、Y144S、Y145N、D215G、P337S、F338L、F338C、G339D、E340K、V341I、A344S、T345S、R346K、A348S、A348T、W353R、N354D、N354K、N354S、S359N、D364Y、V367F、S373L、V382L、P384L、P384S、T385A、T393P、V395I、F400C、R403K、R403S、D405V、R408I、Q414E、Q414K、Q414P、Q414R、T415S、K417N、K417T、K417R、I418V、Y421S、Y423C、Y423F、Y423S、D427Y、S438F、N439K、N440K、L441I、K444R、V445A、V445I、G446V、G446S、N450K、L452R、L452P、L455F、K458N、N460T、D467V、I468F、I468T、I468V、E471O、I472V、A475V、G476S、S477G、S477I、S477N、S477R、T478I、T478K、P479L、P479S、N481D、N481H、V483F、V483A、E484D、E484K、E484K、E484O、G485S、Y489H、Y489D、Y489F、Y489C、Y489N、F490L、F490S、P491R、Q493L、S494P、Y495N、T500N、N501S、N501Y、Y505H、Y508H、R509K、V510L、V511E、V512L、L518I、H519O、A520S、A520V、P521R、P521S、A522P、A522S、A570D、D614G、P680H、P681H、A701V、T716I和D950N。
在一个实例中:(i)所述突变S蛋白在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和/或(ii)所述突变S蛋白在S2'位点处缺乏弗林蛋白酶切割位点;和/或(iii)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变;和/或(iv)包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。
在一个实例中,所述S蛋白在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变。例如,所突变S蛋白由SEQ ID NO:2中所示的序列编码。
在一个实例中,所述S蛋白在S2'位点处缺乏弗林蛋白酶切割位点。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变。例如,所突变S蛋白由SEQ ID NO:7中所示的序列编码。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。
在一个实例中,所述S蛋白(i)在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;以及(ii)在S2'位点处缺乏弗林蛋白酶切割位点。例如,所突变S蛋白由SEQ ID NO:5中所示的序列编码。
在一个实例中,所述S蛋白(i)在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;以及(ii)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变。例如,所突变S蛋白由SEQID NO:4中所示的序列编码。
在一个实例中,所述S蛋白(i)在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;以及(ii)包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。例如,所突变S蛋白由SEQ ID NO:3中所示的序列编码。
在一个实例中,所述S蛋白(i)在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和(ii)在S2'位点处缺乏弗林蛋白酶切割位点;以及(iii)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变。例如,所突变S蛋白由SEQ ID NO:6中所示的序列编码。
在一个实例中,所述S蛋白(i)在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和(ii)在S2'位点处缺乏弗林蛋白酶切割位点;以及(iii)包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。
在一个实例中,所述S蛋白(i)在S2'位点处缺乏弗林蛋白酶切割位点;以及(ii)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变。
在一个实例中,所述S蛋白(i)在S2'位点处缺乏弗林蛋白酶切割位点;以及(ii)包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。
在一个实例中,所述S蛋白(i)在S2'位点处缺乏弗林蛋白酶切割位点;和(ii)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变;以及(iii)包括与SEQ IDNO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。
在一个实例中,所述S蛋白(i)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变;以及(ii)包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。
在一个实例中,所述S蛋白(i)在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和(ii)在S2'位点处缺乏弗林蛋白酶切割位点;和(iii)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变;以及(iv)包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸501相对应的残基处的N变为Y的突变。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸69和70相对应的两个残基的缺失。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸144相对应的一个残基的缺失。
在一个实例中,所述S蛋白(i)包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和(ii)包括与SEQ ID NO:18的核苷酸69和70相对应的两个残基的缺失;和(iii)包括与SEQ ID NO:18的核苷酸144相对应的一个残基的缺失;和(iv)包括与SEQ ID NO:18的核苷酸501相对应的残基处的N变为Y的突变;以及(v)包括与SEQ IDNO:18的核苷酸614相对应的残基处的D变为G的突变。例如,所突变S蛋白由SEQ ID NO:19中所示的序列编码。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸242至244相对应的三个残基的缺失。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸417相对应的残基处的K变为N的突变。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸484相对应的残基处的E变为K的突变。
在一个实例中,所述S蛋白(i)包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和(ii)包括与SEQ ID NO:18的核苷酸242至244相对应的三个残基的缺失;和(iii)包括与SEQ ID NO:18的核苷酸417相对应的残基处的K变为N的突变;和(iv)包括与SEQ ID NO:18的核苷酸484相对应的残基处的E变为K的突变;和(v)包括与SEQ ID NO:18的核苷酸501相对应的残基处的N变为Y的突变;以及(vi)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变。例如,所突变S蛋白由SEQ ID NO:20中所示的序列编码。
在一个实例中,所述S蛋白(i)包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和(ii)包括与SEQ ID NO:18的核苷酸69和70相对应的两个残基的缺失;和(iii)包括与SEQ ID NO:18的核苷酸242至244相对应的三个残基的缺失;和(iv)包括与SEQ ID NO:18的核苷酸417相对应的残基处的K变为N的突变;和(v)包括与SEQID NO:18的核苷酸484相对应的残基处的E变为K的突变;和(vi)包括与SEQ ID NO:18的核苷酸501相对应的残基处的N变为Y的突变;以及(vii)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变。例如,所突变S蛋白由SEQ ID NO:21中所示的序列编码。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸570相对应的残基处的A变为D的突变。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸680相对应的残基处的P变为H的突变。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸716相对应的残基处的T变为I的突变。
在一个实例中,所述S蛋白(i)包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和(ii)包括与SEQ ID NO:18的核苷酸69和70相对应的两个残基的缺失;和(iii)包括与SEQ ID NO:18的核苷酸144相对应的一个残基的缺失;和(iv)包括与SEQ ID NO:18的核苷酸501相对应的残基处的N变为Y的突变;和(v)包括与SEQ ID NO:18的核苷酸570相对应的残基处的A变为D的突变;和(vi)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变;和(vii)包括与SEQ ID NO:18的核苷酸680相对应的残基处的P变为H的突变;以及(viii)包括与SEQ ID NO:18的核苷酸716相对应的残基处的T变为I的突变。例如,所突变S蛋白由SEQ ID NO:22中所示的序列编码。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸18相对应的残基处的L变为F的突变。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸80相对应的残基处的D变为A的突变。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸215相对应的残基处的D变为G的突变。
在一个实例中,所述S蛋白包括与SEQ ID NO:18的核苷酸701相对应的残基处的A变为V的突变。
在一个实例中,所述S蛋白(i)包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和(ii)包括与SEQ ID NO:18的核苷酸18相对应的残基处的L变为F的突变;和(iii)包括与SEQ ID NO:18的核苷酸80相对应的残基处的D变为A的突变;和(iv)包括与SEQ ID NO:18的核苷酸215相对应的残基处的D变为G的突变;和(v)包括与SEQ ID NO:18的核苷酸242至244相对应的三个残基的缺失;和(vi)包括与SEQ ID NO:18的核苷酸417相对应的残基处的K变为N的突变;和(vii)包括与SEQ ID NO:18的核苷酸484相对应的残基处的E变为K的突变;和(viii)包括与SEQ ID NO:18的核苷酸501相对应的残基处的N变为Y的突变;和(ix)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变;以及(x)包括与SEQ ID NO:18的核苷酸701相对应的残基处的A变为V的突变。例如,所突变S蛋白由SEQ ID NO:23中所示的序列编码。
在一个实例中,所述突变S蛋白(i)在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQ ID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和/或(ii)在S2'位点处缺乏弗林蛋白酶切割位点;和/或(iii)包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变;和/或(iv)包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入;和/或(v)包括与SEQ ID NO:18的核苷酸501相对应的残基处的N变为Y的突变;和/或(vi)包括与SEQ ID NO:18的核苷酸69和70相对应的两个残基的缺失;和/或(vii)包括与SEQ ID NO:18的核苷酸144相对应的一个残基的缺失;和/或(viii)包括与SEQ ID NO:18的核苷酸242至244相对应的三个残基的缺失;和/或(ix)包括与SEQ ID NO:18的核苷酸417相对应的残基处的K变为N的突变;和/或(x)包括与SEQ IDNO:18的核苷酸484相对应的残基处的E变为K的突变;和/或(xi)包括与SEQ ID NO:18的核苷酸570相对应的残基处的A变为D的突变;和/或(xii)包括与SEQ ID NO:18的核苷酸680相对应的残基处的P变为H的突变;和/或(xiii)包括与SEQ ID NO:18的核苷酸716相对应的残基处的T变为I的突变;和/或(xix)包括与SEQ ID NO:18的核苷酸18相对应的残基处的L变为F的突变;和/或(xx);和/或包括与SEQ ID NO:18的核苷酸80相对应的残基处的D变为A的突变;和/或(xxi)包括与SEQ ID NO:18的核苷酸215相对应的残基处的D变为G的突变;和/或(xxii)包括与SEQ ID NO:18的核苷酸701相对应的残基处的A变为V的突变。
在一个实例中,所述突变S蛋白由SEQ ID NO:2至7中的任一个中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:2中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:3中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:4中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:5中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:6中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:7中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:2至7和/或19-23中的任一个中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:19至23中的任一个中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:19中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:20中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:21中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:22中所示的序列编码。
在一个实例中,所述突变S蛋白由SEQ ID NO:23中所示的序列编码。
在一个实例中,所述抗原是N蛋白。例如,所N蛋白由SEQ ID NO:8中所示的序列编码。
在一个实例中,所述SG启动子是天然SG启动子。例如,天然SG启动子是源自和/或基于RNA病毒(例如,甲病毒属(alphavirus))的天然启动子。在一个实例中,所述天然SG启动子是天然甲病毒属SG启动子。
在一个实例中,所述天然SG启动子是最小SG启动子。例如,所述最小SG启动子是转录起始所需的最小序列。在一个实例中,所述最小天然SG启动子的长度为49个核苷酸。在一个实例中,所述最小天然SG启动子由包括SEQ ID NO:9中所示的序列或由所述序列组成的序列编码。
在一个实例中,所述自我复制RNA来自甲病毒属。例如,所述甲病毒属选自由以下组成的组:塞姆利基森林病毒(Semliki Forest virus,SFV)、辛德比斯病毒(Sindbisvirus,SIN)和委内瑞拉马脑炎病毒(Venezuelan equine encephalitis virus,VEE)以及其组合。
在一个实例中,所述自我复制RNA来自塞姆利基森林病毒(SFV)。
在一个实例中,所述自我复制RNA来自辛德比斯病毒(SIN)。
在一个实例中,所述自我复制RNA来自委内瑞拉马脑炎病毒(VEE)。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:10至17中的任一个中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:10(Co5)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:11(Co6)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:12(Co16)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:13(Co17)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:14(Co48)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:15(Co49)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:16(Co58)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:17(Co59)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:24(Co77)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:25(Co78)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:26(Co79)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:27(Co80)中所示的序列编码。
在一个实例中,本公开提供了一种自我复制RNA,其由SEQ ID NO:28(Co81)中所示的序列编码。
本公开还提供了一种免疫原性组合物,其包括本公开的自我复制RNA。例如,当施用时,本公开的组合物能够诱导受试者的免疫应答。例如,施用所述组合物诱导体液和/或细胞介导的免疫应答。在一个实例中,所述组合物诱导所述受试者的体液免疫应答。例如,所述体液免疫应答是抗体介导的免疫应答。在另一个实例中,所述组合物诱导细胞介导的免疫应答。例如,所述细胞介导的免疫应答包含抗原特异性细胞毒性T细胞的激活。
在一个实例中,所述免疫原性组合物包括多个自我复制RNA,其中每个自我复制RNA编码不同的多肽抗原序列。例如,不同的多肽抗原序列来自病毒的同一毒株(例如,编码来自同一SARS-CoV-2毒株的抗原)。在一个实例中,不同的多肽抗原序列来自相同病毒的不同毒株(例如,编码来自SARS-CoV-2的不同毒株的抗原)。在一个实例中,不同的多肽抗原序列来自不同的病毒(例如,编码来自SARS-CoV-2的抗原和来自无关病毒,例如流感的抗原)。
本公开还提供了一种药物组合物,其包括本公开的免疫原性组合物以及药学上可接受的载体。适用于本公开的药学上可接受的载体对技术人员来说是显而易见的和/或在本文中进行描述。
在一个实例中,所述药物组合物进一步包括脂质纳米颗粒(LNP)、聚合物微粒和水包油乳液。例如,所述自我复制RNA被包封在LNP、聚合物微粒和水包油乳液中、与LNP、聚合物微粒和水包油乳液结合或吸附在LNP、聚合物微粒和水包油乳液上。
在一个实例中,所述药物组合物进一步包括LNP。例如,所述自我复制RNA被包封在LNP中。在另一个实例中,所述自我复制RNA与LNP结合。在另外的实例中,所述自我复制RNA被吸附到LNP上。
在一个实例中,所述药物组合物进一步包括聚合物微粒。例如,所述自我复制RNA被包封在聚合物微粒中。在另一个实例中,所述自我复制RNA与聚合物微粒结合。在另外的实例中,所述自我复制RNA被吸附到聚合物微粒上。
在一个实例中,所述药物组合物进一步包括水包油乳液。例如,所述自我复制RNA被包封在水包油乳液中。在另一个实例中,所述自我复制RNA与水包油乳液结合。在另一个实例中,所述自我复制RNA被吸附到水包油乳液上。在另一个实例中,所述自我复制RNA重悬于水包油乳液中。
本公开还提供了本公开的免疫原性组合物或药物组合物,其用作疫苗。
本公开进一步提供了一种多核苷酸,其编码本公开的自我复制RNA疫苗。例如,所述多核苷酸是DNA。在一个实例中,本公开提供了一种DNA,其编码本公开的自我复制RNA疫苗。
本公开进一步提供了本公开的免疫原性组合物或药物组合物,其用于治疗或预防选自由以下组成的组的疾病或病状或延缓所述疾病或病状的进展:SARS-2-CoV-2感染、COVID-19、ARDS以及其组合。例如,本公开提供了本公开的免疫原性组合物或药物组合物,其用于治疗SARS-2-CoV-2感染、COVID-19、ARDS以及其组合。在一个实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于预防SARS-2-CoV-2感染、COVID-19、ARDS以及其组合。在另一个实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于延缓SARS-2-CoV-2感染、COVID-19、ARDS以及其组合的进展。
在一个实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于治疗或预防COVID-19或延缓其进展。例如,本公开提供了本公开的免疫原性组合物或药物组合物,其用于治疗COVID-19。在另一个实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于预防COVID-19。在另外的实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于延缓COVID-19的进展。
在一个实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于治疗或预防SARS-CoV-2感染或延缓其进展。例如,本公开提供了本公开的免疫原性组合物或药物组合物,其用于治疗SARS-CoV-2感染。在另一个实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于预防SARS-CoV-2感染。在另外的实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于延缓SARS-CoV-2感染的进展。
在一个实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于治疗或预防ARDS或延缓其进展。例如,本公开提供了本公开的免疫原性组合物或药物组合物,其用于治疗ARDS。在另一个实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于预防ARDS。在另外的实例中,本公开提供了本公开的免疫原性组合物或药物组合物,其用于延缓ARDS的进展。
本公开提供一种治疗或预防受试者的疾病或病状或延缓所述疾病或病状的进展的方法,所述方法包括向有需要的受试者施用本公开的免疫原性组合物或药物组合物。在一个实例中,本公开提供一种治疗受试者的疾病或病状的方法,所述方法包括向有需要的受试者施用本公开的免疫原性组合物或药物组合物。在另一个实例中,本公开提供一种预防受试者的疾病或病状的方法,所述方法包括向有需要的受试者施用本公开的免疫原性组合物或药物组合物。在另外的实例中,本公开提供一种延缓受试者的疾病或病状的进展的方法,所述方法包括向有需要的受试者施用本公开的免疫原性组合物或药物组合物。
在一个实例中,本公开提供了本公开的自我复制RNA在制备用于治疗或预防有需要的受试者的疾病或病状或延缓所述疾病或病状的进展的药物中的用途。例如,本公开提供了本公开的自我复制RNA在制备用于治疗有需要的受试者的疾病或病状的药物中的用途。在另一个实例中,本公开提供了本公开的自我复制RNA在制备用于预防有需要的受试者的疾病或病状的药物中的用途。在另外的实例中,本公开提供了本公开的自我复制RNA在制备用于延缓有需要的受试者的疾病或病状的进展的药物中的用途。
在一个实例中,所述受试者患有疾病或病状。在一个实例中,所述受试者已经被诊断患有疾病或病状。在一个实例中,所述受试者正在接受疾病或病状的治疗。
在一个实例中,所述疾病或病状选自由以下组成的组:SARS-CoV-2感染、COVID-19、ARDS以及其组合。在一个实例中,所述疾病或病状是SARS-CoV-2感染。在另一个实例中,所述疾病或病状是COVID-19。在另外的实例中,所述疾病或病状是ARDS。在一个实例中,ARDS与SARS-CoV-2感染和/或COVID-19相关。例如,所述疾病或病状是ARDS。在一个实例中,ARDS与SARS-CoV-2感染相关。在另一个实例中,所述疾病或病状是ARDS。在一个实例中,ARDS与COVID-19相关。
在本文所描述的任何方法的一个实例中,本公开的自我复制RNA是在受试者发生SARS-CoV-2感染、COVID-19和/或ARDS之前或之后施用的。在本文所描述的任何方法的一个实例中,本公开的自我复制RNA是在受试者发生SARS-CoV-2感染、COVID-19和/或ARDS之前施用的。在本文所描述的任何方法的一个实例中,本公开的自我复制RNA是在受试者发生SARS-CoV-2感染、COVID-19和/或ARDS之后施用的。
在本文所描述的任何方法的一个实例中,本公开的自我复制RNA是在检测到受试者的SARS-CoV-2感染、COVID-19和/或ARDS之后施用的。在本文所描述的任何方法的一个实例中,本公开的自我复制RNA是在检测到SARS-CoV-2感染之后施用的。在另一个实例中,本公开的自我复制RNA是在检测到SARS-CoV-2感染之后但在发生COVID-19之前施用的。在本文所描述的任何方法的另外的实例中,本公开的自我复制RNA是在检测到COVID-19之后施用的。在本文所描述的任何方法的一个实例中,本公开的自我复制RNA是在检测到COVID-19之后但在发生ARDS之前施用的。在本文所描述的任何方法的另一个实例中,本公开的自我复制RNA是在检测到ARDS之后施用的。
在一个实例中,所述受试者处于患上COVID-19或ARDS的风险中。例如,所述受试者处于患上COVID-19的风险中。在另外的实例中,所述受试者处于患上ARDS的风险中。
在一个实例中,本公开的组合物以足以降低SARS-CoV-2感染、COVID-19和/或ARDS的一种或多种症状的严重程度或防止其发作的量施用。SARS-CoV-2感染、COVID-19和/或ARDS的症状对技术人员来说是显而易见的和/或在本文中进行描述。
本公开提供了一种诱导受试者的免疫应答的方法,所述方法包括向有需要的受试者施用本公开的自我复制RNA、免疫原性组合物或药物组合物。
本公开还提供了一种本公开的自我复制RNA、免疫原性组合物或药物组合物在制备用于诱导有需要的受试者的免疫应答的药物中的用途。
在一个实例中,本公开的自我复制RNA、免疫原性组合物或药物组合物诱导体液和/或细胞介导的免疫应答。在一个实例中,所述组合物诱导所述受试者的体液免疫应答。例如,所述体液免疫应答是抗体介导的免疫应答。例如,中和抗体的产生。在另一个实例中,所述组合物诱导细胞介导的免疫应答。例如,所述细胞介导的免疫应答包含抗原特异性细胞毒性T细胞的激活。例如,所述T细胞是CD4 T细胞和/或CD8 T细胞。在一个实例中,所述T细胞是CD4 T细胞。在另一个实例中,所述T细胞是CD8 T细胞。在另外的实例中,所述T细胞是CD4和CD8 T细胞。
在一个实例中,施用本公开的自我复制RNA、免疫原性组合物或药物组合物诱导CD4 T细胞介导的免疫应答。
在一个实例中,施用本公开的自我复制RNA、免疫原性组合物或药物组合物诱导CD8 T细胞介导的免疫应答。
在一个实例中,施用本公开的自我复制RNA、免疫原性组合物或药物组合物诱导CD4和CD8 T细胞介导的免疫应答。
在一个实例中,所述CD4 T细胞介导的免疫应答是Th0、Th1和/或Th2应答。例如,所述CD4 T细胞介导的免疫应答是Th0应答。在另一个实例中,所述CD4 T细胞介导的免疫应答是Th1应答。在另外的实例中,所述CD4 T细胞介导的免疫应答是Th2应答。在一个实例中,所述CD4 T细胞介导的免疫应答是Th0和Th1应答。在另一个实例中,所述CD4 T细胞介导的免疫应答是Th0和Th2应答。在另外的实例中,所述CD4T细胞介导的免疫应答是Th1和Th2应答。在另一个实例中,所述CD4 T细胞介导的免疫应答是Th0、Th1和Th2应答。
在一个实例中,Th0应答细胞因子表达白介素2(IL2+)和/或肿瘤坏死因子α(TNFa+);和/或对干扰素γ(IFNg-)、IL5-和/或IL13-呈阴性。例如,所述细胞因子是IL2+。在另一个实例中,所述细胞因子是TNFa+。在一个实例中,所述细胞因子是IFNg-。在另一个实例中,所述细胞因子是IL5-。在另外的实例中,所述细胞因子是IL13-。
在一个实例中,Th1应答细胞因子表达干扰素γ(IFNg+);和/或对IL5-和/或IL13-呈阴性。例如,所述细胞因子是IFNg+。在另一个实例中,所述细胞因子是IL5-。在另外的实例中,所述细胞因子是IL13-。
在一个实例中,Th2应答细胞因子表达IL5+和/或IL13+;和/或对IFNg呈阴性。例如,所述细胞因子是IL5+。在另外的实例中,所述细胞因子是IL13+。例如,所述细胞因子是IFNg-。
本公开还提供了一种多核苷酸,其编码本公开的自我复制RNA。例如,所述多核苷酸是重组DNA。在一个实例中,所述重组DNA是质粒。在一个实例中,所述质粒包括SEQ IDNO:10至17中的任一个中所示的序列。
本公开还提供了一种试剂盒,其包括至少一种本公开的自我复制RNA,任选地在递送系统和/或药学上可接受的载体或稀释剂中,与说明书一起包装,用于治疗或预防受试者的疾病或病症(例如,SARS-CoV-2感染、COVID-19和/或ARDS)或延缓所述疾病或病症的进展。
本公开还提供了一种试剂盒,其包括至少一种本公开的自我复制RNA,任选地在递送系统和/或药学上可接受的载体或稀释剂中,与说明书一起包装,以将所述RNA施用于患有疾病或病症(例如,SARS-CoV-2感染、COVID-19和/或ARDS)或处于患有所述疾病或病症的风险的受试者。
在一个实例中,本公开的自我复制RNA、免疫原性组合物或药物组合物在小瓶中提供。在另一个实例中,本公开的自我复制RNA、免疫原性组合物或药物组合物在注射器中提供。
附图说明
图1是示出了Co16诱导的抗原特异性T细胞的一系列图形表示。示出了(A)S1特异性CD4 T细胞,(B)S1特异性CD8 T细胞,(C)S2特异性CD4 T细胞,(D)S2特异性CD8 T细胞,和(E)N特异性CD4 T细胞的诱导的净(抗原特异性)细胞因子产生CD4和CD8 T细胞%。
图2是示出了构建体对(A)参考Whuan序列;(B)α变体(B.1.1.7;UK毒株);(C)β变体(B.1.351;南非毒株);(D)γ变体(P.1;巴西毒株);和(E)δ变体(B.1.617.2;印度毒株)的中和能力的一系列图形表示。
图3是示出了所有构建体在高剂量和低剂量下对(A)参考Whuan序列;(B)α变体(B.1.1.7;UK毒株);(C)β变体(B.1.351;南非毒株);(D)γ变体(P.1;巴西毒株);和(E)δ变体(B.1.617.2;印度毒株)产生的总Ig应答的一系列图形表示。
图4是示出了与所有变体B细胞受体特异性探针反应的所有构建体产生的S特异性B细胞的图形表示。非特异性对照(即,无诱饵和阴性对照HA H1)示出了低水平的背景结合。
图5是示出了与S1表位和S2表位具有反应性的所有构建体诱导的抗原特异性(A)CD4 T细胞和(B)CD8 T细胞的一系列图形表示。
序列表符号说明
SEQ ID NO:1全长wt SARS-CoV-2刺突(S)蛋白(可切割)的核苷酸序列
SEQ ID NO:2不可切割的SARS-CoV-2突变的刺突(S)蛋白(S1/S2 RRAR变为
QQAA的突变)的核苷酸序列
SEQ ID NO:3不可切割的SARS-CoV-2刺突(S)蛋白(S1/S2 RRAR变为QQAA的突变和986P/987P突变)的核苷酸序列
SEQ ID NO:4不可切割的SARS-CoV-2刺突(S)蛋白(S1/S2 RRAR变为QQAA的突变和D614G突变)的核苷酸序列
SEQ ID NO:5不可切割的SARS-CoV-2刺突(S)蛋白(S1/S2 RRAR变为QQAA的突变和S2'突变)的核苷酸序列
SEQ ID NO:6不可切割的SARS-CoV-2刺突(S)蛋白(S1/S2 RRAR变为QQAA的突变以及D614G突变和S2'突变)的核苷酸序列
SEQ ID NO:7可切割的SARS-CoV-2刺突(S)蛋白(D614G突变)的核苷酸序列
SEQ ID NO:8全长wt SARS-CoV-2核衣壳(N)蛋白的核苷酸序列
SEQ ID NO:9甲病毒属天然亚基因组启动子的核苷酸序列
SEQ ID NO:10构建体Co5的核苷酸序列
SEQ ID NO:11构建体Co6的核苷酸序列
SEQ ID NO:12构建体Co16的核苷酸序列
SEQ ID NO:13构建体Co17的核苷酸序列
SEQ ID NO:14构建体Co48的核苷酸序列
SEQ ID NO:15构建体Co49的核苷酸序列
SEQ ID NO:16构建体Co58的核苷酸序列
SEQ ID NO:17构建体Co59的核苷酸序列
SEQ ID NO:18全长wt SARS-CoV-2S蛋白的氨基酸序列
SEQ ID NO:19不可切割的SARS-CoV-2刺突(S)蛋白(RRAR→QQAA;Δ69-70;
ΔY144;N501Y;D614G)的核苷酸序列
SEQ ID NO:20不可切割的SARS-CoV-2刺突(S)蛋白(RRAR→QQAA;Δ242-244;
K417N;E484K;N501Y;D614G)的核苷酸序列
SEQ ID NO:21不可切割的SARS-CoV-2刺突(S)蛋白(RRAR→QQAA;Δ69-70;
Δ242-244;K417N;E484K;N501Y;D614G)的核苷酸序列
SEQ ID NO:22不可切割的SARS-CoV-2刺突(S)蛋白(RRAR→QQAA;Δ69-70;
ΔY144;N501Y;A570D;D614G;P680H;T716I)的核苷酸序列
SEQ ID NO:23不可切割的SARS-CoV-2刺突(S)蛋白(RRAR→QQAA;L18F;
D80A;D215G;Δ242-244;K417N;E484K;N501Y;D614G;A701V)的核苷酸序列
SEQ ID NO:24构建体Co77的核苷酸序列
SEQ ID NO:25构建体Co78的核苷酸序列
SEQ ID NO:26构建体Co79的核苷酸序列
SEQ ID NO:27构建体Co80的核苷酸序列
SEQ ID NO:28构建体Co81的核苷酸序列
SEQ ID NO:29VEEV的5'UTR的核苷酸序列
SEQ ID NO:30SINV的3'UTR的核苷酸序列
SEQ ID NO:31富含GC的元件
SEQ ID NO:32富含GC的元件
SEQ ID NO:33富含GC的元件
SEQ ID NO:34组蛋白茎环序列
SEQ ID NO:35Kozak共有序列
SEQ ID NO:36Kozak共有序列
SEQ ID NO:37Poly-A序列
具体实施方式
概述
贯穿本说明书,除非另有明确说明或上下文另有要求,否则对单个步骤、物质组合物、步骤组或物质组合物组的提及应被视为涵盖这些步骤、物质组合物、步骤组或物质组合物组中的一个和多个(即一个和多个)。
本领域的技术人员将理解,除了具体描述的那些之外,本公开容易进行变化和修改。应当理解,本公开包含所有此类变化和修改。本公开还包含本说明书中个别或共同提及或指出的所有步骤、特征、组合物和化合物,以及所述步骤或特征中的任何两者或更多者的任何和所有组合。
本公开不限于本文所描述的具体实例的范围,这些实例旨在仅用于举例说明的目的。功能等效的产品、组合物和方法显然在本公开的范围内。
除非另有明确说明,否则本文中的本公开的任何实例在进行必要的修改后应被视为适用于本公开的任何其它实例。换句话说,本公开的任何具体实例都可以与本公开的任何其它具体实例相结合(互斥的情况除外)。
公开了特定特征或特征组或方法或方法步骤的本公开的任何实例将被用来为否认特定特征或特征组或方法或方法步骤提供明确的支持。
除非另外特别说明,否则本文所使用的所有技术和科学术语应被视为具有与本领域(例如,在细胞培养、分子遗传学、免疫学、免疫组织化学、蛋白质化学和生物化学)的普通技术人员通常所理解的含义相同的含义。
除非另有说明,否则本公开中使用的重组蛋白、细胞培养和免疫学技术是本领域技术人员熟知的标准程序。此类技术在资料来源中的所有文献中进行描述和解释,如J.Perbal,《分子克隆实用指南(A Practical Guide to Molecular Cloning)》,约翰威利父子出版公司(John Wiley and Sons)(1984);J.Sambrook等人《分子克隆:实验室手册(Molecular Cloning:A Laboratory Manual)》,冷泉港实验室出版社(Cold SpringHarbour Laboratory Press)(1989);T.A.Brown(编辑),《基础分子生物学:实用方法(Essential Molecular Biology:A Practical Approach)》,第1卷和第2卷,IRL出版社(IRL Press)(1991);D.M.Glover和B.D.Hames(编辑),《DNA克隆:实用方法(DNA Cloning:APractical Approach)》,第1-4卷,IRL出版社(1995和1996);以及F.M.Ausubel等人(编辑),《当代分子生物学实验指南(Current Protocols in Molecular Biology)》,格林出版协会(Greene Pub.Associates)和威利国际科学出版社(Wiley-Interscience)(1988,包含到目前为止的所有更新);Ed Harlow和David Lane(编辑)《抗体:实验室手册(Antibodies:A Laboratory Manual),冷泉港实验室出版社,(1988);以及J.E.Coligan等人(编辑)《当代免疫学实验指南(Current Protocols in Immunology)》,约翰威利父子出版公司(包含到目前为止的所有更新)。
术语“和/或”,例如,“X和/或Y”应被理解为意指“X和Y”或“X或Y”,并且应被视为对两个含义或任一含义提供明确支持。
贯穿本说明书,词语“包括(comprise)”或如“包括(comprises)”或“包括(comprising)”等变体应当被理解为暗示包含所陈述要素、整数或步骤或要素组、整数组或步骤组,但不排除任何其它要素、整数或步骤或要素组、整数组或步骤组。
如本文所用,术语“源自”应当表示指定的整数可以从特定的来源获得,尽管不一定直接从所述来源获得。类似地,术语“基于”应当被理解为表示可以从特定来源开发或使用指定的整数,尽管不一定直接来自所述来源。
所选定义
如本文所用,术语“自我复制RNA”是指基于RNA病毒的构建体,所述构建体已被工程化以允许异源RNA和蛋白质的表达。自我复制RNA(例如,呈裸RNA的形式)可以在宿主细胞中扩增,导致期望的基因产物在宿主细胞中表达。
如本文所用,提及自我复制RNA的术语“单顺反子”是指编码一种多肽的RNA。
如本文所用的术语“裸”是指基本上不含其它大分子如脂质、聚合物和蛋白质的核酸。“裸”核酸,如自我复制RNA,不与其它大分子一起调配以提高细胞摄取。因此,裸核酸不被包封在LNP、脂质体、聚合物微粒或水包油乳液中、吸附在其上或与其结合。
如本文所用,术语“核苷酸序列”或“核酸序列”将被理解为意指与磷酸二酯骨架共价连接的一系列连续的核苷酸(或碱基)。按照惯例,序列从5'端到3'端呈递,除非另有说明。
如本文所用,术语“抗原”指含有一个或多个表位的分子或结构,所述表位诱导、引发、增强或加强细胞和/或体液免疫应答。抗原可以包含例如来自病原体如病毒、细菌、真菌、原生动物、植物或肿瘤的蛋白质和肽。
如本文所用,术语“可操作地连接”意指相对于核酸定位亚基因组启动子,使得核酸的表达受元件控制或调节。
如本文所用,术语“亚基因组启动子”(SG;也被称为“接合区”启动子)是指引导异源核苷酸序列表达、调节蛋白质表达的启动子。
术语“多肽”或“多肽链”将被理解为意指由肽键连接的一系列连续的氨基酸。例如,蛋白质应当理解为包含单个多肽链,即由肽键连接的一系列连续氨基酸,或彼此共价或非共价连接的一系列多肽链(即,多肽复合物)。这一系列多肽链可以使用合适的化学物质或二硫键共价连接。非共价键的实例包含氢键、离子键、范德华力和疏水相互作用。
术语“重组体”应当理解为意指人工基因重组的产物。
如本文所用,术语“疾病”、“病症”或“病状”是指中断或干扰正常功能,并且不限于任何特定病状,并将包含疾病或病症。
如本文所用,“有风险”患上疾病或病状的受试者可能患有或未患有可检测的疾病或疾病症状,并且在根据本公开的治疗方法之前可能表现出或可能未表现出可检测的疾病或疾病症状。“有风险”表示受试者具有一种或多种风险因素,所述风险因素是与疾病或病状的发展相关的可测量的参数,如所属领域中已知和/或本文所描述。
如本文所用,术语“治疗(treating、treat或treatment)”包含施用本文所描述的RNA或组合物,从而减轻或消除特定疾病或病状的至少一种症状。
如本文所用,术语“预防(preventing/prevent/prevention)”包含提供与个体中的指定疾病或病状的发生或复发相关的防治。个体可能易患疾病或处于患上疾病的风险,但尚未被诊断患有疾病。
如本文所用,短语“延缓发展”包含减少或减缓个体的疾病或病状的进展和/或疾病或病状的至少一种症状。
“有效量”是指至少在必需的剂量和时段下有效实现期望的结果的量。例如,期望的结果可以是治疗性或预防性结果。可以按一次或多次施用的方式来提供有效量。在本公开的一些实例中,术语“有效量”意指有效治疗上文所描述的疾病或病状所必需的量。在本公开的一些实例中,术语“有效量”意指实现与上文所描述的疾病或病状相关的变化所必需的量。有效量可以根据要治疗的疾病或病状或要改变的因素以及根据体重、年龄、种族背景、性别、健康和/或身体状况和与要治疗哺乳动物相关的其它因素而变化。通常,有效量将落入相对较宽的范围(例如,“剂量”范围)内,所述范围可以由执业医师通过常规试验和实验来确定。因此,此术语不应被解释为将本公开限制于特定的量,例如RNA的重量或数量。有效量可以单剂量施用,或者在治疗期内重复一次或若干次施用。
“治疗有效量”至少是影响特定疾病或病状的可测量的改善所需的最小浓度。在本文中,治疗有效量可以根据如疾病状态、患者的年龄、性别和体重以及本公开的RNA在个体中引发期望应答的能力等因素而变化。治疗有效量还是治疗有益效果超过RNA的任何毒性或有害效果的量。
如本文所用,术语“预防有效量”应被理解为意指足够量的本公开的RNA以预防或抑制或延迟如本文所描述的疾病或病症的一种或多种可检测的症状的发作。
如本文所用,术语“受试者”应被理解为意指包含人的任何动物,例如哺乳动物。示例性受试者包含但不限于人类和非人灵长类动物。例如,受试者是人。
自我复制RNA
本公开提供了一种自我复制RNA(也被称为复制子)。例如,本公开提供了一种单顺反子自我复制RNA。
技术人员将理解,本公开的自我复制RNA基于RNA病毒的基因组RNA。RNA应当是正(+)链的,使得在递送到细胞之后可以直接翻译,而不需要介入复制步骤(例如,逆转录)。RNA的翻译导致非结构蛋白(NSP)的产生,所述蛋白组合以形成复制酶复合物(即,RNA依赖性RNA聚合酶)。所述复合物然后扩增原始RNA,产生反义转录物和有义转录物两者,导致多个子RNA的产生,所述子RNA随后可以被翻译和转录,从而增强整体蛋白质表达。
在一个实例中,本公开的自我复制RNA包括RNA病毒的非结构蛋白、5'和3'非翻译区(UTR)和天然亚基因组启动子。
在一个实例中,自我复制RNA包括RNA病毒的一种或多种非结构蛋白。例如,RNA包括至少一种或多种选自由以下组成的组的基因:病毒复制酶(或病毒聚合酶)、病毒蛋白酶、病毒解旋酶和其它非结构病毒蛋白。例如,自我复制RNA包括病毒复制酶(或病毒聚合酶)。
对技术人员来说显而易见的是,适用于本公开的RNA也可以包含5′非翻译区(5'-UTR)、3′非翻译区(3'UTR)和/或编码或翻译序列。另外,RNA可以包括5′帽结构、链终止核苷酸、茎环(例如,组蛋白茎环)、3'加尾序列(例如,聚腺苷酸化信号或一个或多个polyA尾)。在另一个实例中,自我复制RNA包括RNA病毒的5′端和3′端UTR。对技术人员来说显而易见的是,术语5'和3'UTR也涵盖术语5'和3'保守序列元件(CSE)。在一个实例中,自我复制RNA包括5'端和3'端CSE。
本公开的自我复制RNA不能诱导感染性病毒颗粒的产生。例如,本公开的自我复制RNA不包括编码产生病毒颗粒所必需的结构蛋白的病毒基因。
在一个实例中,所述自我复制RNA源自或基于甲病毒属。合适的甲病毒属对技术人员来说是显而易见的和/或在本文中进行描述。
在另一个实例中,自我复制RNA源自或基于除甲病毒属以外的病毒,例如正链RNA病毒。适用于本公开的合适的正链RNA病毒对技术人员来说是显而易见的,并且包含例如小核糖核酸病毒、黄病毒、风疹病毒、瘟病毒、肝炎病毒、杯状病毒或冠状病毒。
甲病毒属
在一个实例中,本公开的自我复制RNA源自(或基于)甲病毒属。
甲病毒属是披膜病毒科中唯一的属,并且是一种具有正义单链RNA基因组的包膜病毒。技术人员将理解甲病毒属基因组包括两个开放阅读框(ORF),非结构的和结构的。第一个ORF编码病毒RNA转录和复制所必需的四种非结构蛋白(NSP1、NSP2、NSP3和NSP4)。第二个编码三种结构蛋白:核心核衣壳蛋白C,以及包膜蛋白P62和E1,其作为异二聚体缔合。病毒膜锚定表面糖蛋白负责受体识别并通过膜融合进入靶细胞。
在一个实例中,本公开的自我复制RNA包括病毒复制酶(或病毒聚合酶)。例如,病毒复制酶是甲病毒属复制酶,如甲病毒属蛋白NSP4。
在一个实例中,本公开的自我复制RNA不编码一种或多种甲病毒属结构蛋白(例如,衣壳和/或包膜糖蛋白)。例如,自我复制RNA不能产生含RNA的甲病毒属病毒粒子(即,感染性病毒颗粒)。
在一个实例中,自我复制RNA包括天然甲病毒属SG启动子。例如,天然甲病毒属SG启动子是最小SG启动子(即,转录起始所需的最小序列)并且包括SEQ ID NO:9中所示的序列。
技术人员将了解适用于本公开的甲病毒属。示例性甲病毒属包含但不限于委内瑞拉马脑炎病毒(VEE;例如特立尼达驴、TC83CR)、塞姆利基森林病毒(SFV)、辛德比斯病毒(SIN)、罗斯河病毒、西部马脑炎病毒、东部马脑炎病毒、基孔肯雅病毒、S.A.AR86病毒、埃沃格雷病毒(Everglades virus)、穆坎博病毒(Mucambo virus)、巴马森林病毒(BarmahForest virus)、米德尔堡病毒(Middelburg virus)、皮库纳病毒(Pixuna virus)、阿尼昂尼昂病毒(O'nyong-nyong virus)、盖塔病毒(Getah virus)、鹭山病毒(Sagiyama virus)、比巴鲁病毒(Bebaru virus)、马亚罗病毒(Mayaro virus)、乌纳病毒(Una virus)、奥拉病毒(Aura virus)、瓦塔罗阿病毒(Whataroa virus)、巴巴基病毒(Banbanki virus)、孜拉加奇病毒(Kyzylagach virus)、高地J病毒(Highlands J virus)、摩根堡病毒(Fort Morganvirus)、恩杜穆病毒(Ndumu virus)和博吉河病毒(Buggy Creek virus)。术语甲病毒属还可以包含嵌合甲病毒属(例如,如通过Perri等人,(2003)《病毒学杂志(J.Virol.)》77(19):10394-403所描述),其含有来自超过一种甲病毒属的基因组序列。
亚基因组启动子
本公开提供了一种自我复制RNA,其包括与SG启动子可操作地连接的编码抗原的核苷酸序列。
适用于本公开的SG启动子(也被称为‘接合区’启动子)对技术人员来说是显而易见的和/或在本文中进行描述。
在一个实例中,所述SG启动子源自或基于甲病毒属SG启动子。例如,所述SG启动子是天然甲病毒属SG启动子。在一个实例中,所述天然SG启动子是最小SG启动子。例如,所述最小SG启动子是转录起始所需的最小序列。
5'非翻译区(5'UTR)
在一个实例中,自我复制RNA包括RNA病毒的5′-UTR。
如本文所用,术语“5'-非翻译区”或“5'-UTR”是指定位于翻译起始序列(AUG)的5'端的mRNA的非编码区。
在一个实例中,5'UTR是委内瑞拉马脑炎病毒(VEEV)或其经修饰形式的5'UTR。例如,5'UTR包括SEQ ID NO:29中所示的序列。
在一个实例中,5'UTR包括至少一个微小RNA结合位点、富含AU的元件(ARE)、富含GC的元件、茎环以及其组合。
微小RNA结合位点
如本文所用,术语“微小RNA结合位点”是指多核苷酸内(例如,DNA或RNA转录物内)的与miRNA的全部或一个区域具有足够的互补性以与微小RNA(miRNA)相互作用、缔合或结合的序列。
如本文所用,术语“微小RNA”或“miRNA”是指19-25个核苷酸长的非编码RNA,其与多核苷酸的5'-UTR结合并下调基因表达(例如,通过抑制翻译)。本公开的5'UTR中的微小RNA结合位点的存在可以起到抑制5'-UTR的翻译的作用。
适用于本公开的合适的miRNA结合位点对技术人员来说是显而易见的和/或在本文中进行描述。
在一个实例中,miRNA结合位点包括组织特异性微小RNA或调节生物过程的微小RNA的结合位点。例如,肝脏(miR-122)、肌肉(miR-133、miR-206、miR-208)、内皮细胞(miR-17-92、miR-126)、骨髓细胞(miR-142-3p、miR-142-5p、miR-16、miR-21、miR-223、miR-24、miR-27)、脂肪组织(let-7、miR-30c)、心脏(miR-id、miR-149)、肾脏(miR-192、miR-194、miR-204)和肺上皮细胞(let-7、miR-133、miR-126)的miRNA。例如,调节如血管生成等生物过程的微小RNA(miR-132)。在美国专利申请US14/043,927中公开了另外的示例性miRNA和miRNA结合位点。
富含AU的元件(ARE)
如本文所用,术语“富含AU的元件(ARE)”或“富含AU的元件(ARE)”指包括腺苷酸(A)和尿苷(U)的片段的核苷酸序列的区域。示例性ARE包含例如来自细胞质myc(c-myc)、成肌细胞决定蛋白1(myoD)、c-Jun、肌细胞生成素、粒细胞-巨噬细胞集落刺激因子(GM-CSF)和肿瘤坏死因子α(TNF-α)或其组合的ARE。
在一个实例中,ARE包括人类抗原R或“HuR”(也被称为Elavl1)特异性结合位点。HuR已知与ARE结合,增加mRNA的稳定性。
富含GC的元件
如本文所用,术语“富含GC的元件”是指与腺嘌呤(A)和胸腺嘧啶(T)/尿嘧啶(U)相比,具有大量鸟嘌呤(G)和/或胞嘧啶(C)的核苷酸序列。多核苷酸(例如,mRNA)中富含GC的元件的存在可以稳定mRNA。
在一个实例中,富含GC的元件包括长度为3个、或4个、或5个、或6个、或7个、或8个、或9个、或10个、或11个、或12个、或13个、或14个、或15个、或16个、或17个、或18个、或19个、或20个、或21个、或22个、或23个、或24个、或25个、或26个、或27个、或28个、或29个或30个核苷酸的序列。
在一个实例中,富含GC的元件包括30%至40%、或40%至50%、或50%至60%或60%至70%胞嘧啶。例如,富含GC的元件包括30%至40%胞嘧啶。例如,富含GC的元件包括40%至50%胞嘧啶。例如,富含GC的元件包括50%至60%胞嘧啶。例如,富含GC的元件包括60%至70%胞嘧啶。
在一个实例中,富含GC的元件包括30%、或40%、或50%、或60%或70%胞嘧啶。例如,富含GC的元件包括30%胞嘧啶。例如,富含GC的元件包括40%胞嘧啶。例如,富含GC的元件包括50%胞嘧啶。例如,富含GC的元件包括60%胞嘧啶。例如,富含GC的元件包括60%胞嘧啶。例如,富含GC的元件包括70%胞嘧啶。
在一个实例中,富含GC的元件为至少50%胞嘧啶。
在一个实例中,富含GC的元件为至少60%胞嘧啶。
在一个实例中,富含GC的元件为至少70%胞嘧啶。
在一个实例中,富含GC的元件包括核苷酸序列CCCCGGCGCC。在另一个实例中,富含GC的元件包括核苷酸序列CCCCGGC。在另外的实例中,富含GC的元件包括核苷酸序列GCGCCCCGCGGCGCCCCGCG。
在一个实例中,富含GC的元件包括SEQ ID NO:31至33中所示的核苷酸序列。在一个实例中,富含GC的元件包括SEQ ID NO:31中所示的核苷酸序列。在另一个实例中,富含GC的元件包括SEQ ID NO:32中所示的核苷酸序列。在另外的实例中,富含GC的元件包括SEQID NO:33中所示的核苷酸序列。
茎环
如本文所用,术语“茎环”是指包括两个相邻的完全或部分反向互补序列的分子内碱基配对以形成茎环的核苷酸序列。茎环可以出现在单链DNA中,或者更常见的是出现在RNA中。茎环也可以被称为发夹或发夹环,其通常由茎和连续序列内的末端环组成,其中茎由两个相邻的完全或部分反向互补序列形成,这两个序列被将环构建成茎环结构的短序列分开。
配对茎环的稳定性取决于其长度、包含的错配或凸起的数量以及配对区域的核苷酸组成。
在一个实例中,茎环的环的长度介于3个与10个核苷酸之间。例如,茎环的环的长度介于3个与8个、或3个与7个、或3个与6个或4个与5个核苷酸之间。
在一个实例中,茎环的环的长度为4个核苷酸。
在一个例子中,茎环是组蛋白茎环。例如,组蛋白茎环包括SEQ ID NO:34中所示的核苷酸序列或由其组成。
Kozak共有序列
如本文所用,术语“Kozak共有序列”是指在真核基因中鉴定的通过含有核糖体识别的起始密码子(也被称为翻译起始密码子)来促进基因的翻译的核苷酸序列。
示例性Kozak共有序列是本领域已知的和/或在本文中进行描述。在一个实例中,Kozak共有序列在SEQ ID NO:35中示出。在另一个实例中,Kozak共有序列在SEQ ID NO:36中示出。在一个实例中,Kozak共有序列是ACCATGG。在另一个实例中,Kozak共有序列是ACCATG。
3'非翻译区(3'UTR)
在一个实例中,自我复制RNA包括RNA病毒的3′-UTR。
如本文所用,术语“3'-UTR”是指定位于翻译终止密码子(例如,终止密码子)的3'端的mRNA的区。
在一个实例中,3'UTR是辛德比斯病毒(SINV)或其经修饰形式的3'UTR。例如,3'UTR包括SEQ ID NO:30中所示的序列。
在一个实例中,本公开的3'UTR进一步包括至少一个微小RNA结合位点、富含AU的元件(ARE)、富含GC的元件、三螺旋、茎环、一个或多个终止密码子或其组合。
终止密码子
如本文所用,术语“终止密码子”是指mRNA内的发出核糖体停止蛋白质合成的信号的三核苷酸序列。
在一个实例中,本公开的多核苷酸在3'-UTR的5'端处包括至少一个终止密码子。例如,终止密码子选自UAG、UAA和UGA。
在一个实例中,多核苷酸包括两个连续的终止密码子,所述终止密码子包括序列UGAUGA。
在一个实例中,多核苷酸包括两个连续的终止密码子,所述终止密码子包括序列UAAUAG。
3'加尾序列
本公开的RNA包括一个或多个定位于3'UTR的3'端的3'加尾序列。
如本文所描述,术语“3'加尾序列(3'tailing sequence)”或“3'加尾序列(3'tailing sequences)”是指诱导将非编码核苷酸添加到mRNA的3'端或定位于mRNA的3'端的核苷酸序列(例如,poly-A序列)核苷酸序列(例如,聚腺苷酸化信号)。技术人员将理解mRNA中的3'加尾序列和/或3'加尾序列的产物用于稳定mRNA和/或防止mRNA降解。
如本文所用,涉及本公开的poly-A或poly-C序列的术语“中断连接子”是指与poly-A或poly-C序列中的一段连续腺苷或胞嘧啶核苷酸连接并中断一段连续腺苷或胞嘧啶核苷酸的单个核苷酸或核苷酸序列。例如,poly-A序列中的中断连接子是单个核苷酸或由除腺苷核苷酸以外的核苷酸组成或包括除腺苷核苷酸以外的核苷酸的核苷酸序列。例如,poly-C序列中的中断连接子是单个核苷酸或由除胞嘧啶核苷酸以外的核苷酸组成或包括除胞嘧啶核苷酸以外的核苷酸的核苷酸序列。
在一个实例中,一个或多个3'加尾序列选自由以下组成的组:poly-A序列、聚腺苷酸化信号、G-四链体、poly-C序列、茎环以及其组合。
Poly-A序列
如本文所用,术语“polyA序列”是指定位于mRNA的3'端的腺嘌呤(A)核苷酸序列。在本公开的上下文中,polyA序列可以定位于mRNA或DNA(例如,用作用于通过载体的转录产生mRNA的模板的DNA质粒)内。
适用于本公开的合适的poly-A序列对技术人员来说是显而易见的和/或在本文中进行描述。在一个实例中,poly-A序列包括任何长度(例如10至300)的连续(即,一个接一个)腺苷核苷酸。例如,poly-A序列包括36个连续的腺苷核苷酸。在一个实例中,poly-A序列包括SEQ ID NO:37中所示的序列。
在一个实例中,poly-A序列包括由一个或多个中断连接子分隔的连续腺苷核苷酸。在一个实例中,poly-A序列包括不具有中断连接子的连续的腺苷核苷酸。
聚腺苷酸化信号
如本文所用,术语“聚腺苷酸化信号”是指诱导聚腺苷酸化的核苷酸序列。聚腺苷酸化通常被理解为将polyA序列添加到RNA(例如,添加到未成熟的mRNA以产生成熟的mRNA)。聚腺苷酸化信号可以定位于要聚腺苷酸化的多核苷酸(例如,mRNA)的3'端的核苷酸序列内。
适用于本公开的合适的聚腺苷酸化信号对技术人员来说是显而易见的和/或在本文中进行描述。
在一个实例中,聚腺苷酸化信号包括由腺嘌呤和尿嘧啶/胸苷核苷酸组成的六聚体。在一个实例中,六聚体序列包括AAUAAA或由其组成。
在一个实例中,3'加尾序列包括聚腺苷酸化信号,但不包括polyA序列。
G-四链体
如本文所用,术语“G-四链体”或“G4”是指富含鸟嘌呤残基的形成四链二级结构的核苷酸序列。例如,G-四链体是由DNA和RNA两者中富含G的序列形成的四个鸟嘌呤核苷酸的环状氢键合的阵列。
在一个实例中,3'加尾序列包括polyA序列和G-四链体。例如,3'加尾序列包括的polyA序列与G-四链体连接以产生polyA-G四联体。
Poly-C序列
如本文所用,术语“poly-C序列”是指定位于mRNA的3'端的胞嘧啶(C)核苷酸序列。在本公开的上下文中,polyC序列可以定位于mRNA或DNA(例如,用作用于通过载体的转录产生mRNA的模板的DNA质粒)内。
适用于本公开的合适的poly-C序列对技术人员来说是显而易见的和/或在本文中进行描述。
在一个实例中,一个或多个3'加尾序列包括一个或多个poly-C序列,每个序列包括10个至300个连续的胞嘧啶核苷酸。例如,所述一个或多个poly-C序列各自包括10至20个、或20至30个、或30至40个、或40至50个、或50至60个、或60至70个、或70至80个、或80至90个、或90至100个、或100至125个、或125至150个、或150至175个、或175至200个、或200至225个、或225至250个、或250至275个或275至300个连续的胞嘧啶核苷酸。例如,所述一个或多个poly-C序列各自包括10个、或20个、或30个、或40个、或50个、或60个、或70个、或80个、或90个、或100个、或125个、或150个、或175个、或200个、或225个、或250个、或275个或300个连续的胞嘧啶核苷酸。
在一个实例中,所述一个或多个poly-C序列被中断连接子分开。例如,包括所述一个或多个3'加尾序列的第四个核苷酸序列按照从5'到3'的顺序包括连续的胞嘧啶核苷酸、中断连接子和另外的连续胞嘧啶核苷酸。
在一个实例中,中断连接子的长度为10至50个、或50至100个或100至150个核苷酸。例如,中断连接子的长度为1个、或2个、或3个、或4个、或5个、或6个、或7个、或8个、或9个、或10个、或11个、或12个、或13个、或14个、或15个、或16个、或17个、或18个、或19个、或20个、或25个、或30个、或35个、或40个、或45个、或50个、或55个、或60个、或65个、或70个、或75个、或80个、或85个、或90个、或95个、或100个、或110个、或120个、或130个、或140个或150个核苷酸。
5'帽
在一个实例中,自我复制RNA包括5'末端帽结构。
如本文所用,术语“5'帽结构”是指mRNA的涉及核输出并结合mRNA帽结合蛋白(CBP)的5'末端处的结构。已知5'帽结构通过CBP与poly(A)结合蛋白缔合以形成成熟的mRNA来稳定mRNA。因此,与没有5'帽的mRNA相比,本公开的mRNA中的5'帽结构的存在可以进一步增加mRNA的稳定性。
示例性5'帽结构包含例如抗反向帽类似物(ARCA)、N7,2'-0-二甲基-鸟苷(mCAP)、肌苷、N1-甲基-鸟苷、2′氟-鸟苷、7-脱氮-鸟苷、8-氧代-鸟苷、2-氨基-鸟苷、LNA-鸟苷、2-叠氮-鸟苷、N6,2'-O-二甲基腺苷、7-甲基鸟苷(m7G)、Cap1和Cap2。
典型地,内源mRNA通过与mRNA的5'末端核苷酸附接的(5)'-ppp-(5)'-三磷酸键用鸟苷进行5'加帽。然后鸟苷帽可以甲基化为7-甲基鸟苷(m7G),产生7mG(5')ppp(5')N,pN2p(Cap0结构),其中N表示mRNA的第一个和第二个5'末端核苷酸。cap0结构可以进一步2'-O-甲基化以产生7mG(5')ppp(5')NlmpNp(Cap1)和/或7mG(5')-ppp(5')NlmpN2mp(Cap2)。
在一个实例中,本公开的多核苷酸包括内源帽。
如本文所用,术语“内源帽”是指在细胞中合成的5'帽。例如,内源帽是天然的5'帽或野生型5'帽。例如,所述内源帽是Cap0、Cap1或Cap2结构。
在一个实例中,本公开的多核苷酸包括内源帽的类似物(也被称为帽类似物)。
如本文所用,内源帽或“帽类似物”上下文中的术语“其类似物”是指合成的5'帽。帽类似物可以用于在体外转录反应中产生5'加帽mRNA。帽类似物可以是化学合成的(即,非酶促合成的)或酶促合成的和/或与核苷酸(例如,mRNA的5'末端核苷酸)连接的。示例性帽类似物是可商购获得的,并且包含例如3″-O-Me-m7G(5′)ppp(5′)G、G(5′)ppp(5′)A、G(5′)ppp(5′)G、m7G(5′)ppp(5′)A、m7G(5′)ppp(5′)G(新英格兰生物实验室(New EnglandBioLabs))。在一个实例中,帽类似物是N7,3′-O-二甲基-鸟苷-5′-三磷酸-5′-鸟苷(即,抗反向帽类似物(ARCA))。
在一个实例中,5'帽结构是不可水解的帽结构。不可水解的帽结构可以防止mRNA脱帽,并且增加mRNA的半衰期。
在一个实例中,不可水解的帽结构包括选自由以下组成的组的经修饰的核苷酸:α-硫代-鸟苷核苷酸、α-甲基-膦酸酯、硒代-磷酸酯和其组合。在一个实例中,经修饰的核苷酸通过α-硫代磷酸酯连接与mRNA的5'端连接。将经修饰的核苷酸与mRNA的5'端连接的方法对技术人员来说是显而易见的。例如,使用牛痘加帽酶(新英格兰生物实验室)。
抗原
本公开的自我复制RNA包括编码抗原(例如,致病抗原)的核苷酸序列。例如,所述抗原诱导受试者的免疫应答。
在一个实例中,本公开的自我复制RNA包括编码来自SARS-CoV-2的抗原的核苷酸序列。
产生方法
用于生产本公开的自我复制RNA的合适方法对技术人员来说是显而易见的和/或在本文中进行描述。
在一个实例中,使用质粒DNA产生自我复制RNA。技术人员将理解质粒DNA是相对稳定的。简言之,用编码本公开的自我复制RNA的DNA质粒转化感受态细菌细胞(例如,大肠杆菌)细胞。分离单独的细菌菌落,并在大肠杆菌培养物中扩增所得质粒DNA。
在一个实例中,发酵后分离质粒DNA。例如,使用可商购获得的试剂盒(例如,Maxiprep DNA试剂盒)或技术人员已知的其它常规方法分离质粒DNA。分离后,通过限制性消化(即,使用限制性酶)将质粒DNA线性化。使用本领域已知的方法去除限制性酶,所述方法包含例如苯酚/氯仿提取和乙醇沉淀。
在一个实例中,mRNA通过使用RNA聚合酶(例如,T7 RNA聚合酶)从线性化的DNA模板体外转录来制备。体外转录后,通过DNA酶消化来去除DNA模板。本领域技术人员将会理解,进行合成mRNA加帽是为了校正mRNA加工并促进mRNA的稳定。在一个实例中,mRNA被酶促5'加帽。例如,所述5'帽是cap0结构或cap1结构。在一个实例中,5'帽是cap0结构,例如,5'-帽(即,cap0)由通过5′-5′三磷酸桥与mRNA的其余部分连接的反向7-甲基鸟苷组成。在一个实例中,5'帽是cap1结构,例如,5'-帽(即,cap1)由cap0与起始核苷酸的2'O位置的另外甲基化组成。
在一个实例中,mRNA被纯化。各种用于纯化mRNA的方法对技术人员来说是显而易见的。例如,使用氯化锂(LiCl)沉淀来纯化mRNA。在另一个实例中,使用切向流过滤(TFF)来纯化mRNA。纯化后,将mRNA重悬于例如无核酸酶的水中。
组合物
本公开提供了一种免疫原性组合物,其包括本公开的自我复制RNA。
本公开还提供了一种药物组合物,其包括本公开的免疫原性组合物以及药学上可接受的载体。
对于技术人员和/或本文所描述,显而易见的是,本公开的自我复制RNA可以以裸RNA的形式存在,或者与脂质、聚合物或其它促进进入细胞的递送系统组合存在。
递送系统
在一个实例中,本公开的药物组合物进一步包括LNP、聚合物微粒和水包油乳液。例如,所述自我复制RNA被包封在LNP、聚合物微粒或水包油乳液中、与LNP、聚合物微粒或水包油乳液结合或吸附在LNP、聚合物微粒或水包油乳液上。
脂质纳米颗粒
在一个实例中,本公开的药物组合物进一步包括LNP。
显而易见,术语“脂质纳米颗粒”是指任何脂质组合物,包含但不限于脂质体或囊泡,其中水性体积被具有非水性核和固体脂质纳米颗粒的两亲性脂质双层(例如,单层;单层或多层;多层)胶束样脂质纳米颗粒包封,其中所述固体脂质纳米颗粒缺乏脂质双层。
适用于本公开的脂质纳米颗粒对技术人员来说是显而易见的和/或在本文中进行描述。脂质可以具有阴离子、阳离子或两性离子亲水头基。
在一个实例中,脂质纳米颗粒包括PEG-脂质、甾醇结构脂质和/或中性脂质。在一个实例中,脂质纳米颗粒进一步包括阳离子脂质。在一个实例中,脂质纳米颗粒不包括阳离子脂质。
在一个实例中,LNP包括PEG脂质。例如,PEG脂质选自由以下组成的组:PEG-c-DMG、PEG-DMG、PEG-DLPE、PEG-DMPE、PEG-DPPC、PEG-DSPE脂质以及其组合。
在一个实例中,LNP包括结构脂质。例如,结构脂质选自由以下组成的组:胆固醇粪甾醇、谷甾醇、菜油甾醇、豆甾醇、油菜素甾醇、麦角甾醇、番茄红素、番茄碱、熊果酸和α-生育酚以及其组合。
在一个实例中,LNP包括中性脂质。用于本公开的示例性磷脂(阴离子或两性离子)包含例如磷脂酰乙醇胺、磷脂酰胆碱、磷脂酰丝氨酸和磷脂酰甘油。例如,中性脂质选自由以下组成的组:1,2-二硬脂酰-sn-甘油-3-磷酸胆碱(DSPC)、1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、1,2-二亚油酰-sn-甘油-3-磷酸胆碱(DLPC)、1,2-二肉豆蔻酰基-sn-甘油-磷酸胆碱(DMPC)、1,2-二油酰-sn-甘油-3-磷酸胆碱(DOPC)、1,2-二棕榈酰-sn-甘油-3-磷酸胆碱(DPPC)、1,2-二十一烷酰基-sn-甘油-磷酸胆碱(DUPC)、1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱(POPC)、1,2-二-O-十八烯基-sn-甘油-3-磷酸胆碱(18:0二醚PC)、1-油酰-2-胆固醇半琥珀酰-sn-甘油-3-磷酸胆碱(OChemsPC)、1-十六烷基-sn-甘油-3-磷酸胆碱(C16溶血PC)、1,2-二亚油酰基-sn-甘油-3-磷酸胆碱、1,2-二花生四烯酸-sn-甘油-3-磷酸胆碱、1,2-二(二十六)碳六烯酰基-sn-甘油-3-磷酸胆碱、1,2-二植烷酰基-sn-甘油-3-磷酸乙醇胺(ME 16.0PE)、1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺(DSPE)、1,2-二亚油酰-sn-甘油-3-磷酸乙醇胺、1,2-二亚油酰-sn-甘油-3-磷酸乙醇胺、1,2-二花生四烯酸-sn-甘油-3-磷酸乙醇胺、1,2-二(二十二)碳六烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-二油酰基-sn-丙三基-3-磷酸-rac-(1-甘油)钠盐(DOPG)和鞘磷脂以及其组合。
在一个实例中,LNP包括阳离子脂质。示例性阳离子脂质包含但不限于二油酰基三甲基铵丙烷(DOTAP)、1,2-二硬脂酰氧基-N,N-二甲基-3-氨基丙烷(DSDMA)、1,2-二油酰氧基-N,N二甲基-3-氨基丙烷(DODMA)、1,2-二油酰氧基-N,N-二甲基-3-氨基丙烷(DLinDMA)、1,2-二亚油酰氧基-N,N-二甲基-3-氨基丙烷(DLenDMA)、2,5-双((9z,12z)-十八碳-9,12,二烯-1-基氧基)苄基-4-(二甲基氨基)丁酸甲酯(LKY750)。在一个实例中,磷脂是2,5-双((9z,12z)-十八碳-9,12,二烯-1-基氧基)苄基-4-(二甲基氨基)丁酸甲酯(LKY750)。示例性两性离子脂质包含但不限于酰基两性离子脂质和醚两性离子脂质,如二棕榈酰磷脂酰胆碱(DPPC)、二油酰磷脂酰胆碱(DOPC)和十二烷基磷酸胆碱。脂质可以是饱和的或不饱和的。
聚合物微粒
在一个实例中,本公开的药物组合物进一步包括聚合物微粒。
技术人员将了解,各种聚合物可以形成微粒以包封或吸附本公开的自我复制RNA。显而易见,使用基本上无毒的聚合物意味着颗粒是安全的,并且使用可生物降解的聚合物意味着颗粒在递送之后可以被代谢以避免长期残留。有用的聚合物也是可灭菌的,有助于制备药物级调配物。
示例性无毒且可生物降解的聚合物包含但不限于聚(α-羟基酸)、多羟基丁酸、聚内酯(包含聚己内酯)、聚二氧环己酮、聚戊内酯、聚原酸酯、聚酸酐、聚氰基丙烯酸酯、酪氨酸衍生的聚碳酸酯、聚乙烯吡咯烷酮或聚酯酰胺以及其组合。
水包油阳离子乳液
在一个实例中,本公开的药物组合物进一步包括水包油阳离子乳液。
适用于水包油乳液的油对于技术人员来说是显而易见的和/或在本文中进行描述。例如,乳液包括一种或多种例如源自动物(例如,鱼)或植物源(例如,坚果、种子、谷物)的油。技术人员将会认识到,优先使用生物相容性和生物可降解的油。示例性动物油(即,鱼油)包含鱼肝油、鲨鱼肝油和鲸油。示例性植物油包含花生油、椰子油、橄榄油、大豆油、荷荷巴油、红花油、棉籽油、葵花籽油、芝麻油、玉米油。
除了油之外,水包油乳液还包括阳离子脂质以促进乳液的形成和稳定。合适的阳离子脂质对技术人员来说是显而易见的和/或在本文中进行描述。示例性阳离子脂质包含但不限于,限于:1,2-二油酰氧基-3-(三甲基铵基)丙烷(DOTAP)、3'-[N-(N',N'-二甲基氨基乙烷)-氨基甲酰基]胆固醇(DC胆固醇)、二甲基双十八烷基铵(DDA)、1,2-二肉豆蔻酰基-3-三甲基-铵丙烷(DMTAP)、二棕榈酰[C16:0]三甲基铵丙烷(DPTAP)和二硬脂酰基三甲基铵丙烷(DSTAP)。
在一些实例中,水包油乳液还包括非离子表面活性剂和/或两性离子表面活性剂。技术人员将了解适用于本公开的表面活性剂。示例性表面活性剂包含但不限于:聚氧乙烯脱水山梨醇酯表面活性剂(例如,聚山梨醇酯20和聚山梨醇酯80)以及环氧乙烷(EO)、环氧丙烷(PO)和/或环氧丁烷(BO)的共聚物。
药学上可接受的载体
合适地,在用于向受试者施用本公开的自我复制RNA的组合物或方法中,自我复制RNA与药学上可接受的载体组合,如本领域所理解的。因此,本公开的一个实例提供了一种组合物(例如,药物组合物),其包括与药学上可接受的载体组合的本公开的自我复制RNA(和任何递送系统)。
一般而言,“载体”是指可以安全地施用于任何受试者例如人的固体或液体填充剂、结合剂、稀释剂、包封物质、乳化剂、润湿剂、溶剂、悬浮剂、包衣或润滑剂。根据特定的施用途径,可以使用本领域已知的各种可接受的载体,例如在《雷明顿氏药物科学(Remington's Pharmaceutical Sciences)》(美国新泽西州的马克出版公司(MackPublishing Co.N.J.USA),1991)中描述的。
本公开的自我复制RNA可用于肠胃外、局部、口服或局部施用、肌内施用、气雾剂施用或透皮施用,用于预防性或治疗性治疗。在一个实例中,自我复制RNA是肠胃外如肌内、皮下或静脉内施用的。例如,自我复制RNA是肌内施用的。
要施用的自我复制RNA的调配物将根据施用途径和所选择的调配物(例如,溶液、乳液、胶囊)而变化。可以在生理上可接受的载体中制备要施用的包括自我复制RNA的合适药物组合物。对于溶液或乳液,合适的载体包含例如水溶液或醇/水溶液、乳液或悬浮液,包含盐水和缓冲介质。肠胃外媒剂可以包含氯化钠溶液、林格氏右旋糖(Ringer'sdextrose)、右旋糖和氯化钠、乳酸林格氏液或固定油。本领域技术人员已知多种合适的水性载体,包含水、缓冲水、缓冲盐水、多元醇(例如,甘油、丙二醇、液体聚乙二醇)、葡萄糖溶液和甘氨酸。静脉内媒剂可以包含各种添加剂、防腐剂或液体、营养或电解质补充剂(通常参见《雷明顿氏药物科学》,第16版,Mack,编辑1980)。组合物可以任选地含有接近生理条件所需的药学上可接受的辅助物质,如pH调节剂和缓冲剂以及毒性调节剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙和乳酸钠。根据本领域已知的冻干和重构技术,自我复制RNA可以储存在液相中,或者可以冻干储存,并在使用前在合适的载体中重构。
活性成分在所选介质中的最佳浓度可以根据本领域技术人员已知的方法凭经验确定,并且将取决于期望的最终药物调配物。
在调配后,本公开的组合物将以与剂量调配物相容的方式并以治疗/预防有效的量施用。本公开的分子的施用剂量范围是那些大到足以产生期望效果的剂量范围。例如,所述组合物包括有效量的自我复制RNA。在一个实例中,所述组合物包括治疗有效量的自我复制RNA。在另一个实例中,所述组合物包括预防有效量的自我复制RNA。
剂量不应太大,以免引起不良副作用。通常,剂量将随患者的年龄、病情、性别和疾病程度而变化,并且可以由本领域的技术人员确定。在有任何并发症的情况下,可以由单独医师调整剂量。
剂量可以从约0.1mg/kg至约300mg/kg变化,例如从约0.2mg/kg至约200mg/kg,如约0.5mg/kg至约20mg/kg,每天一次或多次剂量施用,持续一天或几天。
在一些实例中,自我复制RNA以高于后续(维持剂量)的初始(或负载)剂量施用。例如,自我复制RNA以约10mg/kg至约30mg/kg的初始剂量施用。自我复制RNA然后以约0.0001mg/kg至约10mg/kg的维持剂量施用。维持剂量可以每7-35天施用一次,如每7或14或28天施用一次。
在一些实例中,使用剂量递增方案,其中自我复制RNA最初以低于后续剂量的剂量施用。此剂量方案在受试者最初遭受不良事件的情况下是有用的。
在受试者对治疗没有充分应答的情况下,可以在一周内施用多个剂量。可替代地或另外地,可以施用增加的剂量。
可以通过给予多于一次暴露或一组剂量,如结合蛋白的至少约两次暴露,例如,约2至60次暴露以及更具体地约2至40次暴露,最具体地,约2至20次暴露来用自我复制RNA治疗受试者。
在一个实例中,受试者在第0天用第一剂量的自我复制RNA治疗,并且随后在第21天用第二剂量的自我复制RNA治疗。例如,第一剂量和第二剂量相隔21天(或3周)施用。
在另一个实例中,受试者在第0天用第一剂量的自我复制RNA治疗,并且随后在第28天用第二剂量的自我复制RNA治疗。例如,第一剂量和第二剂量相隔28天(或4周)施用。
在一个实例中,当疾病的体征或症状重新出现时,可以给予任何再治疗。
在另一个实例中,任何再治疗可以以限定的间隔给予。例如,随后的暴露可以以不同的间隔例如约24-28周或48-56周或更长时间施用。例如,此类暴露以约24-26周或约38-42周或约50-54周中的每一个的间隔施用。
在受试者对治疗没有充分应答的情况下,可以在一周内施用多个剂量。可替代地或另外地,可以施用增加的剂量。
在另一个实例中,对于经历不良反应的受试者,初始(或负载)剂量可以在一周内的许多天或在许多连续的天中分开。
根据本公开的方法的自我复制RNA的施用可以是连续的或间歇的,这取决于例如接受者的生理状况、施用的目的是治疗性的还是预防性的以及熟练从业者已知的其它因素。自我复制RNA的施用在预选时间段内可以是基本上连续的,或者可以例如在病状发展期间或之后采用一系列间隔剂量。
筛选测定
本领域技术人员可获得用于选择本公开的自我复制RNA的合适方法。可以进行测定以评估RNA的效率和功效,包含例如血清学和免疫应答。
抗原表达
在一个实例中,评估自我复制RNA的所关注基因的表达。
例如,使用针对所关注基因的抗体来检测抗原表达。在一个实例中,对抗原表达呈阳性的细胞数量通过例如荧光激活细胞分选(FACS)来测量。在另一个实例中,使用例如FACS来确定平均荧光强度(MFI)。在另外的实例中,计算每单位质量RNA的比效力值或成功转染的概率。
微量中和测定
在一个实例中,评估自我复制RNA(裸的和/或调配的)的抗体应答。例如,使用微量中和测定评估自我复制RNA。进行微量中和测定的方法对技术人员来说将是显而易见的。在一个实例中,微量中和测定是一种短形式测定。例如,进行基于病毒荧光焦点的微量中和测定。在另一个实例中,微量中和测定是一种长形式测定。
抗原特异性T细胞应答
在一个实例中,评估自我复制RNA诱导抗原特异性T细胞应答的能力。评估抗原特异性T细胞应答的诱导的方法对技术人员来说将是显而易见的和/或在本文中进行描述。
例如,对脾培养物进行抗原特异性T细胞检测。简言之,脾细胞培养物建立在T细胞培养基中,并且细胞培养物用抗原肽刺激或不刺激。在一个实例中,抗原特异性T细胞应答是使用流式细胞术确定的。
中和测定
可以在体外筛选本公开的自我复制RNA与SARS-CoV-2S蛋白RBD的结合能力以及中和S蛋白RBD与ACE2的结合的能力。合适的测定对技术人员来说将是显而易见的,并且包含例如Vero微量中和测定、sVNT测定或假病毒中和测定(使用例如,HEK-293T细胞或HeLa-ACE2细胞)。
在一个实例中,中和测定是Vero微量中和测定。简言之,SARS-Cov-2野生型病毒在Vero细胞(即,从提取自非洲绿猴的肾上皮细胞中分离的Vero谱系)中传代。将测定蛋白的系列两倍稀释液与100TCID50(即,组织培养感染剂量中值)的SARS-CoV-2一起温育1小时,并在Vero细胞中评估残余病毒感染性;例如,在第5天读取病毒细胞病变效应。使用如先前所描述的Reed/Muench方法计算中和抗体滴度(Houser等人,2016;Subbarao等人2004)。
在一个实例中,中和测定是替代中和测试(sVNT)。简言之,将板的孔在碳酸盐-碳酸氢盐包被缓冲液(例如,pH 9.6)中用hACE2蛋白包被。将与测试蛋白预温育的HRP-缀合的SARS-CoV-2和HRP-缀合的SARS-CoV-RBD添加到不同浓度的hACE2中,并在室温下温育例如1小时。通过洗涤去除未结合的HRP缀合的抗原。HRP与生色底物例如3,3',5,5'-四甲基联苯胺(TMB)的酶促反应产生比色信号。在一个实例中,获取450nm和570nm处的吸光度读段。
在一个实例中,中和是假病毒中和测定。简言之,通过将SARS-2-COV-2刺突质粒与病毒骨架质粒(例如,pDR-NLΔenv FLUC)转染到例如HEK-293T细胞中,产生了用SARS-2-刺突蛋白假型化的HIV报告基因病毒。转染后采集假病毒,并且过滤澄清。以相对荧光素酶单位感染剂量(RLU)报告的病毒原液滴度是通过在Hela-hACE2细胞中限制稀释感染,测量荧光素酶活性作为病毒感染的读数来计算的。
治疗或预防方法
本公开提供了将本公开的免疫原性组合物或药物组合物用作疫苗的方法。
本公开还提供一种治疗或预防受试者的疾病或病状或延缓所述疾病或病状的进展的方法,所述方法包括施用本公开的免疫原性组合物或药物组合物。例如,所述疾病或病状选自由以下组成的组:SARS-CoV-2感染、COVID-19、ARDS以及其组合。
冠状病毒病2019(COVID-19)
本公开提供了例如治疗或预防COVID-19或延缓其进展的方法。
本公开还提供了例如治疗或预防SARS-CoV-2感染或延缓其进展的方法。在本公开的一些实例中,受试者患有SARS-CoV-2感染,但没有临床诊断的COVID-19。
COVID-19是一种由SARS-CoV-2引起的感染性疾病。常见症状包含发烧、咳嗽、疲劳、呼吸急促、嗅觉和味觉丧失。虽然大多数病例会导致轻微症状,但有些病例会发展为ARDS。从暴露到症状发作的时间通常在五天左右,但也可能在二到十四天的范围内。目前还没有针对COVID-19的疫苗或特定的抗病毒治疗,并且管理涉及症状治疗、支持性护理、隔离和实验措施。
因此,在一些实例中,患者患有SARS-CoV-2感染。在一个实例中,受试者患有COVID-19,例如,严重COVID-19。具体地,严重COVID-19通常导致ARDS。本公开的方法可以用于治疗或预防患有COVID-19的受试者的ARDS或延缓其进展。
急性呼吸窘迫综合征(ARDS)
本公开提供了例如治疗或预防受试者的ARDS或延缓其进展的方法。
ARDS是一种威胁生命的病状,其特征在于双侧肺浸润、严重低氧血症和肺泡-毛细血管膜屏障破坏(即,肺血管渗漏),导致非心源性肺水肿。目前没有有效的药物疗法。
感染性病因,包含流感和冠状病毒感染,是ARDS的主要原因。因此,在本公开的一个实例中,ARDS与冠状病毒感染相关。例如,SARS-COV感染。在一个实例中,ARDS与SARS-CoV-2感染相关。
ARDS根据柏林定义(Berlin Definition)进行分类,其包含:
(1)临床损害或呼吸道症状发作1周内出现;
(2)急性低氧性呼吸衰竭,如通过在至少5cm的持续气道正压(CPAP)或呼气末正压(PEEP)下PaO2/FiO2比率为300mmHg或更低来确定,其中PaO2是动脉血中的氧分压,并且FiO2是吸入氧的分数;
(3)肺部射线照片上的双侧阴影不能完全由渗出、实变或肺不张来解释;以及
(4)水肿/呼吸衰竭不能完全用心力衰竭或液体超负荷来解释。
在一个实例中,受试者患有ARDS(即,受试者满足ARDS的柏林定义)。例如,受试者需要治疗(即,有需要)。
在一个实例中,受试者患有或患上与ARDS相关的症状。与ARDS相关的症状和鉴定处于发展为ARDS的风险的受试者的方法对技术人员来说将是显而易见的和/或在本文中进行描述。例如,受试者具有以下症状中的一种或多种或所有症状:
a)呼吸频率大于每分钟30次呼吸;
b)室内空气的氧饱和度(SpO2)为93%或更低;
c)动脉氧分压与吸入氧分数的比率(PaO2/FiO2)小于300mmHg;
d)小于218的SpO2/FiO2比率;以及
e)放射影像肺浸润量大于50%。
目前,ARDS被分类为轻度、中度和重度,其中相关死亡率增加。ARDS的严重程度可以根据柏林定义分类如下:
(i)轻度ARDS:在至少5cm CPAP或PEEP时,PaO2/FiO2为200-300mmHg;
(ii)中度ARDS:在至少5cm PEEP时,PaO2/FiO2为100-200mmHg;以及
(iii)重度ARDS:在至少5cm PEEP时,PaO2/FiO2小于或等于100mmHg。
在一个实例中,ARDS是轻度ARDS。在另一个实例中,ARDS是中度ARDS。在另外的实例中,ARDS是重度ARDS。
除了治疗现有的ARDS之外,本公开的方法还可以用于预防ARDS的发作。因此,在一个实例中,受试者未患有ARDS。
试剂盒
本公开的另一个实例提供了含有本公开的自我复制RNA的试剂盒,其可用于治疗或预防如上文所描述的疾病或病症或延缓所述疾病或病症的进展。
在一个实例中,所述试剂盒包括:(a)容器,所述容器包括任选地在递送系统和/或药学上可接受的载体或稀释剂中的自我复制RNA;以及(b)包装插页,所述包装插页具有用于治疗或预防受试者的疾病或病症(例如,COVID-19或ARDS)或延缓所述疾病或病症的进展的说明。
根据本公开的此实例,包装插页位于容器上或与容器相关。合适的容器包含例如瓶、小瓶、注射器等。所述容器可以由多种材料形成,如玻璃或塑料。容器容纳或含有对本公开的疾病或病症有效的组合物并且可以具有无菌接入端口(例如容器可以是具有皮下注射针可刺穿的塞子的静脉内溶液袋或小瓶)。组合物中的至少一种活性剂是自我复制RNA。标签或包装插页表明,所述组合物用于治疗符合治疗的受试者,例如患有或易患流感、流感病毒感染、SARS-CoV-2感染、COVID-19和/或ARDS的受试者,并提供了关于给药量和治疗间隔以及任何其它药物的具体指导。所述试剂盒可以进一步包括另外的容器,所述另外的容器包括药学上可接受的稀释剂缓冲液,如注射用抑菌水(BWFI)、磷酸盐缓冲盐水、林格氏溶液(Ringer's solution)和/或葡聚糖溶液。所述试剂盒可以进一步包含从商业和用户的角度所期望的其它材料,包含其它缓冲液、稀释剂、过滤器、针和注射器。
本公开包含以下非限制性实例。
实例
实例1:自我复制RNA的产生
编码自我复制RNA的DNA模板在用DNA质粒转化的感受态大肠杆菌细胞中产生。分离单独的细菌菌落,并在大肠杆菌培养物中扩增所得质粒DNA。发酵后,将质粒DNA使用Maxiprep DNA试剂盒分离,并且通过限制性消化线性化。然后使用苯酚/氯仿萃取和乙醇沉淀去除限制性酶。
使用T7 RNA聚合酶从线性化的DNA模板通过体外转录制备mRNA。随后,通过DNA酶消化去除DNA模板。用Cap0进行酶加帽以提供功能性mRNA。将所得的mRNA纯化并重新悬浮在无核酸酶的水中。
使用来自SARS-CoV-2毒株2019-nCoV/USA-WA1/2020的刺突(S)和核衣壳(N)抗原制备自我复制RNA。制备了以下构建体:
●NSP1-4.SGP.S(wt)(Co5)
●NSP1-4.SGP.N(wt)(Co6)
●NSP1-4.SGP.S(RRAR→QQAA)(Co16)
●NSP1-4.SGP.S(RRAR→QQAA和986P/987P)(Co17)
●-NSP1-4.SGP.S(D614G)(Co48)
●NSP1-4.SGP.S(RRAR→QQAA和D614G)(Co49)
●NSP1-4.SGP.S(RRAR→QQAA和S2')(Co58)
●NSP1-4.SGP.S(RRAR→QQAA、S2'和D614G)(Co59)
实例2:自我复制RNA的体外表征
评估实例1中产生的自我复制RNA的所关注基因的表达。
将两倍系列稀释的未调配(裸)或LNP调配的自扩增mRNA构建体电穿孔或转染到幼仓鼠肾(BHK)细胞系中。17-19小时之后,采集细胞并使用抗S抗体或抗N抗体对S或N抗原表达进行染色。通过FACS测量对抗原表达呈阳性的细胞数量和平均荧光强度(MFI)。分析数据以计算比效力值(每单位质量RNA成功转染的概率)。
基于S和N的表达,通过FAC确定未经调配的RNA和LNP的体外活性和效力,并且如下表1所示:
表1:未经调配的RNA和LNP的体外活性和效力
抗体应答
为了评估抗体应答,在研究结束时(即,第一疫苗剂量之后42天或最后一次第二疫苗剂量之后21天)收集血清,并通过微量中和测定(表2)和ACE2结合(表3)进行测试。
对于所有的血清学测定,用霍乱弧菌神经氨酸酶(也被称为受体破坏酶(RDE)(日本东京的电气化学工业有限公司(Denka Seiken Co.Ltd.,Tokyo,Japan))以相同的方式处理血清,并用PBS稀释至1:10的起始稀释度。H5N1病毒的绵羊血清(FDA/CBER肯辛顿批号H5-Ag-1115)用作三次测定的阳性对照血清。
微量中和测定
使用内部开发的方案进行基于病毒荧光焦点的微中和(FFA MN)测定。将RDE处理的测试小鼠样品和阳性对照血清热灭活,用PBS稀释至1:40的起始稀释度,并且使用U底96孔板(伯昂兴业有限公司(BD Falcon))在中和培养基(包含最低必需培养基D-MEM(吉博科公司(GIBCO)),补充有1% BSA(洛克兰(Rockland),BSA-30)、100U/mL青霉素和100ug/mL链霉素(吉博科公司))中进行四倍连续稀释。在中和培养基中将病毒稀释至约1,000-1,500荧光焦点形成单位(FFU)/孔(20,000-30,000FFU/mL),并以1:1比率添加到稀释的血清中。
在37℃,5% CO2下温育2小时之后,将含有MDCK 33016-PF细胞的板(半面积96孔板,康宁公司(Corning))用此混合物接种,并在37℃与5% CO2下温育16-18小时。MDCK33016-PF细胞在6-8小时前以3.0E4/孔(3.0E6/板)接种于细胞生长培养基(包含D-MEM,补充有10% HyClone胎牛血清-FBS(吉博科公司)、100U/mL青霉素和100ug/mL链霉素)中。过夜温育后并且免疫染色前,将细胞用丙酮和甲醇的冷混合物固定。
使用在室温下单独温育1小时的对刺突(S)蛋白具有特异性的单克隆抗体和AlexaFluor 488山羊抗小鼠IgG(H+L)Ab(英杰公司目录号A11001)来使病毒可视化,所述抗体在含有0.05%tween-20(西格玛公司(Sigma))和2% BSA(级分V,Calbiochem公司,2960,1194C175)的PBS缓冲液中稀释。通过CTL免疫斑点分析仪(俄亥俄州克利夫兰市谢克海茨的细胞科技有限公司(Cellular Technology Limited,Shaker Heights,Cleveland,OH)),使用具有482和536nm激发波长和发射波长的异硫氰酸荧光素(FITC)荧光滤光器组,对S蛋白进行定量。使用定制的分析模块,通过使用软件Immunospot7.0.12.1专业分析仪DC对荧光病灶进行计数。通过此软件将数据连续记录到Excel数据分析电子表格中,然后从病毒对照孔(针对每个板)的平均病灶计数计算60%病灶减少终点,并且通过直接在60%终点之上和之下的孔之间的线性插值计算60%病灶减少中和滴度(针对每个样品)。
表2:微量中和测定
载体 | MN滴度-GMT(1ug) | MN滴度-GMT(0.01ug) |
Co16 | 1372.0 | 197.0 |
ACE2结合的抑制
还评估了ACE2结合的抑制。表3中示出了结果。
表3:ACE2结合的抑制
载体 | 50%抑制滴度-GMT(1ug) | 50%抑制滴度-GMT(0.01ug) |
Co16 | 3919 | 886 |
还使用替代病毒中和测试(sVNT)来评估ACE2结合的抑制,所述测试检测中和抗体,而不需要使用任何活病毒或细胞。使用来自病毒刺突(S)蛋白和宿主细胞受体ACE2的受体结合结构域(RBD)蛋白,此测试被设计为通过ELISA板孔中的直接蛋白-蛋白相互作用来模拟病毒-宿主相互作用。然后,高度特异性的相互作用被中和,即以与常规VNT相同的方式被动物血清中的特异性NAb阻断。
表3A中示出了结果。
表3A:ACE2结合的抑制
S蛋白抗体和N蛋白抗体
对N蛋白具有特异性的抗体也通过ELISA进行评估。表4中示出了结果。对S蛋白具有特异性的抗体也通过ELISA进行评估。表5中示出了结果。
表4:N蛋白抗体
载体 | IgG滴度-GMT(1ug) | IgG滴度-GMT(0.01ug) |
Co16 | 1090 | 1090 |
表5:S蛋白抗体
载体 | IgG滴度-GMT(1ug) | IgG滴度-GMT(0.01ug) |
Co5 | 8,411 | 1,390 |
Co6 | - | 1,090 |
Co16 | 39,205 | 946 |
Co17 | 35,455 | 1,554 |
假病毒中和
除了sVNT测定之外,使用假病毒中和测定来评估中和能力。假病毒测定用于证明构建体防止病毒进入细胞的能力。表6中示出了结果。
表6:假病毒中和
载体 | IgG滴度-GMT(1ug) | IgG滴度-GMT(0.01ug) |
Co5 | 1,666 | 1,395 |
Co6 | 62 | 57 |
Co16 | 3,379 | 504 |
Co17 | 13,893 | 397 |
细胞介导的免疫应答
评估自我复制RNA Co5、Co6、Co16(S(QQAA))和Co17(S(QQAA);PP)诱导抗原特异性T细胞应答的能力。
对脾培养物进行抗原特异性T细胞检测。简言之,在解离溶液(MACS BSA储备液与autoMACS冲洗液1:20)中解离脾细胞,并浓缩至4E7个细胞/ml。简言之,将脾细胞培养物在含有RPMI、NEAA、pen/strep和βME的T细胞培养基中的96孔板中建立,并在37℃/5% CO2下培养。将抗CD28(克隆37.51;BD生物科学公司(BD Biosciences)号553294)和抗CD107a(克隆号1D4B;百进生物公司(Biolegend)号121618)添加到每个孔中。细胞培养物被刺激或未被刺激。为了刺激培养物,添加N pep混合物(跨越CoV-2全长N蛋白的氨基酸残基1-419)、Spep混合物1(跨越CoV-2全长S蛋白的氨基酸残基1-643)、S pep混合物2(跨越CoV-2全长S蛋白的氨基酸残基633-1273)、CoV-1S肽(CYGVSATKL)或CoV-2S肽(CYGVSPTKL)。在2小时的刺激后,将高尔基体塞(与布雷菲尔德菌素A;BD生物科学公司号555029)添加到每个孔中。将细胞在37℃下培养总共6小时,之后将细胞转移至4℃并储存过夜。
抗原特异性T细胞应答是使用流式细胞术确定的。简言之,将Fc嵌段混合物(克隆2.4G2;BD生物科学公司号553142)添加到每个孔中,随后进行细胞外染色(包括明亮染色缓冲液加(BD生物科学公司号566385)、ICOS BV711(克隆C398.4A;百进生物公司号313548)、CD44 BUV395(克隆IM7;BD生物科学公司号740215)、CD3 BV786(克隆145-2C11;BD生物科学公司号564379)、CD4 APC-H7(克隆GK1.5,BD生物科学公司号560181)、CD8 AF700(克隆53-6.7,BD生物科学公司号557959)染色缓冲液)。根据制造商的方案,用UltraComp eBeads(e生物科学公司(eBiosciences)号01-222-42)对细胞进行染色,并在避光的情况下在4℃下温育30分钟。将细胞用染色缓冲液洗涤,离心,重悬于染色缓冲液中,并且使用流式细胞术获得数据。
观察到对N构建体和S构建体两者的抗原特异性CD4和CD8 T细胞应答。sa-mRNA疫苗诱导的CD4 T细胞主要是Th0(IL2+和/或TNFa+、IFNg-、IL5-、IL13-)和Th1(IFNg+、IL5-、IL13-),很少或没有Th2(IL5+和/或IL13+、IFNg-)(图1)。发现S1和S2反应性CD4 T细胞的频率相似;然而,对于CD8 T细胞,S1反应性T细胞比具有广泛细胞因子表型的S2反应性T细胞占优势,三重、双重和单一细胞因子产生CD8+T细胞。
IgG亚类
为了表征产生的免疫应答的类型,即Th1对Th2型应答,通过ELISA评估S特异性IgG1和IgG2a IgG亚类。观察到IgG1与IgG2a应答之间的差异很小(表7)。
表7:IgG亚类
载体 | IgG1 ELISA GMT(1ug) | IgG2a ELISA GMT(1ug) |
Co16 | 60,367 | 106,625 |
实例5:用自我复制RNA进行免疫的保护效应
为了评价免疫的保护效应,在第1天和第22天用剂量为3μg RNA/仓鼠或0.3μgRNA/仓鼠的Co16来使仓鼠免疫。所有动物在用SARS-CoV-2US病毒鼻内进行第二次免疫后28天接受攻击,并在4天后被处死,此时收集肺和鼻甲骨用于在肺和鼻甲骨中测量感染性病毒。
在仓鼠中,3.0和0.3μg剂量分别将中和滴度GMT提高到394和270。
为了评估对肺免受病毒感染的保护,比较了用Co16免疫的仓鼠和用PBS免疫的对照仓鼠的从肺中的平均病毒回收率。尽管来自对照仓鼠的病毒滴度为5,011,872TCID50/克,但来自疫苗免疫的仓鼠的平均病毒回收率低于测定的定量限<20TCID50/克,这证明研究中包含的所有疫苗对下呼吸道具有完全保护。
为了评估对上呼吸道的保护,用来自对照仓鼠的120,226,443TCID50/克的平均病毒回收率来测量来自鼻甲的病毒回收率。对于用剂量为3.0进而0.3μg的Co16免疫的仓鼠,病毒滴度降低了104做105倍,分别为1,995和9,120TCID50/克。这些结果表明sa-mRNA S显著降低了上呼吸道的病毒感染。
实例6:向SARS-CoV-2进行自我复制RNA的双倍给药
SARS-CoV-2S和N抗原没有免疫交叉反应性。为了评估临床前动物模型中的抗体免疫应答,雌性BALB/c小鼠在第0天以1μg的剂量进行免疫,以及在第21天以第二剂量进行免疫。在第42天处死动物,并且获得血清以测试中和抗体,以及抑制S蛋白与ACE2受体结合的抗体。
评估了以下第1-第2剂量组合:
●PBS-Co6(N)
●PBS-Co16(S;RRAR→QQAA)
●Co6-Co6
●Co6-Co16
●Co6-PBS
●Co16-Co16
●Co16-Co6
●Co16-PBS
S蛋白抗体和N蛋白抗体
在第42天通过ELISA评估对S蛋白和N蛋白具有特异性的抗体。表8中示出了结果。
表8:初免-加强后的S蛋白抗体
就抗S应答而言,同源初免/加强比异源初免-加强更有效,然而就抗N应答而言,异源初免-加强比同源初免-加强更有效。另外,与用PBS加强相比,用S(即,Co16)加强增加了抗N应答。
在没有加强的情况下,抗S抗体从第21天到第42天增加(数据未显示)。
ACE2结合的抑制
还评估了ACE2结合的抑制。表9中示出了结果。
表9:ACE2结合的抑制
初免 | 加强 | ACE2结合的50%抑制(GMT) |
PBS | Co6 | ND |
PBS | Co16 | 594 |
Co6 | Co6 | 15 |
Co6 | Co16 | 1307 |
Co6 | PBS | 15 |
Co16 | Co16 | 31065 |
Co16 | Co6 | 349 |
Co16 | PBS | 1312 |
微量中和测定
还评估了WT病毒中和。表10中示出了结果。
表10:WT病毒中和
初免 | 加强 | MN滴度(GMT) |
PBS | Co6 | 5 |
PBS | Co16 | 92 |
Co6 | Co6 | 5 |
Co6 | Co16 | 98 |
Co6 | PBS | 5 |
Co16 | Co16 | 2744 |
Co16 | Co6 | 46 |
Co16 | PBS | 211 |
细胞介导的免疫应答
还评估了抗原特异性T细胞应答。用同源抗原和异源抗原两者进行疫苗接种后观察CD4和CD8 T细胞应答。
实例6:自我复制RNA变体的产生
使用来自SARS-CoV-2变体毒株(即,UKα毒株(B.1.1.7)、南非β毒株(B.1.351))的刺突(S)抗原制备自我复制的RNA。制备了以下构建体:
●NSP1-4.SGP.S(RRAR→QQAA)(Co16)
●NSP1-4.SGP.S(RRAR→QQAA和D614G)(Co49)
●NSP1-4.SGP.S(RRAR→QQAA、S2'(R815N)和D614G)(Co59)
●NSP1-4.SGP.S(RRAR→QQAA;Δ69-70;ΔY144;N501Y;D614G)(Co77)
●NSP1-4.SGP.S(RRAR→QQAA;Δ242-244;K417N;E484K;N501Y;D614G)(Co78)
●NSP1-4.SGP.S(RRAR→QQAA;Δ69-70;Δ242-244;K417N;E484K;N501Y;D614G)(Co79)
●NSP1-4.SGP.S(RRAR→QQAA;Δ69-70;ΔY144;N501Y;A570D;D614G;P680H;T716I)(Co80)
●NSP1-4.SGP.S(RRAR→QQAA;L18F;D80A;D215G;Δ242-244;K417N;E484K;N501Y;D614G;A701V)(Co81)
如上文所描述确定LNP调配的RNA的体外活性和效力,并且如下表11所示:
表11:经调配的RNA在LNP中的体外效力
如表12所示,所有构建体都具有体外活性和效力
表12:体外效力和活性
中和测定
为了确定构建体的中和能力,对参考Whuan序列;以及α变体(B.1.1.7;UK毒株);β变体(B.1.351;南非毒株);γ变体(P.1;巴西毒株);和δ变体(B.1.617.2;印度毒株)进行了微量中和测定。
如图2所示,所有构建体都产生了针对所有毒株的免疫应答。
ACE2结合的抑制
还评估了ACE2结合的抑制。表13中示出了结果。所有构建体在第42天抑制ACE2结合。
表13:ACE2结合的抑制
IgG ELISA
如图3所示,所有构建体在高剂量和低剂量下都产生了总Ig应答。所有构建体都产生了高度交叉反应的应答。
细胞介导的免疫应答
表征了由变体构建体诱导的B细胞的频率。
如图4和表14所示,所有构建体都产生S特异性B细胞,所述细胞与所有变体B细胞受体特异性探针反应。非特异性对照(即,无诱饵和阴性对照HA H1)示出了低水平的背景结合。
如上文所描述,抗原特异性T细胞应答是使用流式细胞术确定的。肽池(如上文所描述)与原始CoV-2毒株匹配,并且与变体毒株不匹配。所有构建体诱导了与S1表位和S2表位具有反应性的抗原特异性CD4和CD8 T细胞(图5和表14)。CD4 T细胞主要是Th0(IL2+和/或TNFa+、IFNg-、IL5-、IL13-)和Th1(IFNg+、IL5-、IL13-),很少或没有Th2(IL5+和/或IL13+、IFNg-)。
表15:细胞介导的免疫应答
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序列表
<110> SEQIRUS公司(Seqirus Inc)
<120> 自我复制RNA和其用途
<130> 536512PCT
<160> 37
<170> PatentIn 3.5版
<210> 1
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 全长wt SARS-CoV-2刺突(S)蛋白(可切割)的核苷酸序列
<400> 1
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgac 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc gggacctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgctggccc tgcaccggag ctacctgacc cccggcgaca gcagcagcgg ctggaccgcc 780
ggcgctgccg cctattacgt gggctacctg caacctagaa ccttcctgct gaaatacaac 840
gagaacggca caatcaccga cgccgtggac tgtgccctgg accccctgtc tgagacaaag 900
tgtaccctga agtctttcac cgtggagaag ggcatctacc agaccagcaa cttccgggtg 960
cagcctacag aatctatagt gcggttccct aacatcacca acctgtgtcc ttttggcgag 1020
gtgttcaacg ccactcggtt cgcctctgtc tacgcctgga accggaaacg gatctctaat 1080
tgcgtggccg attacagcgt cctgtataac tccgccagtt tcagcacatt caagtgctac 1140
ggcgtgtcac ccaccaagct gaacgatctg tgcttcacca atgtgtacgc cgatagtttc 1200
gtgatccggg gcgatgaggt gcggcagatc gcccctggac agacaggcaa gatcgccgac 1260
tacaactaca agctgcctga cgacttcaca ggctgtgtga tcgcatggaa cagcaacaac 1320
ctggacagca aggtgggcgg aaactacaac tacctgtaca gactgttcag aaagtccaac 1380
ctgaagcctt tcgagagaga tatatctacc gagatctacc aggccggcag cacaccctgt 1440
aatggagtgg aaggctttaa ctgctacttc cctctgcaaa gctatggatt tcaacctaca 1500
aatggggttg gctaccagcc ttacagagtg gtggtcctta gcttcgagct gctccatgcc 1560
cctgccaccg tgtgcggacc taagaagtcc accaacctgg tgaaaaacaa gtgcgtgaac 1620
tttaatttta acggcctgac cggaacagga gtgctgacag aaagcaacaa aaagttcctg 1680
cctttccagc agttcggcag agacattgcc gacaccacag atgctgttag agacccccag 1740
acgctggaaa tcctggatat caccccctgc tcttttggcg gcgtgagcgt gatcacccca 1800
ggcacaaaca caagcaacca ggtggctgtg ctgtaccagg acgtgaactg tacagaggtc 1860
cctgtggcaa tccacgccga tcagctgacc cctacatggc gggtgtactc cactggatct 1920
aacgtgttcc agacaagggc cggatgcctc atcggcgctg agcacgtgaa caattcttac 1980
gagtgcgaca tccctattgg agcgggcatc tgcgccagct accagacaca gaccaatagc 2040
cctcgcagag ccagaagcgt ggcctcccag agcatcatcg cctacaccat gagcctggga 2100
gccgagaact ctgtggccta cagcaacaac agcatcgcta tccctaccaa cttcaccatc 2160
tctgtcacca ccgaaatcct gcccgtcagt atgaccaaaa ccagcgtcga ctgcaccatg 2220
tacatatgcg gcgatagcac cgaatgcagc aacctgctgc tgcagtatgg ctccttctgc 2280
acccaactta acagagccct gactggcatc gccgtggagc aggacaagaa tacccaggag 2340
gtgttcgccc aggtgaagca gatctacaag acacccccga tcaaggactt cggcggcttt 2400
aatttctctc agatcctgcc agacccatct aaaccctcta agcggagctt tatcgaggac 2460
ctgctgttca acaaggtgac tctggctgac gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca ttgctgctag agacctgatc tgtgcccaga aattcaacgg tcttactgtg 2580
ctgcctcctc tgctgacgga tgagatgatc gcccagtaca ccagcgccct gctggccggc 2640
accatcacat ccggctggac attcggcgcc ggcgcagccc tgcagatccc ttttgccatg 2700
cagatggcct accggttcaa cggaatcgga gtgacacaga acgtgctcta cgaaaatcag 2760
aagttgatcg ccaaccagtt caacagcgcc atcggcaaga ttcaggatag tctgagttcc 2820
accgccagcg ccctgggaaa gctgcaggac gtggtcaatc agaatgccca agccctgaac 2880
accctggtga agcagctgag cagcaacttc ggcgccatca gctctgtgct gaacgacatc 2940
ctgagtagac tggacaaggt ggaagccgaa gtgcagatcg acagattgat caccggaaga 3000
ctgcaaagcc tgcagaccta cgtgacccag cagctgataa gagctgctga aatcagagcc 3060
agcgctaatc tggccgctac caagatgagc gagtgcgttc tgggccagtc taagagagtg 3120
gacttctgcg gaaaaggcta ccacctgatg tcctttcctc agtctgcccc ccacggcgtg 3180
gtgttcctgc acgtcacata cgtgcccgct caagagaaaa acttcaccac ggcccctgcc 3240
atctgtcacg acggcaaggc ccacttcccc agagagggcg tgttcgtgag caatggcacc 3300
cactggtttg tgactcagag aaacttctac gagccacaga ttatcaccac agataacacc 3360
ttcgtgtctg gcaactgcga cgtggtgatc ggcatcgtca acaacacagt gtacgaccca 3420
ctgcaacctg agctggactc attcaaggag gaactggata agtacttcaa gaatcacacc 3480
agccccgacg ttgacctggg cgacatcagc ggcattaacg cctctgtggt caacatccag 3540
aaggaaatcg acagactgaa tgaggtggcc aagaatttga acgagagcct gattgatctg 3600
caggagctgg gcaaatacga gcagtacatc aagtggcctt ggtacatctg gctgggcttc 3660
atcgccgggc tgatcgccat cgttatggtg acaatcatgc tgtgttgcat gacaagctgt 3720
tgtagctgcc tgaaaggctg ctgctcctgc ggcagctgtt gcaagtttga cgaagatgac 3780
agcgagcccg tgctgaaagg cgtcaagctg cactacacct ga 3822
<210> 2
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2突变的刺突(S)蛋白(S1/S2 RRAR变为QQAA的
突变)的核苷酸序列
<400> 2
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgac 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc gggacctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgctggccc tgcaccggag ctacctgacc cccggcgaca gcagcagcgg ctggaccgcc 780
ggcgctgccg cctattacgt gggctacctg caacctagaa ccttcctgct gaaatacaac 840
gagaacggca caatcaccga cgccgtggac tgtgccctgg accccctgtc tgagacaaag 900
tgtaccctga agtctttcac cgtggagaag ggcatctacc agaccagcaa cttccgggtg 960
cagcctacag aatctatagt gcggttccct aacatcacca acctgtgtcc ttttggcgag 1020
gtgttcaacg ccactcggtt cgcctctgtc tacgcctgga accggaaacg gatctctaat 1080
tgcgtggccg attacagcgt cctgtataac tccgccagtt tcagcacatt caagtgctac 1140
ggcgtgtcac ccaccaagct gaacgatctg tgcttcacca atgtgtacgc cgatagtttc 1200
gtgatccggg gcgatgaggt gcggcagatc gcccctggac agacaggcaa gatcgccgac 1260
tacaactaca agctgcctga cgacttcaca ggctgtgtga tcgcatggaa cagcaacaac 1320
ctggacagca aggtgggcgg aaactacaac tacctgtaca gactgttcag aaagtccaac 1380
ctgaagcctt tcgagagaga tatatctacc gagatctacc aggccggcag cacaccctgt 1440
aatggagtgg aaggctttaa ctgctacttc cctctgcaaa gctatggatt tcaacctaca 1500
aatggggttg gctaccagcc ttacagagtg gtggtcctta gcttcgagct gctccatgcc 1560
cctgccaccg tgtgcggacc taagaagtcc accaacctgg tgaaaaacaa gtgcgtgaac 1620
tttaatttta acggcctgac cggaacagga gtgctgacag aaagcaacaa aaagttcctg 1680
cctttccagc agttcggcag agacattgcc gacaccacag atgctgttag agacccccag 1740
acgctggaaa tcctggatat caccccctgc tcttttggcg gcgtgagcgt gatcacccca 1800
ggcacaaaca caagcaacca ggtggctgtg ctgtaccagg acgtgaactg tacagaggtc 1860
cctgtggcaa tccacgccga tcagctgacc cctacatggc gggtgtactc cactggatct 1920
aacgtgttcc agacaagggc cggatgcctc atcggcgctg agcacgtgaa caattcttac 1980
gagtgcgaca tccctattgg agcgggcatc tgcgccagct accagacaca gaccaatagc 2040
cctcagcaag ccgctagcgt ggcctcccag agcatcatcg cctacaccat gagcctggga 2100
gccgagaact ctgtggccta cagcaacaac agcatcgcta tccctaccaa cttcaccatc 2160
tctgtcacca ccgaaatcct gcccgtcagt atgaccaaaa ccagcgtcga ctgcaccatg 2220
tacatatgcg gcgatagcac cgaatgcagc aacctgctgc tgcagtatgg ctccttctgc 2280
acccaactta acagagccct gactggcatc gccgtggagc aggacaagaa tacccaggag 2340
gtgttcgccc aggtgaagca gatctacaag acacccccga tcaaggactt cggcggcttt 2400
aatttctctc agatcctgcc agacccatct aaaccctcta agcggagctt tatcgaggac 2460
ctgctgttca acaaggtgac tctggctgac gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca ttgctgctag agacctgatc tgtgcccaga aattcaacgg tcttactgtg 2580
ctgcctcctc tgctgacgga tgagatgatc gcccagtaca ccagcgccct gctggccggc 2640
accatcacat ccggctggac attcggcgcc ggcgcagccc tgcagatccc ttttgccatg 2700
cagatggcct accggttcaa cggaatcgga gtgacacaga acgtgctcta cgaaaatcag 2760
aagttgatcg ccaaccagtt caacagcgcc atcggcaaga ttcaggatag tctgagttcc 2820
accgccagcg ccctgggaaa gctgcaggac gtggtcaatc agaatgccca agccctgaac 2880
accctggtga agcagctgag cagcaacttc ggcgccatca gctctgtgct gaacgacatc 2940
ctgagtagac tggacaaggt ggaagccgaa gtgcagatcg acagattgat caccggaaga 3000
ctgcaaagcc tgcagaccta cgtgacccag cagctgataa gagctgctga aatcagagcc 3060
agcgctaatc tggccgctac caagatgagc gagtgcgttc tgggccagtc taagagagtg 3120
gacttctgcg gaaaaggcta ccacctgatg tcctttcctc agtctgcccc ccacggcgtg 3180
gtgttcctgc acgtcacata cgtgcccgct caagagaaaa acttcaccac ggcccctgcc 3240
atctgtcacg acggcaaggc ccacttcccc agagagggcg tgttcgtgag caatggcacc 3300
cactggtttg tgactcagag aaacttctac gagccacaga ttatcaccac agataacacc 3360
ttcgtgtctg gcaactgcga cgtggtgatc ggcatcgtca acaacacagt gtacgaccca 3420
ctgcaacctg agctggactc attcaaggag gaactggata agtacttcaa gaatcacacc 3480
agccccgacg ttgacctggg cgacatcagc ggcattaacg cctctgtggt caacatccag 3540
aaggaaatcg acagactgaa tgaggtggcc aagaatttga acgagagcct gattgatctg 3600
caggagctgg gcaaatacga gcagtacatc aagtggcctt ggtacatctg gctgggcttc 3660
atcgccgggc tgatcgccat cgttatggtg acaatcatgc tgtgttgcat gacaagctgt 3720
tgtagctgcc tgaaaggctg ctgctcctgc ggcagctgtt gcaagtttga cgaagatgac 3780
agcgagcccg tgctgaaagg cgtcaagctg cactacacct ga 3822
<210> 3
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2刺突(S)蛋白(S1/S2 RRAR变为QQAA的突变
和986P/987P突变)的核苷酸序列
<400> 3
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgac 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc gggacctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgctggccc tgcaccggag ctacctgacc cccggcgaca gcagcagcgg ctggaccgcc 780
ggcgctgccg cctattacgt gggctacctg caacctagaa ccttcctgct gaaatacaac 840
gagaacggca caatcaccga cgccgtggac tgtgccctgg accccctgtc tgagacaaag 900
tgtaccctga agtctttcac cgtggagaag ggcatctacc agaccagcaa cttccgggtg 960
cagcctacag aatctatagt gcggttccct aacatcacca acctgtgtcc ttttggcgag 1020
gtgttcaacg ccactcggtt cgcctctgtc tacgcctgga accggaaacg gatctctaat 1080
tgcgtggccg attacagcgt cctgtataac tccgccagtt tcagcacatt caagtgctac 1140
ggcgtgtcac ccaccaagct gaacgatctg tgcttcacca atgtgtacgc cgatagtttc 1200
gtgatccggg gcgatgaggt gcggcagatc gcccctggac agacaggcaa gatcgccgac 1260
tacaactaca agctgcctga cgacttcaca ggctgtgtga tcgcatggaa cagcaacaac 1320
ctggacagca aggtgggcgg aaactacaac tacctgtaca gactgttcag aaagtccaac 1380
ctgaagcctt tcgagagaga tatatctacc gagatctacc aggccggcag cacaccctgt 1440
aatggagtgg aaggctttaa ctgctacttc cctctgcaaa gctatggatt tcaacctaca 1500
aatggggttg gctaccagcc ttacagagtg gtggtcctta gcttcgagct gctccatgcc 1560
cctgccaccg tgtgcggacc taagaagtcc accaacctgg tgaaaaacaa gtgcgtgaac 1620
tttaatttta acggcctgac cggaacagga gtgctgacag aaagcaacaa aaagttcctg 1680
cctttccagc agttcggcag agacattgcc gacaccacag atgctgttag agacccccag 1740
acgctggaaa tcctggatat caccccctgc tcttttggcg gcgtgagcgt gatcacccca 1800
ggcacaaaca caagcaacca ggtggctgtg ctgtaccagg acgtgaactg tacagaggtc 1860
cctgtggcaa tccacgccga tcagctgacc cctacatggc gggtgtactc cactggatct 1920
aacgtgttcc agacaagggc cggatgcctc atcggcgctg agcacgtgaa caattcttac 1980
gagtgcgaca tccctattgg agcgggcatc tgcgccagct accagacaca gaccaatagc 2040
cctcagcaag ccgctagcgt ggcctcccag agcatcatcg cctacaccat gagcctggga 2100
gccgagaact ctgtggccta cagcaacaac agcatcgcta tccctaccaa cttcaccatc 2160
tctgtcacca ccgaaatcct gcccgtcagt atgaccaaaa ccagcgtcga ctgcaccatg 2220
tacatatgcg gcgatagcac cgaatgcagc aacctgctgc tgcagtatgg ctccttctgc 2280
acccaactta acagagccct gactggcatc gccgtggagc aggacaagaa tacccaggag 2340
gtgttcgccc aggtgaagca gatctacaag acacccccga tcaaggactt cggcggcttt 2400
aatttctctc agatcctgcc agacccatct aaaccctcta agcggagctt tatcgaggac 2460
ctgctgttca acaaggtgac tctggctgac gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca ttgctgctag agacctgatc tgtgcccaga aattcaacgg tcttactgtg 2580
ctgcctcctc tgctgacgga tgagatgatc gcccagtaca ccagcgccct gctggccggc 2640
accatcacat ccggctggac attcggcgcc ggcgcagccc tgcagatccc ttttgccatg 2700
cagatggcct accggttcaa cggaatcgga gtgacacaga acgtgctcta cgaaaatcag 2760
aagttgatcg ccaaccagtt caacagcgcc atcggcaaga ttcaggatag tctgagttcc 2820
accgccagcg ccctgggaaa gctgcaggac gtggtcaatc agaatgccca agccctgaac 2880
accctggtga agcagctgag cagcaacttc ggcgccatca gctctgtgct gaacgacatc 2940
ctgagtagac tggacccacc tgaagccgaa gtgcagatcg acagattgat caccggaaga 3000
ctgcaaagcc tgcagaccta cgtgacccag cagctgataa gagctgctga aatcagagcc 3060
agcgctaatc tggccgctac caagatgagc gagtgcgttc tgggccagtc taagagagtg 3120
gacttctgcg gaaaaggcta ccacctgatg tcctttcctc agtctgcccc ccacggcgtg 3180
gtgttcctgc acgtcacata cgtgcccgct caagagaaaa acttcaccac ggcccctgcc 3240
atctgtcacg acggcaaggc ccacttcccc agagagggcg tgttcgtgag caatggcacc 3300
cactggtttg tgactcagag aaacttctac gagccacaga ttatcaccac agataacacc 3360
ttcgtgtctg gcaactgcga cgtggtgatc ggcatcgtca acaacacagt gtacgaccca 3420
ctgcaacctg agctggactc attcaaggag gaactggata agtacttcaa gaatcacacc 3480
agccccgacg ttgacctggg cgacatcagc ggcattaacg cctctgtggt caacatccag 3540
aaggaaatcg acagactgaa tgaggtggcc aagaatttga acgagagcct gattgatctg 3600
caggagctgg gcaaatacga gcagtacatc aagtggcctt ggtacatctg gctgggcttc 3660
atcgccgggc tgatcgccat cgttatggtg acaatcatgc tgtgttgcat gacaagctgt 3720
tgtagctgcc tgaaaggctg ctgctcctgc ggcagctgtt gcaagtttga cgaagatgac 3780
agcgagcccg tgctgaaagg cgtcaagctg cactacacct ga 3822
<210> 4
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2修饰的刺突(S)蛋白(S1/S2 RRAR变为QQAA的
突变和D614G突变)的核苷酸序列
<400> 4
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgac 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc gggacctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgctggccc tgcaccggag ctacctgacc cccggcgaca gcagcagcgg ctggaccgcc 780
ggcgctgccg cctattacgt gggctacctg caacctagaa ccttcctgct gaaatacaac 840
gagaacggca caatcaccga cgccgtggac tgtgccctgg accccctgtc tgagacaaag 900
tgtaccctga agtctttcac cgtggagaag ggcatctacc agaccagcaa cttccgggtg 960
cagcctacag aatctatagt gcggttccct aacatcacca acctgtgtcc ttttggcgag 1020
gtgttcaacg ccactcggtt cgcctctgtc tacgcctgga accggaaacg gatctctaat 1080
tgcgtggccg attacagcgt cctgtataac tccgccagtt tcagcacatt caagtgctac 1140
ggcgtgtcac ccaccaagct gaacgatctg tgcttcacca atgtgtacgc cgatagtttc 1200
gtgatccggg gcgatgaggt gcggcagatc gcccctggac agacaggcaa gatcgccgac 1260
tacaactaca agctgcctga cgacttcaca ggctgtgtga tcgcatggaa cagcaacaac 1320
ctggacagca aggtgggcgg aaactacaac tacctgtaca gactgttcag aaagtccaac 1380
ctgaagcctt tcgagagaga tatatctacc gagatctacc aggccggcag cacaccctgt 1440
aatggagtgg aaggctttaa ctgctacttc cctctgcaaa gctatggatt tcaacctaca 1500
aatggggttg gctaccagcc ttacagagtg gtggtcctta gcttcgagct gctccatgcc 1560
cctgccaccg tgtgcggacc taagaagtcc accaacctgg tgaaaaacaa gtgcgtgaac 1620
tttaatttta acggcctgac cggaacagga gtgctgacag aaagcaacaa aaagttcctg 1680
cctttccagc agttcggcag agacattgcc gacaccacag atgctgttag agacccccag 1740
acgctggaaa tcctggatat caccccctgc tcttttggcg gcgtgagcgt gatcacccca 1800
ggcacaaaca caagcaacca ggtggctgtg ctgtaccagg gcgtgaactg tacagaggtc 1860
cctgtggcaa tccacgccga tcagctgacc cctacatggc gggtgtactc cactggatct 1920
aacgtgttcc agacaagggc cggatgcctc atcggcgctg agcacgtgaa caattcttac 1980
gagtgcgaca tccctattgg agcgggcatc tgcgccagct accagacaca gaccaatagc 2040
cctcagcaag ccgctagcgt ggcctcccag agcatcatcg cctacaccat gagcctggga 2100
gccgagaact ctgtggccta cagcaacaac agcatcgcta tccctaccaa cttcaccatc 2160
tctgtcacca ccgaaatcct gcccgtcagt atgaccaaaa ccagcgtcga ctgcaccatg 2220
tacatatgcg gcgatagcac cgaatgcagc aacctgctgc tgcagtatgg ctccttctgc 2280
acccaactta acagagccct gactggcatc gccgtggagc aggacaagaa tacccaggag 2340
gtgttcgccc aggtgaagca gatctacaag acacccccga tcaaggactt cggcggcttt 2400
aatttctctc agatcctgcc agacccatct aaaccctcta agcggagctt tatcgaggac 2460
ctgctgttca acaaggtgac tctggctgac gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca ttgctgctag agacctgatc tgtgcccaga aattcaacgg tcttactgtg 2580
ctgcctcctc tgctgacgga tgagatgatc gcccagtaca ccagcgccct gctggccggc 2640
accatcacat ccggctggac attcggcgcc ggcgcagccc tgcagatccc ttttgccatg 2700
cagatggcct accggttcaa cggaatcgga gtgacacaga acgtgctcta cgaaaatcag 2760
aagttgatcg ccaaccagtt caacagcgcc atcggcaaga ttcaggatag tctgagttcc 2820
accgccagcg ccctgggaaa gctgcaggac gtggtcaatc agaatgccca agccctgaac 2880
accctggtga agcagctgag cagcaacttc ggcgccatca gctctgtgct gaacgacatc 2940
ctgagtagac tggacaaggt ggaagccgaa gtgcagatcg acagattgat caccggaaga 3000
ctgcaaagcc tgcagaccta cgtgacccag cagctgataa gagctgctga aatcagagcc 3060
agcgctaatc tggccgctac caagatgagc gagtgcgttc tgggccagtc taagagagtg 3120
gacttctgcg gaaaaggcta ccacctgatg tcctttcctc agtctgcccc ccacggcgtg 3180
gtgttcctgc acgtcacata cgtgcccgct caagagaaaa acttcaccac ggcccctgcc 3240
atctgtcacg acggcaaggc ccacttcccc agagagggcg tgttcgtgag caatggcacc 3300
cactggtttg tgactcagag aaacttctac gagccacaga ttatcaccac agataacacc 3360
ttcgtgtctg gcaactgcga cgtggtgatc ggcatcgtca acaacacagt gtacgaccca 3420
ctgcaacctg agctggactc attcaaggag gaactggata agtacttcaa gaatcacacc 3480
agccccgacg ttgacctggg cgacatcagc ggcattaacg cctctgtggt caacatccag 3540
aaggaaatcg acagactgaa tgaggtggcc aagaatttga acgagagcct gattgatctg 3600
caggagctgg gcaaatacga gcagtacatc aagtggcctt ggtacatctg gctgggcttc 3660
atcgccgggc tgatcgccat cgttatggtg acaatcatgc tgtgttgcat gacaagctgt 3720
tgtagctgcc tgaaaggctg ctgctcctgc ggcagctgtt gcaagtttga cgaagatgac 3780
agcgagcccg tgctgaaagg cgtcaagctg cactacacct ga 3822
<210> 5
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2刺突(S)蛋白(S1/S2 RRAR变为QQAA的突变
和S2’突变)的核苷酸序列
<400> 5
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgac 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc gggacctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgctggccc tgcaccggag ctacctgacc cccggcgaca gcagcagcgg ctggaccgcc 780
ggcgctgccg cctattacgt gggctacctg caacctagaa ccttcctgct gaaatacaac 840
gagaacggca caatcaccga cgccgtggac tgtgccctgg accccctgtc tgagacaaag 900
tgtaccctga agtctttcac cgtggagaag ggcatctacc agaccagcaa cttccgggtg 960
cagcctacag aatctatagt gcggttccct aacatcacca acctgtgtcc ttttggcgag 1020
gtgttcaacg ccactcggtt cgcctctgtc tacgcctgga accggaaacg gatctctaat 1080
tgcgtggccg attacagcgt cctgtataac tccgccagtt tcagcacatt caagtgctac 1140
ggcgtgtcac ccaccaagct gaacgatctg tgcttcacca atgtgtacgc cgatagtttc 1200
gtgatccggg gcgatgaggt gcggcagatc gcccctggac agacaggcaa gatcgccgac 1260
tacaactaca agctgcctga cgacttcaca ggctgtgtga tcgcatggaa cagcaacaac 1320
ctggacagca aggtgggcgg aaactacaac tacctgtaca gactgttcag aaagtccaac 1380
ctgaagcctt tcgagagaga tatatctacc gagatctacc aggccggcag cacaccctgt 1440
aatggagtgg aaggctttaa ctgctacttc cctctgcaaa gctatggatt tcaacctaca 1500
aatggggttg gctaccagcc ttacagagtg gtggtcctta gcttcgagct gctccatgcc 1560
cctgccaccg tgtgcggacc taagaagtcc accaacctgg tgaaaaacaa gtgcgtgaac 1620
tttaatttta acggcctgac cggaacagga gtgctgacag aaagcaacaa aaagttcctg 1680
cctttccagc agttcggcag agacattgcc gacaccacag atgctgttag agacccccag 1740
acgctggaaa tcctggatat caccccctgc tcttttggcg gcgtgagcgt gatcacccca 1800
ggcacaaaca caagcaacca ggtggctgtg ctgtaccagg acgtgaactg tacagaggtc 1860
cctgtggcaa tccacgccga tcagctgacc cctacatggc gggtgtactc cactggatct 1920
aacgtgttcc agacaagggc cggatgcctc atcggcgctg agcacgtgaa caattcttac 1980
gagtgcgaca tccctattgg agcgggcatc tgcgccagct accagacaca gaccaatagc 2040
cctcagcaag ccgctagcgt ggcctcccag agcatcatcg cctacaccat gagcctggga 2100
gccgagaact ctgtggccta cagcaacaac agcatcgcta tccctaccaa cttcaccatc 2160
tctgtcacca ccgaaatcct gcccgtcagt atgaccaaaa ccagcgtcga ctgcaccatg 2220
tacatatgcg gcgatagcac cgaatgcagc aacctgctgc tgcagtatgg ctccttctgc 2280
acccaactta acagagccct gactggcatc gccgtggagc aggacaagaa tacccaggag 2340
gtgttcgccc aggtgaagca gatctacaag acacccccga tcaaggactt cggcggcttt 2400
aatttctctc agatcctgcc agacccatct aaaccctcta agaacagctt tatcgaggac 2460
ctgctgttca acaaggtgac tctggctgac gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca ttgctgctag agacctgatc tgtgcccaga aattcaacgg tcttactgtg 2580
ctgcctcctc tgctgacgga tgagatgatc gcccagtaca ccagcgccct gctggccggc 2640
accatcacat ccggctggac attcggcgcc ggcgcagccc tgcagatccc ttttgccatg 2700
cagatggcct accggttcaa cggaatcgga gtgacacaga acgtgctcta cgaaaatcag 2760
aagttgatcg ccaaccagtt caacagcgcc atcggcaaga ttcaggatag tctgagttcc 2820
accgccagcg ccctgggaaa gctgcaggac gtggtcaatc agaatgccca agccctgaac 2880
accctggtga agcagctgag cagcaacttc ggcgccatca gctctgtgct gaacgacatc 2940
ctgagtagac tggacaaggt ggaagccgaa gtgcagatcg acagattgat caccggaaga 3000
ctgcaaagcc tgcagaccta cgtgacccag cagctgataa gagctgctga aatcagagcc 3060
agcgctaatc tggccgctac caagatgagc gagtgcgttc tgggccagtc taagagagtg 3120
gacttctgcg gaaaaggcta ccacctgatg tcctttcctc agtctgcccc ccacggcgtg 3180
gtgttcctgc acgtcacata cgtgcccgct caagagaaaa acttcaccac ggcccctgcc 3240
atctgtcacg acggcaaggc ccacttcccc agagagggcg tgttcgtgag caatggcacc 3300
cactggtttg tgactcagag aaacttctac gagccacaga ttatcaccac agataacacc 3360
ttcgtgtctg gcaactgcga cgtggtgatc ggcatcgtca acaacacagt gtacgaccca 3420
ctgcaacctg agctggactc attcaaggag gaactggata agtacttcaa gaatcacacc 3480
agccccgacg ttgacctggg cgacatcagc ggcattaacg cctctgtggt caacatccag 3540
aaggaaatcg acagactgaa tgaggtggcc aagaatttga acgagagcct gattgatctg 3600
caggagctgg gcaaatacga gcagtacatc aagtggcctt ggtacatctg gctgggcttc 3660
atcgccgggc tgatcgccat cgttatggtg acaatcatgc tgtgttgcat gacaagctgt 3720
tgtagctgcc tgaaaggctg ctgctcctgc ggcagctgtt gcaagtttga cgaagatgac 3780
agcgagcccg tgctgaaagg cgtcaagctg cactacacct ga 3822
<210> 6
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2修饰的刺突(S)蛋白(S1/S2 RRAR变为QQAA的
突变以及D614G突变和S2’突变)的核苷酸序列
<400> 6
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgac 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc gggacctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgctggccc tgcaccggag ctacctgacc cccggcgaca gcagcagcgg ctggaccgcc 780
ggcgctgccg cctattacgt gggctacctg caacctagaa ccttcctgct gaaatacaac 840
gagaacggca caatcaccga cgccgtggac tgtgccctgg accccctgtc tgagacaaag 900
tgtaccctga agtctttcac cgtggagaag ggcatctacc agaccagcaa cttccgggtg 960
cagcctacag aatctatagt gcggttccct aacatcacca acctgtgtcc ttttggcgag 1020
gtgttcaacg ccactcggtt cgcctctgtc tacgcctgga accggaaacg gatctctaat 1080
tgcgtggccg attacagcgt cctgtataac tccgccagtt tcagcacatt caagtgctac 1140
ggcgtgtcac ccaccaagct gaacgatctg tgcttcacca atgtgtacgc cgatagtttc 1200
gtgatccggg gcgatgaggt gcggcagatc gcccctggac agacaggcaa gatcgccgac 1260
tacaactaca agctgcctga cgacttcaca ggctgtgtga tcgcatggaa cagcaacaac 1320
ctggacagca aggtgggcgg aaactacaac tacctgtaca gactgttcag aaagtccaac 1380
ctgaagcctt tcgagagaga tatatctacc gagatctacc aggccggcag cacaccctgt 1440
aatggagtgg aaggctttaa ctgctacttc cctctgcaaa gctatggatt tcaacctaca 1500
aatggggttg gctaccagcc ttacagagtg gtggtcctta gcttcgagct gctccatgcc 1560
cctgccaccg tgtgcggacc taagaagtcc accaacctgg tgaaaaacaa gtgcgtgaac 1620
tttaatttta acggcctgac cggaacagga gtgctgacag aaagcaacaa aaagttcctg 1680
cctttccagc agttcggcag agacattgcc gacaccacag atgctgttag agacccccag 1740
acgctggaaa tcctggatat caccccctgc tcttttggcg gcgtgagcgt gatcacccca 1800
ggcacaaaca caagcaacca ggtggctgtg ctgtaccagg gcgtgaactg tacagaggtc 1860
cctgtggcaa tccacgccga tcagctgacc cctacatggc gggtgtactc cactggatct 1920
aacgtgttcc agacaagggc cggatgcctc atcggcgctg agcacgtgaa caattcttac 1980
gagtgcgaca tccctattgg agcgggcatc tgcgccagct accagacaca gaccaatagc 2040
cctcagcaag ccgctagcgt ggcctcccag agcatcatcg cctacaccat gagcctggga 2100
gccgagaact ctgtggccta cagcaacaac agcatcgcta tccctaccaa cttcaccatc 2160
tctgtcacca ccgaaatcct gcccgtcagt atgaccaaaa ccagcgtcga ctgcaccatg 2220
tacatatgcg gcgatagcac cgaatgcagc aacctgctgc tgcagtatgg ctccttctgc 2280
acccaactta acagagccct gactggcatc gccgtggagc aggacaagaa tacccaggag 2340
gtgttcgccc aggtgaagca gatctacaag acacccccga tcaaggactt cggcggcttt 2400
aatttctctc agatcctgcc agacccatct aaaccctcta agaacagctt tatcgaggac 2460
ctgctgttca acaaggtgac tctggctgac gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca ttgctgctag agacctgatc tgtgcccaga aattcaacgg tcttactgtg 2580
ctgcctcctc tgctgacgga tgagatgatc gcccagtaca ccagcgccct gctggccggc 2640
accatcacat ccggctggac attcggcgcc ggcgcagccc tgcagatccc ttttgccatg 2700
cagatggcct accggttcaa cggaatcgga gtgacacaga acgtgctcta cgaaaatcag 2760
aagttgatcg ccaaccagtt caacagcgcc atcggcaaga ttcaggatag tctgagttcc 2820
accgccagcg ccctgggaaa gctgcaggac gtggtcaatc agaatgccca agccctgaac 2880
accctggtga agcagctgag cagcaacttc ggcgccatca gctctgtgct gaacgacatc 2940
ctgagtagac tggacaaggt ggaagccgaa gtgcagatcg acagattgat caccggaaga 3000
ctgcaaagcc tgcagaccta cgtgacccag cagctgataa gagctgctga aatcagagcc 3060
agcgctaatc tggccgctac caagatgagc gagtgcgttc tgggccagtc taagagagtg 3120
gacttctgcg gaaaaggcta ccacctgatg tcctttcctc agtctgcccc ccacggcgtg 3180
gtgttcctgc acgtcacata cgtgcccgct caagagaaaa acttcaccac ggcccctgcc 3240
atctgtcacg acggcaaggc ccacttcccc agagagggcg tgttcgtgag caatggcacc 3300
cactggtttg tgactcagag aaacttctac gagccacaga ttatcaccac agataacacc 3360
ttcgtgtctg gcaactgcga cgtggtgatc ggcatcgtca acaacacagt gtacgaccca 3420
ctgcaacctg agctggactc attcaaggag gaactggata agtacttcaa gaatcacacc 3480
agccccgacg ttgacctggg cgacatcagc ggcattaacg cctctgtggt caacatccag 3540
aaggaaatcg acagactgaa tgaggtggcc aagaatttga acgagagcct gattgatctg 3600
caggagctgg gcaaatacga gcagtacatc aagtggcctt ggtacatctg gctgggcttc 3660
atcgccgggc tgatcgccat cgttatggtg acaatcatgc tgtgttgcat gacaagctgt 3720
tgtagctgcc tgaaaggctg ctgctcctgc ggcagctgtt gcaagtttga cgaagatgac 3780
agcgagcccg tgctgaaagg cgtcaagctg cactacacct ga 3822
<210> 7
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 可切割的SARS-CoV-2刺突(S)蛋白(D614G突变)的核苷酸序列
<400> 7
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgac 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc gggacctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgctggccc tgcaccggag ctacctgacc cccggcgaca gcagcagcgg ctggaccgcc 780
ggcgctgccg cctattacgt gggctacctg caacctagaa ccttcctgct gaaatacaac 840
gagaacggca caatcaccga cgccgtggac tgtgccctgg accccctgtc tgagacaaag 900
tgtaccctga agtctttcac cgtggagaag ggcatctacc agaccagcaa cttccgggtg 960
cagcctacag aatctatagt gcggttccct aacatcacca acctgtgtcc ttttggcgag 1020
gtgttcaacg ccactcggtt cgcctctgtc tacgcctgga accggaaacg gatctctaat 1080
tgcgtggccg attacagcgt cctgtataac tccgccagtt tcagcacatt caagtgctac 1140
ggcgtgtcac ccaccaagct gaacgatctg tgcttcacca atgtgtacgc cgatagtttc 1200
gtgatccggg gcgatgaggt gcggcagatc gcccctggac agacaggcaa gatcgccgac 1260
tacaactaca agctgcctga cgacttcaca ggctgtgtga tcgcatggaa cagcaacaac 1320
ctggacagca aggtgggcgg aaactacaac tacctgtaca gactgttcag aaagtccaac 1380
ctgaagcctt tcgagagaga tatatctacc gagatctacc aggccggcag cacaccctgt 1440
aatggagtgg aaggctttaa ctgctacttc cctctgcaaa gctatggatt tcaacctaca 1500
aatggggttg gctaccagcc ttacagagtg gtggtcctta gcttcgagct gctccatgcc 1560
cctgccaccg tgtgcggacc taagaagtcc accaacctgg tgaaaaacaa gtgcgtgaac 1620
tttaatttta acggcctgac cggaacagga gtgctgacag aaagcaacaa aaagttcctg 1680
cctttccagc agttcggcag agacattgcc gacaccacag atgctgttag agacccccag 1740
acgctggaaa tcctggatat caccccctgc tcttttggcg gcgtgagcgt gatcacccca 1800
ggcacaaaca caagcaacca ggtggctgtg ctgtaccagg gcgtgaactg tacagaggtc 1860
cctgtggcaa tccacgccga tcagctgacc cctacatggc gggtgtactc cactggatct 1920
aacgtgttcc agacaagggc cggatgcctc atcggcgctg agcacgtgaa caattcttac 1980
gagtgcgaca tccctattgg agcgggcatc tgcgccagct accagacaca gaccaatagc 2040
cctcgcagag ccagaagcgt ggcctcccag agcatcatcg cctacaccat gagcctggga 2100
gccgagaact ctgtggccta cagcaacaac agcatcgcta tccctaccaa cttcaccatc 2160
tctgtcacca ccgaaatcct gcccgtcagt atgaccaaaa ccagcgtcga ctgcaccatg 2220
tacatatgcg gcgatagcac cgaatgcagc aacctgctgc tgcagtatgg ctccttctgc 2280
acccaactta acagagccct gactggcatc gccgtggagc aggacaagaa tacccaggag 2340
gtgttcgccc aggtgaagca gatctacaag acacccccga tcaaggactt cggcggcttt 2400
aatttctctc agatcctgcc agacccatct aaaccctcta agcggagctt tatcgaggac 2460
ctgctgttca acaaggtgac tctggctgac gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca ttgctgctag agacctgatc tgtgcccaga aattcaacgg tcttactgtg 2580
ctgcctcctc tgctgacgga tgagatgatc gcccagtaca ccagcgccct gctggccggc 2640
accatcacat ccggctggac attcggcgcc ggcgcagccc tgcagatccc ttttgccatg 2700
cagatggcct accggttcaa cggaatcgga gtgacacaga acgtgctcta cgaaaatcag 2760
aagttgatcg ccaaccagtt caacagcgcc atcggcaaga ttcaggatag tctgagttcc 2820
accgccagcg ccctgggaaa gctgcaggac gtggtcaatc agaatgccca agccctgaac 2880
accctggtga agcagctgag cagcaacttc ggcgccatca gctctgtgct gaacgacatc 2940
ctgagtagac tggacaaggt ggaagccgaa gtgcagatcg acagattgat caccggaaga 3000
ctgcaaagcc tgcagaccta cgtgacccag cagctgataa gagctgctga aatcagagcc 3060
agcgctaatc tggccgctac caagatgagc gagtgcgttc tgggccagtc taagagagtg 3120
gacttctgcg gaaaaggcta ccacctgatg tcctttcctc agtctgcccc ccacggcgtg 3180
gtgttcctgc acgtcacata cgtgcccgct caagagaaaa acttcaccac ggcccctgcc 3240
atctgtcacg acggcaaggc ccacttcccc agagagggcg tgttcgtgag caatggcacc 3300
cactggtttg tgactcagag aaacttctac gagccacaga ttatcaccac agataacacc 3360
ttcgtgtctg gcaactgcga cgtggtgatc ggcatcgtca acaacacagt gtacgaccca 3420
ctgcaacctg agctggactc attcaaggag gaactggata agtacttcaa gaatcacacc 3480
agccccgacg ttgacctggg cgacatcagc ggcattaacg cctctgtggt caacatccag 3540
aaggaaatcg acagactgaa tgaggtggcc aagaatttga acgagagcct gattgatctg 3600
caggagctgg gcaaatacga gcagtacatc aagtggcctt ggtacatctg gctgggcttc 3660
atcgccgggc tgatcgccat cgttatggtg acaatcatgc tgtgttgcat gacaagctgt 3720
tgtagctgcc tgaaaggctg ctgctcctgc ggcagctgtt gcaagtttga cgaagatgac 3780
agcgagcccg tgctgaaagg cgtcaagctg cactacacct ga 3822
<210> 8
<211> 1260
<212> DNA
<213> 人工序列
<220>
<223> 全长wt SARS-CoV-2核衣壳(N)蛋白的核苷酸序列
<400> 8
atgagcgaca acggacctca gaaccagaga aatgccccta gaatcacctt tggcggacct 60
agcgacagca ccggcagcaa ccagaatggc gagagaagcg gcgccagatc taagcagcgg 120
cgtccacagg gactgcccaa caacaccgcc agctggttca ccgccctcac ccagcacggc 180
aaagaggacc tgaagttccc ccggggacag ggcgtgccaa tcaacacaaa ctctagcccc 240
gacgaccaga tcggctacta tagacgggcc accagaagga tcagaggagg tgatggcaag 300
atgaaggacc tgagccctag atggtacttc tactacctgg gcacaggccc agaagccggc 360
ctgccttacg gcgccaacaa ggacggcatc atctgggtcg ccaccgaggg cgctctcaac 420
acccctaagg accacattgg aactcggaac cccgctaata acgccgctat cgtgctgcag 480
ctgcctcagg gcacgaccct gcccaagggc ttctacgccg aaggcagcag aggcggcagc 540
caggcctcta gccggtccag ctctcggagc agaaacagca gcagaaactc cacccctggc 600
agcagccgcg gcaccagccc cgccagaatg gccggaaatg gcggcgatgc cgctctggcc 660
ctgctgctgc tggatagact gaaccagctg gaatccaaga tgtctggcaa gggccagcag 720
caacagggcc agaccgtgac caagaaaagc gcagctgaag cctctaaaaa acctcggcag 780
aagcggaccg ccacaaaggc ttacaacgtg acacaggcct ttggcagaag aggacctgag 840
cagacacagg gcaacttcgg cgaccaggag ctgatccggc agggcacaga ctacaagcat 900
tggcctcaga tcgcccagtt cgcccctagt gccagcgcct tcttcggcat gagccggatc 960
ggcatggaag tgacccctag cggcacatgg ctgacctaca ccggcgccat caagctggac 1020
gataaggacc ccaattttaa ggaccaagtg atcctgctga acaagcacat cgacgcctat 1080
aagaccttcc cacctacaga gcctaagaaa gataagaaaa agaaggccga cgagacacaa 1140
gccctgcccc agagacagaa aaagcaacaa acagtgaccc tgctgcctgc cgctgatctg 1200
gatgacttca gcaagcagct gcagcaatct atgagctccg ccgatagcac ccaggcctga 1260
<210> 9
<211> 49
<212> DNA
<213> 人工序列
<220>
<223> 甲病毒属天然亚基因组启动子的核苷酸序列
<400> 9
ctctctacgg ctaacctgaa tggactacga catagtctag tccgccaag 49
<210> 10
<211> 14014
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co5的核苷酸序列
<400> 10
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcga 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgctggcc ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc 8340
cggcgctgcc gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa 8400
cgagaacggc acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa 8460
gtgtaccctg aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt 8520
gcagcctaca gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga 8580
ggtgttcaac gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa 8640
ttgcgtggcc gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta 8700
cggcgtgtca cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt 8760
cgtgatccgg ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga 8820
ctacaactac aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa 8880
cctggacagc aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa 8940
cctgaagcct ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg 9000
taatggagtg gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac 9060
aaatggggtt ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc 9120
ccctgccacc gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa 9180
ctttaatttt aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct 9240
gcctttccag cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca 9300
gacgctggaa atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc 9360
aggcacaaac acaagcaacc aggtggctgt gctgtaccag gacgtgaact gtacagaggt 9420
ccctgtggca atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc 9480
taacgtgttc cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta 9540
cgagtgcgac atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag 9600
ccctcgcaga gccagaagcg tggcctccca gagcatcatc gcctacacca tgagcctggg 9660
agccgagaac tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat 9720
ctctgtcacc accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat 9780
gtacatatgc ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg 9840
cacccaactt aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga 9900
ggtgttcgcc caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt 9960
taatttctct cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga 10020
cctgctgttc aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg 10080
cctgggcgac attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt 10140
gctgcctcct ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg 10200
caccatcaca tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat 10260
gcagatggcc taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca 10320
gaagttgatc gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc 10380
caccgccagc gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa 10440
caccctggtg aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat 10500
cctgagtaga ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag 10560
actgcaaagc ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc 10620
cagcgctaat ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt 10680
ggacttctgc ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt 10740
ggtgttcctg cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc 10800
catctgtcac gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac 10860
ccactggttt gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac 10920
cttcgtgtct ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc 10980
actgcaacct gagctggact cattcaagga ggaactggat aagtacttca agaatcacac 11040
cagccccgac gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca 11100
gaaggaaatc gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct 11160
gcaggagctg ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt 11220
catcgccggg ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg 11280
ttgtagctgc ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga 11340
cagcgagccc gtgctgaaag gcgtcaagct gcactacacc tgaggcgcgc ccacccagcg 11400
gccgcccgct acgccccaat gatccgacca gcaaaactcg atgtacttcc gaggaactga 11460
tgtgcataat gcatcaggct ggtacattag atccccgctt accgcgggca atatagcaac 11520
actaaaaact cgatgtactt ccgaggaagc gcagtgcata atgctgcgca gtgttgccac 11580
ataaccacta tattaaccat ttatctagcg gacgccaaaa actcaatgta tttctgagga 11640
agcgtggtgc ataatgccac gcagcgtctg cataactttt attatttctt ttattaatca 11700
acaaaatttt gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11760
agaagagcgt ttaaacacgt gatatctggc ctcatgggcc ttcctttcac tgcccgcttt 11820
ccagtcggga aacctgtcgt gccagctgca ttaacatggt catagctgtt tccttgcgta 11880
ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc gggtaaagcc 11940
tggggtgcct aatgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 12000
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 12060
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 12120
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 12180
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 12240
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 12300
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 12360
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 12420
tggtggccta actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag 12480
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 12540
agcggtggtt tttttgtttg caggcagcag attacgcgca gaaaaaaagg atctcaagaa 12600
gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 12660
attttggtca tgaatacacg gtgcctgact gcgttagcaa tttaactgtg ataaactacc 12720
gcattaaagc ttatcgatga taagctgtca aacatgagaa ttcttagaaa aactcatcga 12780
gcatcaaatg aaactgcaat ttattcatat caggattatc aataccatat ttttgaaaaa 12840
gccgtttctg taatgaagga gaaaactcac cgaggcagtt ccataggatg gcaagatcct 12900
ggtatcggtc tgcgattccg actcgtccaa catcaataca acctattaat ttcccctcgt 12960
caaaaataag gttatcaagt gagaaatcac catgagtgac gactgaatcc ggtgagaatg 13020
gcaaaagctt atgcatttct ttccagactt gttcaacagg ccagccatta cgctcgtcat 13080
caaaatcact cgcatcaacc aaaccgttat tcattcgtga ttgcgcctga gcgagacgaa 13140
atacgcgatc gctgttaaaa ggacaattac aaacaggaat cgaatgcaac cggcgcagga 13200
acactgccag cgcatcaaca atattttcac ctgaatcagg atattcttct aatacctgga 13260
atgctgtttt cccggggatc gcagtggtga gtaaccatgc atcatcagga gtacggataa 13320
aatgcttgat ggtcggaaga ggcataaatt ccgtcagcca gtttagtctg accatctcat 13380
ctgtaacatc attggcaacg ctacctttgc catgtttcag aaacaactct ggcgcatcgg 13440
gcttcccata caatcgatag attgtcgcac ctgattgccc gacattatcg cgagcccatt 13500
tatacccata taaatcagca tccatgttgg aatttaatcg cggcctcgag caagacgttt 13560
cccgttgaat atggctcata acaccccttg tattactgtt tatgtaagca gacagtttta 13620
ttgttcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg 13680
cgcacatttc cccgaaaagt gccacctaaa ttgtaagcgt taatattttg ttaaaattcg 13740
cgttaaattt ttgttaaatc agctcatttt ttaaccaata ggccgaaatc ggcaaaatcc 13800
cttataaatc aaaagaatag accgagatag ggttgagtgg ccgctacagg gcgctcccat 13860
tcgccattca ggctgcgcaa ctgttgggaa gggcgtttcg gtgcgggcct cttcgctatt 13920
acgccagctg gcgaaagggg gatgtgctgc aaggcgatta agttgggtaa cgccagggtt 13980
ttcccagtca cacgcgtaat acgactcact atag 14014
<210> 11
<211> 11452
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co6的核苷酸序列
<400> 11
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgagcgac aacggacctc agaaccagag aaatgcccct agaatcacct ttggcggacc 7620
tagcgacagc accggcagca accagaatgg cgagagaagc ggcgccagat ctaagcagcg 7680
gcgtccacag ggactgccca acaacaccgc cagctggttc accgccctca cccagcacgg 7740
caaagaggac ctgaagttcc cccggggaca gggcgtgcca atcaacacaa actctagccc 7800
cgacgaccag atcggctact atagacgggc caccagaagg atcagaggag gtgatggcaa 7860
gatgaaggac ctgagcccta gatggtactt ctactacctg ggcacaggcc cagaagccgg 7920
cctgccttac ggcgccaaca aggacggcat catctgggtc gccaccgagg gcgctctcaa 7980
cacccctaag gaccacattg gaactcggaa ccccgctaat aacgccgcta tcgtgctgca 8040
gctgcctcag ggcacgaccc tgcccaaggg cttctacgcc gaaggcagca gaggcggcag 8100
ccaggcctct agccggtcca gctctcggag cagaaacagc agcagaaact ccacccctgg 8160
cagcagccgc ggcaccagcc ccgccagaat ggccggaaat ggcggcgatg ccgctctggc 8220
cctgctgctg ctggatagac tgaaccagct ggaatccaag atgtctggca agggccagca 8280
gcaacagggc cagaccgtga ccaagaaaag cgcagctgaa gcctctaaaa aacctcggca 8340
gaagcggacc gccacaaagg cttacaacgt gacacaggcc tttggcagaa gaggacctga 8400
gcagacacag ggcaacttcg gcgaccagga gctgatccgg cagggcacag actacaagca 8460
ttggcctcag atcgcccagt tcgcccctag tgccagcgcc ttcttcggca tgagccggat 8520
cggcatggaa gtgaccccta gcggcacatg gctgacctac accggcgcca tcaagctgga 8580
cgataaggac cccaatttta aggaccaagt gatcctgctg aacaagcaca tcgacgccta 8640
taagaccttc ccacctacag agcctaagaa agataagaaa aagaaggccg acgagacaca 8700
agccctgccc cagagacaga aaaagcaaca aacagtgacc ctgctgcctg ccgctgatct 8760
ggatgacttc agcaagcagc tgcagcaatc tatgagctcc gccgatagca cccaggcctg 8820
aggcgcgccc acccagcggc cgcccgctac gccccaatga tccgaccagc aaaactcgat 8880
gtacttccga ggaactgatg tgcataatgc atcaggctgg tacattagat ccccgcttac 8940
cgcgggcaat atagcaacac taaaaactcg atgtacttcc gaggaagcgc agtgcataat 9000
gctgcgcagt gttgccacat aaccactata ttaaccattt atctagcgga cgccaaaaac 9060
tcaatgtatt tctgaggaag cgtggtgcat aatgccacgc agcgtctgca taacttttat 9120
tatttctttt attaatcaac aaaattttgt ttttaacatt tcaaaaaaaa aaaaaaaaaa 9180
aaaaaaaaaa aaaaaaaaag aagagcgttt aaacacgtga tatctggcct catgggcctt 9240
cctttcactg cccgctttcc agtcgggaaa cctgtcgtgc cagctgcatt aacatggtca 9300
tagctgtttc cttgcgtatt gggcgctctc cgcttcctcg ctcactgact cgctgcgctc 9360
ggtcgttcgg gtaaagcctg gggtgcctaa tgagcaaaag gccagcaaaa ggccaggaac 9420
cgtaaaaagg ccgcgttgct ggcgtttttc cataggctcc gcccccctga cgagcatcac 9480
aaaaatcgac gctcaagtca gaggtggcga aacccgacag gactataaag ataccaggcg 9540
tttccccctg gaagctccct cgtgcgctct cctgttccga ccctgccgct taccggatac 9600
ctgtccgcct ttctcccttc gggaagcgtg gcgctttctc atagctcacg ctgtaggtat 9660
ctcagttcgg tgtaggtcgt tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag 9720
cccgaccgct gcgccttatc cggtaactat cgtcttgagt ccaacccggt aagacacgac 9780
ttatcgccac tggcagcagc cactggtaac aggattagca gagcgaggta tgtaggcggt 9840
gctacagagt tcttgaagtg gtggcctaac tacggctaca ctagaagaac agtatttggt 9900
atctgcgctc tgctgaagcc agttaccttc ggaaaaagag ttggtagctc ttgatccggc 9960
aaacaaacca ccgctggtag cggtggtttt tttgtttgca ggcagcagat tacgcgcaga 10020
aaaaaaggat ctcaagaaga tcctttgatc ttttctacgg ggtctgacgc tcagtggaac 10080
gaaaactcac gttaagggat tttggtcatg aatacacggt gcctgactgc gttagcaatt 10140
taactgtgat aaactaccgc attaaagctt atcgatgata agctgtcaaa catgagaatt 10200
cttagaaaaa ctcatcgagc atcaaatgaa actgcaattt attcatatca ggattatcaa 10260
taccatattt ttgaaaaagc cgtttctgta atgaaggaga aaactcaccg aggcagttcc 10320
ataggatggc aagatcctgg tatcggtctg cgattccgac tcgtccaaca tcaatacaac 10380
ctattaattt cccctcgtca aaaataaggt tatcaagtga gaaatcacca tgagtgacga 10440
ctgaatccgg tgagaatggc aaaagcttat gcatttcttt ccagacttgt tcaacaggcc 10500
agccattacg ctcgtcatca aaatcactcg catcaaccaa accgttattc attcgtgatt 10560
gcgcctgagc gagacgaaat acgcgatcgc tgttaaaagg acaattacaa acaggaatcg 10620
aatgcaaccg gcgcaggaac actgccagcg catcaacaat attttcacct gaatcaggat 10680
attcttctaa tacctggaat gctgttttcc cggggatcgc agtggtgagt aaccatgcat 10740
catcaggagt acggataaaa tgcttgatgg tcggaagagg cataaattcc gtcagccagt 10800
ttagtctgac catctcatct gtaacatcat tggcaacgct acctttgcca tgtttcagaa 10860
acaactctgg cgcatcgggc ttcccataca atcgatagat tgtcgcacct gattgcccga 10920
cattatcgcg agcccattta tacccatata aatcagcatc catgttggaa tttaatcgcg 10980
gcctcgagca agacgtttcc cgttgaatat ggctcataac accccttgta ttactgttta 11040
tgtaagcaga cagttttatt gttcatgagc ggatacatat ttgaatgtat ttagaaaaat 11100
aaacaaatag gggttccgcg cacatttccc cgaaaagtgc cacctaaatt gtaagcgtta 11160
atattttgtt aaaattcgcg ttaaattttt gttaaatcag ctcatttttt aaccaatagg 11220
ccgaaatcgg caaaatccct tataaatcaa aagaatagac cgagataggg ttgagtggcc 11280
gctacagggc gctcccattc gccattcagg ctgcgcaact gttgggaagg gcgtttcggt 11340
gcgggcctct tcgctattac gccagctggc gaaaggggga tgtgctgcaa ggcgattaag 11400
ttgggtaacg ccagggtttt cccagtcaca cgcgtaatac gactcactat ag 11452
<210> 12
<211> 14014
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co16的核苷酸序列
<400> 12
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcga 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgctggcc ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc 8340
cggcgctgcc gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa 8400
cgagaacggc acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa 8460
gtgtaccctg aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt 8520
gcagcctaca gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga 8580
ggtgttcaac gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa 8640
ttgcgtggcc gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta 8700
cggcgtgtca cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt 8760
cgtgatccgg ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga 8820
ctacaactac aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa 8880
cctggacagc aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa 8940
cctgaagcct ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg 9000
taatggagtg gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac 9060
aaatggggtt ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc 9120
ccctgccacc gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa 9180
ctttaatttt aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct 9240
gcctttccag cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca 9300
gacgctggaa atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc 9360
aggcacaaac acaagcaacc aggtggctgt gctgtaccag gacgtgaact gtacagaggt 9420
ccctgtggca atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc 9480
taacgtgttc cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta 9540
cgagtgcgac atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag 9600
ccctcagcaa gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg 9660
agccgagaac tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat 9720
ctctgtcacc accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat 9780
gtacatatgc ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg 9840
cacccaactt aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga 9900
ggtgttcgcc caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt 9960
taatttctct cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga 10020
cctgctgttc aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg 10080
cctgggcgac attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt 10140
gctgcctcct ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg 10200
caccatcaca tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat 10260
gcagatggcc taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca 10320
gaagttgatc gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc 10380
caccgccagc gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa 10440
caccctggtg aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat 10500
cctgagtaga ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag 10560
actgcaaagc ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc 10620
cagcgctaat ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt 10680
ggacttctgc ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt 10740
ggtgttcctg cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc 10800
catctgtcac gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac 10860
ccactggttt gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac 10920
cttcgtgtct ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc 10980
actgcaacct gagctggact cattcaagga ggaactggat aagtacttca agaatcacac 11040
cagccccgac gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca 11100
gaaggaaatc gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct 11160
gcaggagctg ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt 11220
catcgccggg ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg 11280
ttgtagctgc ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga 11340
cagcgagccc gtgctgaaag gcgtcaagct gcactacacc tgaggcgcgc ccacccagcg 11400
gccgcccgct acgccccaat gatccgacca gcaaaactcg atgtacttcc gaggaactga 11460
tgtgcataat gcatcaggct ggtacattag atccccgctt accgcgggca atatagcaac 11520
actaaaaact cgatgtactt ccgaggaagc gcagtgcata atgctgcgca gtgttgccac 11580
ataaccacta tattaaccat ttatctagcg gacgccaaaa actcaatgta tttctgagga 11640
agcgtggtgc ataatgccac gcagcgtctg cataactttt attatttctt ttattaatca 11700
acaaaatttt gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11760
agaagagcgt ttaaacacgt gatatctggc ctcatgggcc ttcctttcac tgcccgcttt 11820
ccagtcggga aacctgtcgt gccagctgca ttaacatggt catagctgtt tccttgcgta 11880
ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc gggtaaagcc 11940
tggggtgcct aatgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 12000
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 12060
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 12120
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 12180
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 12240
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 12300
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 12360
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 12420
tggtggccta actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag 12480
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 12540
agcggtggtt tttttgtttg caggcagcag attacgcgca gaaaaaaagg atctcaagaa 12600
gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 12660
attttggtca tgaatacacg gtgcctgact gcgttagcaa tttaactgtg ataaactacc 12720
gcattaaagc ttatcgatga taagctgtca aacatgagaa ttcttagaaa aactcatcga 12780
gcatcaaatg aaactgcaat ttattcatat caggattatc aataccatat ttttgaaaaa 12840
gccgtttctg taatgaagga gaaaactcac cgaggcagtt ccataggatg gcaagatcct 12900
ggtatcggtc tgcgattccg actcgtccaa catcaataca acctattaat ttcccctcgt 12960
caaaaataag gttatcaagt gagaaatcac catgagtgac gactgaatcc ggtgagaatg 13020
gcaaaagctt atgcatttct ttccagactt gttcaacagg ccagccatta cgctcgtcat 13080
caaaatcact cgcatcaacc aaaccgttat tcattcgtga ttgcgcctga gcgagacgaa 13140
atacgcgatc gctgttaaaa ggacaattac aaacaggaat cgaatgcaac cggcgcagga 13200
acactgccag cgcatcaaca atattttcac ctgaatcagg atattcttct aatacctgga 13260
atgctgtttt cccggggatc gcagtggtga gtaaccatgc atcatcagga gtacggataa 13320
aatgcttgat ggtcggaaga ggcataaatt ccgtcagcca gtttagtctg accatctcat 13380
ctgtaacatc attggcaacg ctacctttgc catgtttcag aaacaactct ggcgcatcgg 13440
gcttcccata caatcgatag attgtcgcac ctgattgccc gacattatcg cgagcccatt 13500
tatacccata taaatcagca tccatgttgg aatttaatcg cggcctcgag caagacgttt 13560
cccgttgaat atggctcata acaccccttg tattactgtt tatgtaagca gacagtttta 13620
ttgttcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg 13680
cgcacatttc cccgaaaagt gccacctaaa ttgtaagcgt taatattttg ttaaaattcg 13740
cgttaaattt ttgttaaatc agctcatttt ttaaccaata ggccgaaatc ggcaaaatcc 13800
cttataaatc aaaagaatag accgagatag ggttgagtgg ccgctacagg gcgctcccat 13860
tcgccattca ggctgcgcaa ctgttgggaa gggcgtttcg gtgcgggcct cttcgctatt 13920
acgccagctg gcgaaagggg gatgtgctgc aaggcgatta agttgggtaa cgccagggtt 13980
ttcccagtca cacgcgtaat acgactcact atag 14014
<210> 13
<211> 14014
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co17的核苷酸序列
<400> 13
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcga 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgctggcc ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc 8340
cggcgctgcc gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa 8400
cgagaacggc acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa 8460
gtgtaccctg aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt 8520
gcagcctaca gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga 8580
ggtgttcaac gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa 8640
ttgcgtggcc gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta 8700
cggcgtgtca cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt 8760
cgtgatccgg ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga 8820
ctacaactac aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa 8880
cctggacagc aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa 8940
cctgaagcct ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg 9000
taatggagtg gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac 9060
aaatggggtt ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc 9120
ccctgccacc gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa 9180
ctttaatttt aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct 9240
gcctttccag cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca 9300
gacgctggaa atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc 9360
aggcacaaac acaagcaacc aggtggctgt gctgtaccag gacgtgaact gtacagaggt 9420
ccctgtggca atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc 9480
taacgtgttc cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta 9540
cgagtgcgac atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag 9600
ccctcagcaa gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg 9660
agccgagaac tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat 9720
ctctgtcacc accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat 9780
gtacatatgc ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg 9840
cacccaactt aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga 9900
ggtgttcgcc caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt 9960
taatttctct cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga 10020
cctgctgttc aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg 10080
cctgggcgac attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt 10140
gctgcctcct ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg 10200
caccatcaca tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat 10260
gcagatggcc taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca 10320
gaagttgatc gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc 10380
caccgccagc gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa 10440
caccctggtg aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat 10500
cctgagtaga ctggacccac ctgaagccga agtgcagatc gacagattga tcaccggaag 10560
actgcaaagc ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc 10620
cagcgctaat ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt 10680
ggacttctgc ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt 10740
ggtgttcctg cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc 10800
catctgtcac gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac 10860
ccactggttt gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac 10920
cttcgtgtct ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc 10980
actgcaacct gagctggact cattcaagga ggaactggat aagtacttca agaatcacac 11040
cagccccgac gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca 11100
gaaggaaatc gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct 11160
gcaggagctg ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt 11220
catcgccggg ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg 11280
ttgtagctgc ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga 11340
cagcgagccc gtgctgaaag gcgtcaagct gcactacacc tgaggcgcgc ccacccagcg 11400
gccgcccgct acgccccaat gatccgacca gcaaaactcg atgtacttcc gaggaactga 11460
tgtgcataat gcatcaggct ggtacattag atccccgctt accgcgggca atatagcaac 11520
actaaaaact cgatgtactt ccgaggaagc gcagtgcata atgctgcgca gtgttgccac 11580
ataaccacta tattaaccat ttatctagcg gacgccaaaa actcaatgta tttctgagga 11640
agcgtggtgc ataatgccac gcagcgtctg cataactttt attatttctt ttattaatca 11700
acaaaatttt gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11760
agaagagcgt ttaaacacgt gatatctggc ctcatgggcc ttcctttcac tgcccgcttt 11820
ccagtcggga aacctgtcgt gccagctgca ttaacatggt catagctgtt tccttgcgta 11880
ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc gggtaaagcc 11940
tggggtgcct aatgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 12000
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 12060
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 12120
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 12180
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 12240
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 12300
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 12360
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 12420
tggtggccta actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag 12480
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 12540
agcggtggtt tttttgtttg caggcagcag attacgcgca gaaaaaaagg atctcaagaa 12600
gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 12660
attttggtca tgaatacacg gtgcctgact gcgttagcaa tttaactgtg ataaactacc 12720
gcattaaagc ttatcgatga taagctgtca aacatgagaa ttcttagaaa aactcatcga 12780
gcatcaaatg aaactgcaat ttattcatat caggattatc aataccatat ttttgaaaaa 12840
gccgtttctg taatgaagga gaaaactcac cgaggcagtt ccataggatg gcaagatcct 12900
ggtatcggtc tgcgattccg actcgtccaa catcaataca acctattaat ttcccctcgt 12960
caaaaataag gttatcaagt gagaaatcac catgagtgac gactgaatcc ggtgagaatg 13020
gcaaaagctt atgcatttct ttccagactt gttcaacagg ccagccatta cgctcgtcat 13080
caaaatcact cgcatcaacc aaaccgttat tcattcgtga ttgcgcctga gcgagacgaa 13140
atacgcgatc gctgttaaaa ggacaattac aaacaggaat cgaatgcaac cggcgcagga 13200
acactgccag cgcatcaaca atattttcac ctgaatcagg atattcttct aatacctgga 13260
atgctgtttt cccggggatc gcagtggtga gtaaccatgc atcatcagga gtacggataa 13320
aatgcttgat ggtcggaaga ggcataaatt ccgtcagcca gtttagtctg accatctcat 13380
ctgtaacatc attggcaacg ctacctttgc catgtttcag aaacaactct ggcgcatcgg 13440
gcttcccata caatcgatag attgtcgcac ctgattgccc gacattatcg cgagcccatt 13500
tatacccata taaatcagca tccatgttgg aatttaatcg cggcctcgag caagacgttt 13560
cccgttgaat atggctcata acaccccttg tattactgtt tatgtaagca gacagtttta 13620
ttgttcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg 13680
cgcacatttc cccgaaaagt gccacctaaa ttgtaagcgt taatattttg ttaaaattcg 13740
cgttaaattt ttgttaaatc agctcatttt ttaaccaata ggccgaaatc ggcaaaatcc 13800
cttataaatc aaaagaatag accgagatag ggttgagtgg ccgctacagg gcgctcccat 13860
tcgccattca ggctgcgcaa ctgttgggaa gggcgtttcg gtgcgggcct cttcgctatt 13920
acgccagctg gcgaaagggg gatgtgctgc aaggcgatta agttgggtaa cgccagggtt 13980
ttcccagtca cacgcgtaat acgactcact atag 14014
<210> 14
<211> 14014
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co48的核苷酸序列
<400> 14
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcga 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgctggcc ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc 8340
cggcgctgcc gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa 8400
cgagaacggc acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa 8460
gtgtaccctg aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt 8520
gcagcctaca gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga 8580
ggtgttcaac gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa 8640
ttgcgtggcc gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta 8700
cggcgtgtca cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt 8760
cgtgatccgg ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga 8820
ctacaactac aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa 8880
cctggacagc aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa 8940
cctgaagcct ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg 9000
taatggagtg gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac 9060
aaatggggtt ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc 9120
ccctgccacc gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa 9180
ctttaatttt aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct 9240
gcctttccag cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca 9300
gacgctggaa atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc 9360
aggcacaaac acaagcaacc aggtggctgt gctgtaccag ggcgtgaact gtacagaggt 9420
ccctgtggca atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc 9480
taacgtgttc cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta 9540
cgagtgcgac atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag 9600
ccctcgcaga gccagaagcg tggcctccca gagcatcatc gcctacacca tgagcctggg 9660
agccgagaac tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat 9720
ctctgtcacc accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat 9780
gtacatatgc ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg 9840
cacccaactt aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga 9900
ggtgttcgcc caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt 9960
taatttctct cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga 10020
cctgctgttc aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg 10080
cctgggcgac attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt 10140
gctgcctcct ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg 10200
caccatcaca tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat 10260
gcagatggcc taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca 10320
gaagttgatc gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc 10380
caccgccagc gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa 10440
caccctggtg aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat 10500
cctgagtaga ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag 10560
actgcaaagc ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc 10620
cagcgctaat ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt 10680
ggacttctgc ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt 10740
ggtgttcctg cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc 10800
catctgtcac gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac 10860
ccactggttt gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac 10920
cttcgtgtct ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc 10980
actgcaacct gagctggact cattcaagga ggaactggat aagtacttca agaatcacac 11040
cagccccgac gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca 11100
gaaggaaatc gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct 11160
gcaggagctg ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt 11220
catcgccggg ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg 11280
ttgtagctgc ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga 11340
cagcgagccc gtgctgaaag gcgtcaagct gcactacacc tgaggcgcgc ccacccagcg 11400
gccgcccgct acgccccaat gatccgacca gcaaaactcg atgtacttcc gaggaactga 11460
tgtgcataat gcatcaggct ggtacattag atccccgctt accgcgggca atatagcaac 11520
actaaaaact cgatgtactt ccgaggaagc gcagtgcata atgctgcgca gtgttgccac 11580
ataaccacta tattaaccat ttatctagcg gacgccaaaa actcaatgta tttctgagga 11640
agcgtggtgc ataatgccac gcagcgtctg cataactttt attatttctt ttattaatca 11700
acaaaatttt gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11760
agaagagcgt ttaaacacgt gatatctggc ctcatgggcc ttcctttcac tgcccgcttt 11820
ccagtcggga aacctgtcgt gccagctgca ttaacatggt catagctgtt tccttgcgta 11880
ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc gggtaaagcc 11940
tggggtgcct aatgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 12000
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 12060
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 12120
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 12180
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 12240
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 12300
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 12360
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 12420
tggtggccta actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag 12480
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 12540
agcggtggtt tttttgtttg caggcagcag attacgcgca gaaaaaaagg atctcaagaa 12600
gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 12660
attttggtca tgaatacacg gtgcctgact gcgttagcaa tttaactgtg ataaactacc 12720
gcattaaagc ttatcgatga taagctgtca aacatgagaa ttcttagaaa aactcatcga 12780
gcatcaaatg aaactgcaat ttattcatat caggattatc aataccatat ttttgaaaaa 12840
gccgtttctg taatgaagga gaaaactcac cgaggcagtt ccataggatg gcaagatcct 12900
ggtatcggtc tgcgattccg actcgtccaa catcaataca acctattaat ttcccctcgt 12960
caaaaataag gttatcaagt gagaaatcac catgagtgac gactgaatcc ggtgagaatg 13020
gcaaaagctt atgcatttct ttccagactt gttcaacagg ccagccatta cgctcgtcat 13080
caaaatcact cgcatcaacc aaaccgttat tcattcgtga ttgcgcctga gcgagacgaa 13140
atacgcgatc gctgttaaaa ggacaattac aaacaggaat cgaatgcaac cggcgcagga 13200
acactgccag cgcatcaaca atattttcac ctgaatcagg atattcttct aatacctgga 13260
atgctgtttt cccggggatc gcagtggtga gtaaccatgc atcatcagga gtacggataa 13320
aatgcttgat ggtcggaaga ggcataaatt ccgtcagcca gtttagtctg accatctcat 13380
ctgtaacatc attggcaacg ctacctttgc catgtttcag aaacaactct ggcgcatcgg 13440
gcttcccata caatcgatag attgtcgcac ctgattgccc gacattatcg cgagcccatt 13500
tatacccata taaatcagca tccatgttgg aatttaatcg cggcctcgag caagacgttt 13560
cccgttgaat atggctcata acaccccttg tattactgtt tatgtaagca gacagtttta 13620
ttgttcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg 13680
cgcacatttc cccgaaaagt gccacctaaa ttgtaagcgt taatattttg ttaaaattcg 13740
cgttaaattt ttgttaaatc agctcatttt ttaaccaata ggccgaaatc ggcaaaatcc 13800
cttataaatc aaaagaatag accgagatag ggttgagtgg ccgctacagg gcgctcccat 13860
tcgccattca ggctgcgcaa ctgttgggaa gggcgtttcg gtgcgggcct cttcgctatt 13920
acgccagctg gcgaaagggg gatgtgctgc aaggcgatta agttgggtaa cgccagggtt 13980
ttcccagtca cacgcgtaat acgactcact atag 14014
<210> 15
<211> 14014
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co49的核苷酸序列
<400> 15
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcga 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgctggcc ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc 8340
cggcgctgcc gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa 8400
cgagaacggc acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa 8460
gtgtaccctg aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt 8520
gcagcctaca gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga 8580
ggtgttcaac gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa 8640
ttgcgtggcc gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta 8700
cggcgtgtca cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt 8760
cgtgatccgg ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga 8820
ctacaactac aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa 8880
cctggacagc aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa 8940
cctgaagcct ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg 9000
taatggagtg gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac 9060
aaatggggtt ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc 9120
ccctgccacc gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa 9180
ctttaatttt aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct 9240
gcctttccag cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca 9300
gacgctggaa atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc 9360
aggcacaaac acaagcaacc aggtggctgt gctgtaccag ggcgtgaact gtacagaggt 9420
ccctgtggca atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc 9480
taacgtgttc cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta 9540
cgagtgcgac atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag 9600
ccctcagcaa gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg 9660
agccgagaac tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat 9720
ctctgtcacc accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat 9780
gtacatatgc ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg 9840
cacccaactt aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga 9900
ggtgttcgcc caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt 9960
taatttctct cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga 10020
cctgctgttc aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg 10080
cctgggcgac attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt 10140
gctgcctcct ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg 10200
caccatcaca tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat 10260
gcagatggcc taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca 10320
gaagttgatc gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc 10380
caccgccagc gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa 10440
caccctggtg aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat 10500
cctgagtaga ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag 10560
actgcaaagc ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc 10620
cagcgctaat ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt 10680
ggacttctgc ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt 10740
ggtgttcctg cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc 10800
catctgtcac gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac 10860
ccactggttt gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac 10920
cttcgtgtct ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc 10980
actgcaacct gagctggact cattcaagga ggaactggat aagtacttca agaatcacac 11040
cagccccgac gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca 11100
gaaggaaatc gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct 11160
gcaggagctg ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt 11220
catcgccggg ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg 11280
ttgtagctgc ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga 11340
cagcgagccc gtgctgaaag gcgtcaagct gcactacacc tgaggcgcgc ccacccagcg 11400
gccgcccgct acgccccaat gatccgacca gcaaaactcg atgtacttcc gaggaactga 11460
tgtgcataat gcatcaggct ggtacattag atccccgctt accgcgggca atatagcaac 11520
actaaaaact cgatgtactt ccgaggaagc gcagtgcata atgctgcgca gtgttgccac 11580
ataaccacta tattaaccat ttatctagcg gacgccaaaa actcaatgta tttctgagga 11640
agcgtggtgc ataatgccac gcagcgtctg cataactttt attatttctt ttattaatca 11700
acaaaatttt gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11760
agaagagcgt ttaaacacgt gatatctggc ctcatgggcc ttcctttcac tgcccgcttt 11820
ccagtcggga aacctgtcgt gccagctgca ttaacatggt catagctgtt tccttgcgta 11880
ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc gggtaaagcc 11940
tggggtgcct aatgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 12000
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 12060
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 12120
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 12180
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 12240
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 12300
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 12360
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 12420
tggtggccta actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag 12480
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 12540
agcggtggtt tttttgtttg caggcagcag attacgcgca gaaaaaaagg atctcaagaa 12600
gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 12660
attttggtca tgaatacacg gtgcctgact gcgttagcaa tttaactgtg ataaactacc 12720
gcattaaagc ttatcgatga taagctgtca aacatgagaa ttcttagaaa aactcatcga 12780
gcatcaaatg aaactgcaat ttattcatat caggattatc aataccatat ttttgaaaaa 12840
gccgtttctg taatgaagga gaaaactcac cgaggcagtt ccataggatg gcaagatcct 12900
ggtatcggtc tgcgattccg actcgtccaa catcaataca acctattaat ttcccctcgt 12960
caaaaataag gttatcaagt gagaaatcac catgagtgac gactgaatcc ggtgagaatg 13020
gcaaaagctt atgcatttct ttccagactt gttcaacagg ccagccatta cgctcgtcat 13080
caaaatcact cgcatcaacc aaaccgttat tcattcgtga ttgcgcctga gcgagacgaa 13140
atacgcgatc gctgttaaaa ggacaattac aaacaggaat cgaatgcaac cggcgcagga 13200
acactgccag cgcatcaaca atattttcac ctgaatcagg atattcttct aatacctgga 13260
atgctgtttt cccggggatc gcagtggtga gtaaccatgc atcatcagga gtacggataa 13320
aatgcttgat ggtcggaaga ggcataaatt ccgtcagcca gtttagtctg accatctcat 13380
ctgtaacatc attggcaacg ctacctttgc catgtttcag aaacaactct ggcgcatcgg 13440
gcttcccata caatcgatag attgtcgcac ctgattgccc gacattatcg cgagcccatt 13500
tatacccata taaatcagca tccatgttgg aatttaatcg cggcctcgag caagacgttt 13560
cccgttgaat atggctcata acaccccttg tattactgtt tatgtaagca gacagtttta 13620
ttgttcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg 13680
cgcacatttc cccgaaaagt gccacctaaa ttgtaagcgt taatattttg ttaaaattcg 13740
cgttaaattt ttgttaaatc agctcatttt ttaaccaata ggccgaaatc ggcaaaatcc 13800
cttataaatc aaaagaatag accgagatag ggttgagtgg ccgctacagg gcgctcccat 13860
tcgccattca ggctgcgcaa ctgttgggaa gggcgtttcg gtgcgggcct cttcgctatt 13920
acgccagctg gcgaaagggg gatgtgctgc aaggcgatta agttgggtaa cgccagggtt 13980
ttcccagtca cacgcgtaat acgactcact atag 14014
<210> 16
<211> 14014
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co58的核苷酸序列
<400> 16
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcga 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgctggcc ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc 8340
cggcgctgcc gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa 8400
cgagaacggc acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa 8460
gtgtaccctg aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt 8520
gcagcctaca gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga 8580
ggtgttcaac gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa 8640
ttgcgtggcc gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta 8700
cggcgtgtca cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt 8760
cgtgatccgg ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga 8820
ctacaactac aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa 8880
cctggacagc aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa 8940
cctgaagcct ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg 9000
taatggagtg gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac 9060
aaatggggtt ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc 9120
ccctgccacc gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa 9180
ctttaatttt aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct 9240
gcctttccag cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca 9300
gacgctggaa atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc 9360
aggcacaaac acaagcaacc aggtggctgt gctgtaccag gacgtgaact gtacagaggt 9420
ccctgtggca atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc 9480
taacgtgttc cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta 9540
cgagtgcgac atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag 9600
ccctcagcaa gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg 9660
agccgagaac tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat 9720
ctctgtcacc accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat 9780
gtacatatgc ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg 9840
cacccaactt aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga 9900
ggtgttcgcc caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt 9960
taatttctct cagatcctgc cagacccatc taaaccctct aagaacagct ttatcgagga 10020
cctgctgttc aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg 10080
cctgggcgac attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt 10140
gctgcctcct ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg 10200
caccatcaca tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat 10260
gcagatggcc taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca 10320
gaagttgatc gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc 10380
caccgccagc gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa 10440
caccctggtg aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat 10500
cctgagtaga ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag 10560
actgcaaagc ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc 10620
cagcgctaat ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt 10680
ggacttctgc ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt 10740
ggtgttcctg cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc 10800
catctgtcac gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac 10860
ccactggttt gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac 10920
cttcgtgtct ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc 10980
actgcaacct gagctggact cattcaagga ggaactggat aagtacttca agaatcacac 11040
cagccccgac gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca 11100
gaaggaaatc gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct 11160
gcaggagctg ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt 11220
catcgccggg ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg 11280
ttgtagctgc ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga 11340
cagcgagccc gtgctgaaag gcgtcaagct gcactacacc tgaggcgcgc ccacccagcg 11400
gccgcccgct acgccccaat gatccgacca gcaaaactcg atgtacttcc gaggaactga 11460
tgtgcataat gcatcaggct ggtacattag atccccgctt accgcgggca atatagcaac 11520
actaaaaact cgatgtactt ccgaggaagc gcagtgcata atgctgcgca gtgttgccac 11580
ataaccacta tattaaccat ttatctagcg gacgccaaaa actcaatgta tttctgagga 11640
agcgtggtgc ataatgccac gcagcgtctg cataactttt attatttctt ttattaatca 11700
acaaaatttt gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11760
agaagagcgt ttaaacacgt gatatctggc ctcatgggcc ttcctttcac tgcccgcttt 11820
ccagtcggga aacctgtcgt gccagctgca ttaacatggt catagctgtt tccttgcgta 11880
ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc gggtaaagcc 11940
tggggtgcct aatgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 12000
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 12060
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 12120
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 12180
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 12240
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 12300
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 12360
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 12420
tggtggccta actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag 12480
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 12540
agcggtggtt tttttgtttg caggcagcag attacgcgca gaaaaaaagg atctcaagaa 12600
gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 12660
attttggtca tgaatacacg gtgcctgact gcgttagcaa tttaactgtg ataaactacc 12720
gcattaaagc ttatcgatga taagctgtca aacatgagaa ttcttagaaa aactcatcga 12780
gcatcaaatg aaactgcaat ttattcatat caggattatc aataccatat ttttgaaaaa 12840
gccgtttctg taatgaagga gaaaactcac cgaggcagtt ccataggatg gcaagatcct 12900
ggtatcggtc tgcgattccg actcgtccaa catcaataca acctattaat ttcccctcgt 12960
caaaaataag gttatcaagt gagaaatcac catgagtgac gactgaatcc ggtgagaatg 13020
gcaaaagctt atgcatttct ttccagactt gttcaacagg ccagccatta cgctcgtcat 13080
caaaatcact cgcatcaacc aaaccgttat tcattcgtga ttgcgcctga gcgagacgaa 13140
atacgcgatc gctgttaaaa ggacaattac aaacaggaat cgaatgcaac cggcgcagga 13200
acactgccag cgcatcaaca atattttcac ctgaatcagg atattcttct aatacctgga 13260
atgctgtttt cccggggatc gcagtggtga gtaaccatgc atcatcagga gtacggataa 13320
aatgcttgat ggtcggaaga ggcataaatt ccgtcagcca gtttagtctg accatctcat 13380
ctgtaacatc attggcaacg ctacctttgc catgtttcag aaacaactct ggcgcatcgg 13440
gcttcccata caatcgatag attgtcgcac ctgattgccc gacattatcg cgagcccatt 13500
tatacccata taaatcagca tccatgttgg aatttaatcg cggcctcgag caagacgttt 13560
cccgttgaat atggctcata acaccccttg tattactgtt tatgtaagca gacagtttta 13620
ttgttcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg 13680
cgcacatttc cccgaaaagt gccacctaaa ttgtaagcgt taatattttg ttaaaattcg 13740
cgttaaattt ttgttaaatc agctcatttt ttaaccaata ggccgaaatc ggcaaaatcc 13800
cttataaatc aaaagaatag accgagatag ggttgagtgg ccgctacagg gcgctcccat 13860
tcgccattca ggctgcgcaa ctgttgggaa gggcgtttcg gtgcgggcct cttcgctatt 13920
acgccagctg gcgaaagggg gatgtgctgc aaggcgatta agttgggtaa cgccagggtt 13980
ttcccagtca cacgcgtaat acgactcact atag 14014
<210> 17
<211> 14014
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co59的核苷酸序列
<400> 17
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcga 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgctggcc ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc 8340
cggcgctgcc gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa 8400
cgagaacggc acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa 8460
gtgtaccctg aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt 8520
gcagcctaca gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga 8580
ggtgttcaac gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa 8640
ttgcgtggcc gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta 8700
cggcgtgtca cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt 8760
cgtgatccgg ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga 8820
ctacaactac aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa 8880
cctggacagc aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa 8940
cctgaagcct ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg 9000
taatggagtg gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac 9060
aaatggggtt ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc 9120
ccctgccacc gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa 9180
ctttaatttt aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct 9240
gcctttccag cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca 9300
gacgctggaa atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc 9360
aggcacaaac acaagcaacc aggtggctgt gctgtaccag ggcgtgaact gtacagaggt 9420
ccctgtggca atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc 9480
taacgtgttc cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta 9540
cgagtgcgac atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag 9600
ccctcagcaa gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg 9660
agccgagaac tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat 9720
ctctgtcacc accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat 9780
gtacatatgc ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg 9840
cacccaactt aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga 9900
ggtgttcgcc caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt 9960
taatttctct cagatcctgc cagacccatc taaaccctct aagaacagct ttatcgagga 10020
cctgctgttc aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg 10080
cctgggcgac attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt 10140
gctgcctcct ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg 10200
caccatcaca tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat 10260
gcagatggcc taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca 10320
gaagttgatc gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc 10380
caccgccagc gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa 10440
caccctggtg aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat 10500
cctgagtaga ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag 10560
actgcaaagc ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc 10620
cagcgctaat ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt 10680
ggacttctgc ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt 10740
ggtgttcctg cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc 10800
catctgtcac gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac 10860
ccactggttt gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac 10920
cttcgtgtct ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc 10980
actgcaacct gagctggact cattcaagga ggaactggat aagtacttca agaatcacac 11040
cagccccgac gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca 11100
gaaggaaatc gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct 11160
gcaggagctg ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt 11220
catcgccggg ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg 11280
ttgtagctgc ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga 11340
cagcgagccc gtgctgaaag gcgtcaagct gcactacacc tgaggcgcgc ccacccagcg 11400
gccgcccgct acgccccaat gatccgacca gcaaaactcg atgtacttcc gaggaactga 11460
tgtgcataat gcatcaggct ggtacattag atccccgctt accgcgggca atatagcaac 11520
actaaaaact cgatgtactt ccgaggaagc gcagtgcata atgctgcgca gtgttgccac 11580
ataaccacta tattaaccat ttatctagcg gacgccaaaa actcaatgta tttctgagga 11640
agcgtggtgc ataatgccac gcagcgtctg cataactttt attatttctt ttattaatca 11700
acaaaatttt gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11760
agaagagcgt ttaaacacgt gatatctggc ctcatgggcc ttcctttcac tgcccgcttt 11820
ccagtcggga aacctgtcgt gccagctgca ttaacatggt catagctgtt tccttgcgta 11880
ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc gggtaaagcc 11940
tggggtgcct aatgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 12000
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 12060
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 12120
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 12180
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 12240
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 12300
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 12360
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 12420
tggtggccta actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag 12480
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 12540
agcggtggtt tttttgtttg caggcagcag attacgcgca gaaaaaaagg atctcaagaa 12600
gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 12660
attttggtca tgaatacacg gtgcctgact gcgttagcaa tttaactgtg ataaactacc 12720
gcattaaagc ttatcgatga taagctgtca aacatgagaa ttcttagaaa aactcatcga 12780
gcatcaaatg aaactgcaat ttattcatat caggattatc aataccatat ttttgaaaaa 12840
gccgtttctg taatgaagga gaaaactcac cgaggcagtt ccataggatg gcaagatcct 12900
ggtatcggtc tgcgattccg actcgtccaa catcaataca acctattaat ttcccctcgt 12960
caaaaataag gttatcaagt gagaaatcac catgagtgac gactgaatcc ggtgagaatg 13020
gcaaaagctt atgcatttct ttccagactt gttcaacagg ccagccatta cgctcgtcat 13080
caaaatcact cgcatcaacc aaaccgttat tcattcgtga ttgcgcctga gcgagacgaa 13140
atacgcgatc gctgttaaaa ggacaattac aaacaggaat cgaatgcaac cggcgcagga 13200
acactgccag cgcatcaaca atattttcac ctgaatcagg atattcttct aatacctgga 13260
atgctgtttt cccggggatc gcagtggtga gtaaccatgc atcatcagga gtacggataa 13320
aatgcttgat ggtcggaaga ggcataaatt ccgtcagcca gtttagtctg accatctcat 13380
ctgtaacatc attggcaacg ctacctttgc catgtttcag aaacaactct ggcgcatcgg 13440
gcttcccata caatcgatag attgtcgcac ctgattgccc gacattatcg cgagcccatt 13500
tatacccata taaatcagca tccatgttgg aatttaatcg cggcctcgag caagacgttt 13560
cccgttgaat atggctcata acaccccttg tattactgtt tatgtaagca gacagtttta 13620
ttgttcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg 13680
cgcacatttc cccgaaaagt gccacctaaa ttgtaagcgt taatattttg ttaaaattcg 13740
cgttaaattt ttgttaaatc agctcatttt ttaaccaata ggccgaaatc ggcaaaatcc 13800
cttataaatc aaaagaatag accgagatag ggttgagtgg ccgctacagg gcgctcccat 13860
tcgccattca ggctgcgcaa ctgttgggaa gggcgtttcg gtgcgggcct cttcgctatt 13920
acgccagctg gcgaaagggg gatgtgctgc aaggcgatta agttgggtaa cgccagggtt 13980
ttcccagtca cacgcgtaat acgactcact atag 14014
<210> 18
<211> 1273
<212> PRT
<213> 人工序列
<220>
<223> 全长wt SARS-CoV-2刺突(S)蛋白(可切割)的氨基酸序列
<400> 18
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 19
<211> 3813
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2刺突(S)蛋白(RRAR-QQAA;del69-70;
delY144;N501Y;D614G)的核苷酸序列
<400> 19
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catctctggc accaacggca caaagcgctt cgacaatcct 240
gtgttgccgt ttaacgacgg cgtttacttc gccagcacag aaaagagcaa catcatccgg 300
ggctggatct tcggcaccac cctggacagc aaaacccaaa gcctgctcat cgtgaacaac 360
gccaccaacg tggtgatcaa ggtgtgcgag ttccagttct gcaatgatcc ttttctgggc 420
gtgtatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta ttctagcgcc 480
aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga aggcaagcag 540
ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta cttcaagatc 600
tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt cagcgccctg 660
gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac cctgctggcc 720
ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc cggcgctgcc 780
gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa cgagaacggc 840
acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa gtgtaccctg 900
aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt gcagcctaca 960
gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga ggtgttcaac 1020
gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa ttgcgtggcc 1080
gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta cggcgtgtca 1140
cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt cgtgatccgg 1200
ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga ctacaactac 1260
aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa cctggacagc 1320
aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa cctgaagcct 1380
ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg taatggagtg 1440
gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac atatggggtt 1500
ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc ccctgccacc 1560
gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa ctttaatttt 1620
aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct gcctttccag 1680
cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca gacgctggaa 1740
atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc aggcacaaac 1800
acaagcaacc aggtggctgt gctgtaccag ggcgtgaact gtacagaggt ccctgtggca 1860
atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc taacgtgttc 1920
cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta cgagtgcgac 1980
atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag ccctcagcaa 2040
gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg agccgagaac 2100
tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat ctctgtcacc 2160
accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat gtacatatgc 2220
ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg cacccaactt 2280
aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga ggtgttcgcc 2340
caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt taatttctct 2400
cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga cctgctgttc 2460
aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg cctgggcgac 2520
attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt gctgcctcct 2580
ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg caccatcaca 2640
tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat gcagatggcc 2700
taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca gaagttgatc 2760
gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc caccgccagc 2820
gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa caccctggtg 2880
aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat cctgagtaga 2940
ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag actgcaaagc 3000
ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc cagcgctaat 3060
ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt ggacttctgc 3120
ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt ggtgttcctg 3180
cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc catctgtcac 3240
gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac ccactggttt 3300
gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac cttcgtgtct 3360
ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc actgcaacct 3420
gagctggact cattcaagga ggaactggat aagtacttca agaatcacac cagccccgac 3480
gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca gaaggaaatc 3540
gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct gcaggagctg 3600
ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt catcgccggg 3660
ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg ttgtagctgc 3720
ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga cagcgagccc 3780
gtgctgaaag gcgtcaagct gcactacacc tga 3813
<210> 20
<211> 3813
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2刺突(S)蛋白(RRAR-QQAA;del242-244;
K417N;E484K;N501Y;D614G)的核苷酸序列
<400> 20
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgac 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc gggacctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc cggcgctgcc 780
gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa cgagaacggc 840
acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa gtgtaccctg 900
aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt gcagcctaca 960
gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga ggtgttcaac 1020
gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa ttgcgtggcc 1080
gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta cggcgtgtca 1140
cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt cgtgatccgg 1200
ggcgatgagg tgcggcagat cgcccctgga cagacaggca acatcgccga ctacaactac 1260
aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa cctggacagc 1320
aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa cctgaagcct 1380
ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg taatggagtg 1440
aaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac atatggggtt 1500
ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc ccctgccacc 1560
gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa ctttaatttt 1620
aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct gcctttccag 1680
cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca gacgctggaa 1740
atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc aggcacaaac 1800
acaagcaacc aggtggctgt gctgtaccag ggcgtgaact gtacagaggt ccctgtggca 1860
atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc taacgtgttc 1920
cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta cgagtgcgac 1980
atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag ccctcagcaa 2040
gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg agccgagaac 2100
tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat ctctgtcacc 2160
accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat gtacatatgc 2220
ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg cacccaactt 2280
aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga ggtgttcgcc 2340
caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt taatttctct 2400
cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga cctgctgttc 2460
aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg cctgggcgac 2520
attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt gctgcctcct 2580
ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg caccatcaca 2640
tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat gcagatggcc 2700
taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca gaagttgatc 2760
gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc caccgccagc 2820
gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa caccctggtg 2880
aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat cctgagtaga 2940
ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag actgcaaagc 3000
ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc cagcgctaat 3060
ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt ggacttctgc 3120
ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt ggtgttcctg 3180
cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc catctgtcac 3240
gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac ccactggttt 3300
gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac cttcgtgtct 3360
ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc actgcaacct 3420
gagctggact cattcaagga ggaactggat aagtacttca agaatcacac cagccccgac 3480
gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca gaaggaaatc 3540
gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct gcaggagctg 3600
ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt catcgccggg 3660
ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg ttgtagctgc 3720
ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga cagcgagccc 3780
gtgctgaaag gcgtcaagct gcactacacc tga 3813
<210> 21
<211> 3804
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2刺突(S)蛋白(RRAR-QQAA;del69-70;
del242-244;K417N;E484K;N501Y;D614G)的核苷酸序列
<400> 21
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catctctggc accaacggca caaagcgctt cgacaatcct 240
gtgttgccgt ttaacgacgg cgtttacttc gccagcacag aaaagagcaa catcatccgg 300
ggctggatct tcggcaccac cctggacagc aaaacccaaa gcctgctcat cgtgaacaac 360
gccaccaacg tggtgatcaa ggtgtgcgag ttccagttct gcaatgatcc ttttctgggc 420
gtgtatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta ttctagcgcc 480
aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga aggcaagcag 540
ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta cttcaagatc 600
tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt cagcgccctg 660
gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac cctgcaccgg 720
agctacctga cccccggcga cagcagcagc ggctggaccg ccggcgctgc cgcctattac 780
gtgggctacc tgcaacctag aaccttcctg ctgaaataca acgagaacgg cacaatcacc 840
gacgccgtgg actgtgccct ggaccccctg tctgagacaa agtgtaccct gaagtctttc 900
accgtggaga agggcatcta ccagaccagc aacttccggg tgcagcctac agaatctata 960
gtgcggttcc ctaacatcac caacctgtgt ccttttggcg aggtgttcaa cgccactcgg 1020
ttcgcctctg tctacgcctg gaaccggaaa cggatctcta attgcgtggc cgattacagc 1080
gtcctgtata actccgccag tttcagcaca ttcaagtgct acggcgtgtc acccaccaag 1140
ctgaacgatc tgtgcttcac caatgtgtac gccgatagtt tcgtgatccg gggcgatgag 1200
gtgcggcaga tcgcccctgg acagacaggc aacatcgccg actacaacta caagctgcct 1260
gacgacttca caggctgtgt gatcgcatgg aacagcaaca acctggacag caaggtgggc 1320
ggaaactaca actacctgta cagactgttc agaaagtcca acctgaagcc tttcgagaga 1380
gatatatcta ccgagatcta ccaggccggc agcacaccct gtaatggagt gaaaggcttt 1440
aactgctact tccctctgca aagctatgga tttcaaccta catatggggt tggctaccag 1500
ccttacagag tggtggtcct tagcttcgag ctgctccatg cccctgccac cgtgtgcgga 1560
cctaagaagt ccaccaacct ggtgaaaaac aagtgcgtga actttaattt taacggcctg 1620
accggaacag gagtgctgac agaaagcaac aaaaagttcc tgcctttcca gcagttcggc 1680
agagacattg ccgacaccac agatgctgtt agagaccccc agacgctgga aatcctggat 1740
atcaccccct gctcttttgg cggcgtgagc gtgatcaccc caggcacaaa cacaagcaac 1800
caggtggctg tgctgtacca gggcgtgaac tgtacagagg tccctgtggc aatccacgcc 1860
gatcagctga cccctacatg gcgggtgtac tccactggat ctaacgtgtt ccagacaagg 1920
gccggatgcc tcatcggcgc tgagcacgtg aacaattctt acgagtgcga catccctatt 1980
ggagcgggca tctgcgccag ctaccagaca cagaccaata gccctcagca agccgctagc 2040
gtggcctccc agagcatcat cgcctacacc atgagcctgg gagccgagaa ctctgtggcc 2100
tacagcaaca acagcatcgc tatccctacc aacttcacca tctctgtcac caccgaaatc 2160
ctgcccgtca gtatgaccaa aaccagcgtc gactgcacca tgtacatatg cggcgatagc 2220
accgaatgca gcaacctgct gctgcagtat ggctccttct gcacccaact taacagagcc 2280
ctgactggca tcgccgtgga gcaggacaag aatacccagg aggtgttcgc ccaggtgaag 2340
cagatctaca agacaccccc gatcaaggac ttcggcggct ttaatttctc tcagatcctg 2400
ccagacccat ctaaaccctc taagcggagc tttatcgagg acctgctgtt caacaaggtg 2460
actctggctg acgccggctt catcaagcag tacggcgatt gcctgggcga cattgctgct 2520
agagacctga tctgtgccca gaaattcaac ggtcttactg tgctgcctcc tctgctgacg 2580
gatgagatga tcgcccagta caccagcgcc ctgctggccg gcaccatcac atccggctgg 2640
acattcggcg ccggcgcagc cctgcagatc ccttttgcca tgcagatggc ctaccggttc 2700
aacggaatcg gagtgacaca gaacgtgctc tacgaaaatc agaagttgat cgccaaccag 2760
ttcaacagcg ccatcggcaa gattcaggat agtctgagtt ccaccgccag cgccctggga 2820
aagctgcagg acgtggtcaa tcagaatgcc caagccctga acaccctggt gaagcagctg 2880
agcagcaact tcggcgccat cagctctgtg ctgaacgaca tcctgagtag actggacaag 2940
gtggaagccg aagtgcagat cgacagattg atcaccggaa gactgcaaag cctgcagacc 3000
tacgtgaccc agcagctgat aagagctgct gaaatcagag ccagcgctaa tctggccgct 3060
accaagatga gcgagtgcgt tctgggccag tctaagagag tggacttctg cggaaaaggc 3120
taccacctga tgtcctttcc tcagtctgcc ccccacggcg tggtgttcct gcacgtcaca 3180
tacgtgcccg ctcaagagaa aaacttcacc acggcccctg ccatctgtca cgacggcaag 3240
gcccacttcc ccagagaggg cgtgttcgtg agcaatggca cccactggtt tgtgactcag 3300
agaaacttct acgagccaca gattatcacc acagataaca ccttcgtgtc tggcaactgc 3360
gacgtggtga tcggcatcgt caacaacaca gtgtacgacc cactgcaacc tgagctggac 3420
tcattcaagg aggaactgga taagtacttc aagaatcaca ccagccccga cgttgacctg 3480
ggcgacatca gcggcattaa cgcctctgtg gtcaacatcc agaaggaaat cgacagactg 3540
aatgaggtgg ccaagaattt gaacgagagc ctgattgatc tgcaggagct gggcaaatac 3600
gagcagtaca tcaagtggcc ttggtacatc tggctgggct tcatcgccgg gctgatcgcc 3660
atcgttatgg tgacaatcat gctgtgttgc atgacaagct gttgtagctg cctgaaaggc 3720
tgctgctcct gcggcagctg ttgcaagttt gacgaagatg acagcgagcc cgtgctgaaa 3780
ggcgtcaagc tgcactacac ctga 3804
<210> 22
<211> 3813
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2刺突(S)蛋白(RRAR-QQAA;del69-70;
delY144;N501Y;A570D;D614G;P680H;T716I)的核苷酸序列
<400> 22
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tctgaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catctctggc accaacggca caaagcgctt cgacaatcct 240
gtgttgccgt ttaacgacgg cgtttacttc gccagcacag aaaagagcaa catcatccgg 300
ggctggatct tcggcaccac cctggacagc aaaacccaaa gcctgctcat cgtgaacaac 360
gccaccaacg tggtgatcaa ggtgtgcgag ttccagttct gcaatgatcc ttttctgggc 420
gtgtatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta ttctagcgcc 480
aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga aggcaagcag 540
ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta cttcaagatc 600
tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt cagcgccctg 660
gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac cctgctggcc 720
ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc cggcgctgcc 780
gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa cgagaacggc 840
acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa gtgtaccctg 900
aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt gcagcctaca 960
gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga ggtgttcaac 1020
gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa ttgcgtggcc 1080
gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta cggcgtgtca 1140
cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt cgtgatccgg 1200
ggcgatgagg tgcggcagat cgcccctgga cagacaggca agatcgccga ctacaactac 1260
aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa cctggacagc 1320
aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa cctgaagcct 1380
ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg taatggagtg 1440
gaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac atatggggtt 1500
ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc ccctgccacc 1560
gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa ctttaatttt 1620
aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct gcctttccag 1680
cagttcggca gagacattga cgacaccaca gatgctgtta gagaccccca gacgctggaa 1740
atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc aggcacaaac 1800
acaagcaacc aggtggctgt gctgtaccag ggcgtgaact gtacagaggt ccctgtggca 1860
atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc taacgtgttc 1920
cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta cgagtgcgac 1980
atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag ccatcagcaa 2040
gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg agccgagaac 2100
tctgtggcct acagcaacaa cagcatcgct atccctatca acttcaccat ctctgtcacc 2160
accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat gtacatatgc 2220
ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg cacccaactt 2280
aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga ggtgttcgcc 2340
caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt taatttctct 2400
cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga cctgctgttc 2460
aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg cctgggcgac 2520
attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt gctgcctcct 2580
ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg caccatcaca 2640
tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat gcagatggcc 2700
taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca gaagttgatc 2760
gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc caccgccagc 2820
gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa caccctggtg 2880
aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat cctggctaga 2940
ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag actgcaaagc 3000
ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc cagcgctaat 3060
ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt ggacttctgc 3120
ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt ggtgttcctg 3180
cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc catctgtcac 3240
gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac ccactggttt 3300
gtgactcaga gaaacttcta cgagccacag attatcacca cacataacac cttcgtgtct 3360
ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc actgcaacct 3420
gagctggact cattcaagga ggaactggat aagtacttca agaatcacac cagccccgac 3480
gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca gaaggaaatc 3540
gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct gcaggagctg 3600
ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt catcgccggg 3660
ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg ttgtagctgc 3720
ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga cagcgagccc 3780
gtgctgaaag gcgtcaagct gcactacacc tga 3813
<210> 23
<211> 3813
<212> DNA
<213> 人工序列
<220>
<223> 不可切割的SARS-CoV-2刺突(S)蛋白(RRAR-QQAA;L18F;D80A;D215G;
del242-244;K417N;E484K;N501Y;D614G;A701V)的核苷酸序列
<400> 23
atgttcgtgt tcctggtgct gctgcccctc gttagcagcc agtgcgtgaa tttcaccacc 60
cgcacccagc tgccaccagc ctacacaaac agcttcacca gaggagtgta ttaccctgat 120
aaggtcttta gatcctccgt cctgcattct acgcaggatc tcttcttgcc attcttcagc 180
aacgtgacat ggttccacgc catccacgtt tctggcacca acggcacaaa gcgcttcgcc 240
aatcctgtgt tgccgtttaa cgacggcgtt tacttcgcca gcacagaaaa gagcaacatc 300
atccggggct ggatcttcgg caccaccctg gacagcaaaa cccaaagcct gctcatcgtg 360
aacaacgcca ccaacgtggt gatcaaggtg tgcgagttcc agttctgcaa tgatcctttt 420
ctgggcgtgt actatcacaa gaacaacaag agctggatgg aaagcgagtt cagagtgtat 480
tctagcgcca acaactgcac ctttgagtac gtgtcccagc cctttcttat ggacctggaa 540
ggcaagcagg gcaacttcaa gaatctgaga gaattcgtgt tcaagaacat tgatggctac 600
ttcaagatct acagcaagca cacccctatc aacctggttc ggggcctgcc acaaggcttc 660
agcgccctgg aacctctggt ggacctgcct atcggcatca acatcacacg gttccaaacc 720
ctgcaccgga gctacctgac ccccggcgac agcagcagcg gctggaccgc cggcgctgcc 780
gcctattacg tgggctacct gcaacctaga accttcctgc tgaaatacaa cgagaacggc 840
acaatcaccg acgccgtgga ctgtgccctg gaccccctgt ctgagacaaa gtgtaccctg 900
aagtctttca ccgtggagaa gggcatctac cagaccagca acttccgggt gcagcctaca 960
gaatctatag tgcggttccc taacatcacc aacctgtgtc cttttggcga ggtgttcaac 1020
gccactcggt tcgcctctgt ctacgcctgg aaccggaaac ggatctctaa ttgcgtggcc 1080
gattacagcg tcctgtataa ctccgccagt ttcagcacat tcaagtgcta cggcgtgtca 1140
cccaccaagc tgaacgatct gtgcttcacc aatgtgtacg ccgatagttt cgtgatccgg 1200
ggcgatgagg tgcggcagat cgcccctgga cagacaggca atatcgccga ctacaactac 1260
aagctgcctg acgacttcac aggctgtgtg atcgcatgga acagcaacaa cctggacagc 1320
aaggtgggcg gaaactacaa ctacctgtac agactgttca gaaagtccaa cctgaagcct 1380
ttcgagagag atatatctac cgagatctac caggccggca gcacaccctg taatggagtg 1440
aaaggcttta actgctactt ccctctgcaa agctatggat ttcaacctac atatggggtt 1500
ggctaccagc cttacagagt ggtggtcctt agcttcgagc tgctccatgc ccctgccacc 1560
gtgtgcggac ctaagaagtc caccaacctg gtgaaaaaca agtgcgtgaa ctttaatttt 1620
aacggcctga ccggaacagg agtgctgaca gaaagcaaca aaaagttcct gcctttccag 1680
cagttcggca gagacattgc cgacaccaca gatgctgtta gagaccccca gacgctggaa 1740
atcctggata tcaccccctg ctcttttggc ggcgtgagcg tgatcacccc aggcacaaac 1800
acaagcaacc aggtggctgt gctgtaccag ggcgtgaact gtacagaggt ccctgtggca 1860
atccacgccg atcagctgac ccctacatgg cgggtgtact ccactggatc taacgtgttc 1920
cagacaaggg ccggatgcct catcggcgct gagcacgtga acaattctta cgagtgcgac 1980
atccctattg gagcgggcat ctgcgccagc taccagacac agaccaatag ccctcagcaa 2040
gccgctagcg tggcctccca gagcatcatc gcctacacca tgagcctggg agtcgagaac 2100
tctgtggcct acagcaacaa cagcatcgct atccctacca acttcaccat ctctgtcacc 2160
accgaaatcc tgcccgtcag tatgaccaaa accagcgtcg actgcaccat gtacatatgc 2220
ggcgatagca ccgaatgcag caacctgctg ctgcagtatg gctccttctg cacccaactt 2280
aacagagccc tgactggcat cgccgtggag caggacaaga atacccagga ggtgttcgcc 2340
caggtgaagc agatctacaa gacacccccg atcaaggact tcggcggctt taatttctct 2400
cagatcctgc cagacccatc taaaccctct aagcggagct ttatcgagga cctgctgttc 2460
aacaaggtga ctctggctga cgccggcttc atcaagcagt acggcgattg cctgggcgac 2520
attgctgcta gagacctgat ctgtgcccag aaattcaacg gtcttactgt gctgcctcct 2580
ctgctgacgg atgagatgat cgcccagtac accagcgccc tgctggccgg caccatcaca 2640
tccggctgga cattcggcgc cggcgcagcc ctgcagatcc cttttgccat gcagatggcc 2700
taccggttca acggaatcgg agtgacacag aacgtgctct acgaaaatca gaagttgatc 2760
gccaaccagt tcaacagcgc catcggcaag attcaggata gtctgagttc caccgccagc 2820
gccctgggaa agctgcagga cgtggtcaat cagaatgccc aagccctgaa caccctggtg 2880
aagcagctga gcagcaactt cggcgccatc agctctgtgc tgaacgacat cctgagtaga 2940
ctggacaagg tggaagccga agtgcagatc gacagattga tcaccggaag actgcaaagc 3000
ctgcagacct acgtgaccca gcagctgata agagctgctg aaatcagagc cagcgctaat 3060
ctggccgcta ccaagatgag cgagtgcgtt ctgggccagt ctaagagagt ggacttctgc 3120
ggaaaaggct accacctgat gtcctttcct cagtctgccc cccacggcgt ggtgttcctg 3180
cacgtcacat acgtgcccgc tcaagagaaa aacttcacca cggcccctgc catctgtcac 3240
gacggcaagg cccacttccc cagagagggc gtgttcgtga gcaatggcac ccactggttt 3300
gtgactcaga gaaacttcta cgagccacag attatcacca cagataacac cttcgtgtct 3360
ggcaactgcg acgtggtgat cggcatcgtc aacaacacag tgtacgaccc actgcaacct 3420
gagctggact cattcaagga ggaactggat aagtacttca agaatcacac cagccccgac 3480
gttgacctgg gcgacatcag cggcattaac gcctctgtgg tcaacatcca gaaggaaatc 3540
gacagactga atgaggtggc caagaatttg aacgagagcc tgattgatct gcaggagctg 3600
ggcaaatacg agcagtacat caagtggcct tggtacatct ggctgggctt catcgccggg 3660
ctgatcgcca tcgttatggt gacaatcatg ctgtgttgca tgacaagctg ttgtagctgc 3720
ctgaaaggct gctgctcctg cggcagctgt tgcaagtttg acgaagatga cagcgagccc 3780
gtgctgaaag gcgtcaagct gcactacacc tga 3813
<210> 24
<211> 14005
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co77的核苷酸序列
<400> 24
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatctctgg caccaacggc acaaagcgct tcgacaatcc 7800
tgtgttgccg tttaacgacg gcgtttactt cgccagcaca gaaaagagca acatcatccg 7860
gggctggatc ttcggcacca ccctggacag caaaacccaa agcctgctca tcgtgaacaa 7920
cgccaccaac gtggtgatca aggtgtgcga gttccagttc tgcaatgatc cttttctggg 7980
cgtgtatcac aagaacaaca agagctggat ggaaagcgag ttcagagtgt attctagcgc 8040
caacaactgc acctttgagt acgtgtccca gccctttctt atggacctgg aaggcaagca 8100
gggcaacttc aagaatctga gagaattcgt gttcaagaac attgatggct acttcaagat 8160
ctacagcaag cacaccccta tcaacctggt tcgggacctg ccacaaggct tcagcgccct 8220
ggaacctctg gtggacctgc ctatcggcat caacatcaca cggttccaaa ccctgctggc 8280
cctgcaccgg agctacctga cccccggcga cagcagcagc ggctggaccg ccggcgctgc 8340
cgcctattac gtgggctacc tgcaacctag aaccttcctg ctgaaataca acgagaacgg 8400
cacaatcacc gacgccgtgg actgtgccct ggaccccctg tctgagacaa agtgtaccct 8460
gaagtctttc accgtggaga agggcatcta ccagaccagc aacttccggg tgcagcctac 8520
agaatctata gtgcggttcc ctaacatcac caacctgtgt ccttttggcg aggtgttcaa 8580
cgccactcgg ttcgcctctg tctacgcctg gaaccggaaa cggatctcta attgcgtggc 8640
cgattacagc gtcctgtata actccgccag tttcagcaca ttcaagtgct acggcgtgtc 8700
acccaccaag ctgaacgatc tgtgcttcac caatgtgtac gccgatagtt tcgtgatccg 8760
gggcgatgag gtgcggcaga tcgcccctgg acagacaggc aagatcgccg actacaacta 8820
caagctgcct gacgacttca caggctgtgt gatcgcatgg aacagcaaca acctggacag 8880
caaggtgggc ggaaactaca actacctgta cagactgttc agaaagtcca acctgaagcc 8940
tttcgagaga gatatatcta ccgagatcta ccaggccggc agcacaccct gtaatggagt 9000
ggaaggcttt aactgctact tccctctgca aagctatgga tttcaaccta catatggggt 9060
tggctaccag ccttacagag tggtggtcct tagcttcgag ctgctccatg cccctgccac 9120
cgtgtgcgga cctaagaagt ccaccaacct ggtgaaaaac aagtgcgtga actttaattt 9180
taacggcctg accggaacag gagtgctgac agaaagcaac aaaaagttcc tgcctttcca 9240
gcagttcggc agagacattg ccgacaccac agatgctgtt agagaccccc agacgctgga 9300
aatcctggat atcaccccct gctcttttgg cggcgtgagc gtgatcaccc caggcacaaa 9360
cacaagcaac caggtggctg tgctgtacca gggcgtgaac tgtacagagg tccctgtggc 9420
aatccacgcc gatcagctga cccctacatg gcgggtgtac tccactggat ctaacgtgtt 9480
ccagacaagg gccggatgcc tcatcggcgc tgagcacgtg aacaattctt acgagtgcga 9540
catccctatt ggagcgggca tctgcgccag ctaccagaca cagaccaata gccctcagca 9600
agccgctagc gtggcctccc agagcatcat cgcctacacc atgagcctgg gagccgagaa 9660
ctctgtggcc tacagcaaca acagcatcgc tatccctacc aacttcacca tctctgtcac 9720
caccgaaatc ctgcccgtca gtatgaccaa aaccagcgtc gactgcacca tgtacatatg 9780
cggcgatagc accgaatgca gcaacctgct gctgcagtat ggctccttct gcacccaact 9840
taacagagcc ctgactggca tcgccgtgga gcaggacaag aatacccagg aggtgttcgc 9900
ccaggtgaag cagatctaca agacaccccc gatcaaggac ttcggcggct ttaatttctc 9960
tcagatcctg ccagacccat ctaaaccctc taagcggagc tttatcgagg acctgctgtt 10020
caacaaggtg actctggctg acgccggctt catcaagcag tacggcgatt gcctgggcga 10080
cattgctgct agagacctga tctgtgccca gaaattcaac ggtcttactg tgctgcctcc 10140
tctgctgacg gatgagatga tcgcccagta caccagcgcc ctgctggccg gcaccatcac 10200
atccggctgg acattcggcg ccggcgcagc cctgcagatc ccttttgcca tgcagatggc 10260
ctaccggttc aacggaatcg gagtgacaca gaacgtgctc tacgaaaatc agaagttgat 10320
cgccaaccag ttcaacagcg ccatcggcaa gattcaggat agtctgagtt ccaccgccag 10380
cgccctggga aagctgcagg acgtggtcaa tcagaatgcc caagccctga acaccctggt 10440
gaagcagctg agcagcaact tcggcgccat cagctctgtg ctgaacgaca tcctgagtag 10500
actggacaag gtggaagccg aagtgcagat cgacagattg atcaccggaa gactgcaaag 10560
cctgcagacc tacgtgaccc agcagctgat aagagctgct gaaatcagag ccagcgctaa 10620
tctggccgct accaagatga gcgagtgcgt tctgggccag tctaagagag tggacttctg 10680
cggaaaaggc taccacctga tgtcctttcc tcagtctgcc ccccacggcg tggtgttcct 10740
gcacgtcaca tacgtgcccg ctcaagagaa aaacttcacc acggcccctg ccatctgtca 10800
cgacggcaag gcccacttcc ccagagaggg cgtgttcgtg agcaatggca cccactggtt 10860
tgtgactcag agaaacttct acgagccaca gattatcacc acagataaca ccttcgtgtc 10920
tggcaactgc gacgtggtga tcggcatcgt caacaacaca gtgtacgacc cactgcaacc 10980
tgagctggac tcattcaagg aggaactgga taagtacttc aagaatcaca ccagccccga 11040
cgttgacctg ggcgacatca gcggcattaa cgcctctgtg gtcaacatcc agaaggaaat 11100
cgacagactg aatgaggtgg ccaagaattt gaacgagagc ctgattgatc tgcaggagct 11160
gggcaaatac gagcagtaca tcaagtggcc ttggtacatc tggctgggct tcatcgccgg 11220
gctgatcgcc atcgttatgg tgacaatcat gctgtgttgc atgacaagct gttgtagctg 11280
cctgaaaggc tgctgctcct gcggcagctg ttgcaagttt gacgaagatg acagcgagcc 11340
cgtgctgaaa ggcgtcaagc tgcactacac ctgaggcgcg cccacccagc ggccgcccgc 11400
tacgccccaa tgatccgacc agcaaaactc gatgtacttc cgaggaactg atgtgcataa 11460
tgcatcaggc tggtacatta gatccccgct taccgcgggc aatatagcaa cactaaaaac 11520
tcgatgtact tccgaggaag cgcagtgcat aatgctgcgc agtgttgcca cataaccact 11580
atattaacca tttatctagc ggacgccaaa aactcaatgt atttctgagg aagcgtggtg 11640
cataatgcca cgcagcgtct gcataacttt tattatttct tttattaatc aacaaaattt 11700
tgtttttaac atttcaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aagaagagcg 11760
tttaaacacg tgatatctgg cctcatgggc cttcctttca ctgcccgctt tccagtcggg 11820
aaacctgtcg tgccagctgc attaacatgg tcatagctgt ttccttgcgt attgggcgct 11880
ctccgcttcc tcgctcactg actcgctgcg ctcggtcgtt cgggtaaagc ctggggtgcc 11940
taatgagcaa aaggccagca aaaggccagg aaccgtaaaa aggccgcgtt gctggcgttt 12000
ttccataggc tccgcccccc tgacgagcat cacaaaaatc gacgctcaag tcagaggtgg 12060
cgaaacccga caggactata aagataccag gcgtttcccc ctggaagctc cctcgtgcgc 12120
tctcctgttc cgaccctgcc gcttaccgga tacctgtccg cctttctccc ttcgggaagc 12180
gtggcgcttt ctcatagctc acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc 12240
aagctgggct gtgtgcacga accccccgtt cagcccgacc gctgcgcctt atccggtaac 12300
tatcgtcttg agtccaaccc ggtaagacac gacttatcgc cactggcagc agccactggt 12360
aacaggatta gcagagcgag gtatgtaggc ggtgctacag agttcttgaa gtggtggcct 12420
aactacggct acactagaag aacagtattt ggtatctgcg ctctgctgaa gccagttacc 12480
ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt 12540
ttttttgttt gcaggcagca gattacgcgc agaaaaaaag gatctcaaga agatcctttg 12600
atcttttcta cggggtctga cgctcagtgg aacgaaaact cacgttaagg gattttggtc 12660
atgaatacac ggtgcctgac tgcgttagca atttaactgt gataaactac cgcattaaag 12720
cttatcgatg ataagctgtc aaacatgaga attcttagaa aaactcatcg agcatcaaat 12780
gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa agccgtttct 12840
gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc tggtatcggt 12900
ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg tcaaaaataa 12960
ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat ggcaaaagct 13020
tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca tcaaaatcac 13080
tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga aatacgcgat 13140
cgctgttaaa aggacaatta caaacaggaa tcgaatgcaa ccggcgcagg aacactgcca 13200
gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg aatgctgttt 13260
tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata aaatgcttga 13320
tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca tctgtaacat 13380
cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg ggcttcccat 13440
acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat ttatacccat 13500
ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt tcccgttgaa 13560
tatggctcat aacacccctt gtattactgt ttatgtaagc agacagtttt attgttcatg 13620
agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt 13680
ccccgaaaag tgccacctaa attgtaagcg ttaatatttt gttaaaattc gcgttaaatt 13740
tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaaaatc ccttataaat 13800
caaaagaata gaccgagata gggttgagtg gccgctacag ggcgctccca ttcgccattc 13860
aggctgcgca actgttggga agggcgtttc ggtgcgggcc tcttcgctat tacgccagct 13920
ggcgaaaggg ggatgtgctg caaggcgatt aagttgggta acgccagggt tttcccagtc 13980
acacgcgtaa tacgactcac tatag 14005
<210> 25
<211> 14005
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co78的核苷酸序列
<400> 25
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcga 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cgggacctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgcaccgg agctacctga cccccggcga cagcagcagc ggctggaccg ccggcgctgc 8340
cgcctattac gtgggctacc tgcaacctag aaccttcctg ctgaaataca acgagaacgg 8400
cacaatcacc gacgccgtgg actgtgccct ggaccccctg tctgagacaa agtgtaccct 8460
gaagtctttc accgtggaga agggcatcta ccagaccagc aacttccggg tgcagcctac 8520
agaatctata gtgcggttcc ctaacatcac caacctgtgt ccttttggcg aggtgttcaa 8580
cgccactcgg ttcgcctctg tctacgcctg gaaccggaaa cggatctcta attgcgtggc 8640
cgattacagc gtcctgtata actccgccag tttcagcaca ttcaagtgct acggcgtgtc 8700
acccaccaag ctgaacgatc tgtgcttcac caatgtgtac gccgatagtt tcgtgatccg 8760
gggcgatgag gtgcggcaga tcgcccctgg acagacaggc aacatcgccg actacaacta 8820
caagctgcct gacgacttca caggctgtgt gatcgcatgg aacagcaaca acctggacag 8880
caaggtgggc ggaaactaca actacctgta cagactgttc agaaagtcca acctgaagcc 8940
tttcgagaga gatatatcta ccgagatcta ccaggccggc agcacaccct gtaatggagt 9000
gaaaggcttt aactgctact tccctctgca aagctatgga tttcaaccta catatggggt 9060
tggctaccag ccttacagag tggtggtcct tagcttcgag ctgctccatg cccctgccac 9120
cgtgtgcgga cctaagaagt ccaccaacct ggtgaaaaac aagtgcgtga actttaattt 9180
taacggcctg accggaacag gagtgctgac agaaagcaac aaaaagttcc tgcctttcca 9240
gcagttcggc agagacattg ccgacaccac agatgctgtt agagaccccc agacgctgga 9300
aatcctggat atcaccccct gctcttttgg cggcgtgagc gtgatcaccc caggcacaaa 9360
cacaagcaac caggtggctg tgctgtacca gggcgtgaac tgtacagagg tccctgtggc 9420
aatccacgcc gatcagctga cccctacatg gcgggtgtac tccactggat ctaacgtgtt 9480
ccagacaagg gccggatgcc tcatcggcgc tgagcacgtg aacaattctt acgagtgcga 9540
catccctatt ggagcgggca tctgcgccag ctaccagaca cagaccaata gccctcagca 9600
agccgctagc gtggcctccc agagcatcat cgcctacacc atgagcctgg gagccgagaa 9660
ctctgtggcc tacagcaaca acagcatcgc tatccctacc aacttcacca tctctgtcac 9720
caccgaaatc ctgcccgtca gtatgaccaa aaccagcgtc gactgcacca tgtacatatg 9780
cggcgatagc accgaatgca gcaacctgct gctgcagtat ggctccttct gcacccaact 9840
taacagagcc ctgactggca tcgccgtgga gcaggacaag aatacccagg aggtgttcgc 9900
ccaggtgaag cagatctaca agacaccccc gatcaaggac ttcggcggct ttaatttctc 9960
tcagatcctg ccagacccat ctaaaccctc taagcggagc tttatcgagg acctgctgtt 10020
caacaaggtg actctggctg acgccggctt catcaagcag tacggcgatt gcctgggcga 10080
cattgctgct agagacctga tctgtgccca gaaattcaac ggtcttactg tgctgcctcc 10140
tctgctgacg gatgagatga tcgcccagta caccagcgcc ctgctggccg gcaccatcac 10200
atccggctgg acattcggcg ccggcgcagc cctgcagatc ccttttgcca tgcagatggc 10260
ctaccggttc aacggaatcg gagtgacaca gaacgtgctc tacgaaaatc agaagttgat 10320
cgccaaccag ttcaacagcg ccatcggcaa gattcaggat agtctgagtt ccaccgccag 10380
cgccctggga aagctgcagg acgtggtcaa tcagaatgcc caagccctga acaccctggt 10440
gaagcagctg agcagcaact tcggcgccat cagctctgtg ctgaacgaca tcctgagtag 10500
actggacaag gtggaagccg aagtgcagat cgacagattg atcaccggaa gactgcaaag 10560
cctgcagacc tacgtgaccc agcagctgat aagagctgct gaaatcagag ccagcgctaa 10620
tctggccgct accaagatga gcgagtgcgt tctgggccag tctaagagag tggacttctg 10680
cggaaaaggc taccacctga tgtcctttcc tcagtctgcc ccccacggcg tggtgttcct 10740
gcacgtcaca tacgtgcccg ctcaagagaa aaacttcacc acggcccctg ccatctgtca 10800
cgacggcaag gcccacttcc ccagagaggg cgtgttcgtg agcaatggca cccactggtt 10860
tgtgactcag agaaacttct acgagccaca gattatcacc acagataaca ccttcgtgtc 10920
tggcaactgc gacgtggtga tcggcatcgt caacaacaca gtgtacgacc cactgcaacc 10980
tgagctggac tcattcaagg aggaactgga taagtacttc aagaatcaca ccagccccga 11040
cgttgacctg ggcgacatca gcggcattaa cgcctctgtg gtcaacatcc agaaggaaat 11100
cgacagactg aatgaggtgg ccaagaattt gaacgagagc ctgattgatc tgcaggagct 11160
gggcaaatac gagcagtaca tcaagtggcc ttggtacatc tggctgggct tcatcgccgg 11220
gctgatcgcc atcgttatgg tgacaatcat gctgtgttgc atgacaagct gttgtagctg 11280
cctgaaaggc tgctgctcct gcggcagctg ttgcaagttt gacgaagatg acagcgagcc 11340
cgtgctgaaa ggcgtcaagc tgcactacac ctgaggcgcg cccacccagc ggccgcccgc 11400
tacgccccaa tgatccgacc agcaaaactc gatgtacttc cgaggaactg atgtgcataa 11460
tgcatcaggc tggtacatta gatccccgct taccgcgggc aatatagcaa cactaaaaac 11520
tcgatgtact tccgaggaag cgcagtgcat aatgctgcgc agtgttgcca cataaccact 11580
atattaacca tttatctagc ggacgccaaa aactcaatgt atttctgagg aagcgtggtg 11640
cataatgcca cgcagcgtct gcataacttt tattatttct tttattaatc aacaaaattt 11700
tgtttttaac atttcaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aagaagagcg 11760
tttaaacacg tgatatctgg cctcatgggc cttcctttca ctgcccgctt tccagtcggg 11820
aaacctgtcg tgccagctgc attaacatgg tcatagctgt ttccttgcgt attgggcgct 11880
ctccgcttcc tcgctcactg actcgctgcg ctcggtcgtt cgggtaaagc ctggggtgcc 11940
taatgagcaa aaggccagca aaaggccagg aaccgtaaaa aggccgcgtt gctggcgttt 12000
ttccataggc tccgcccccc tgacgagcat cacaaaaatc gacgctcaag tcagaggtgg 12060
cgaaacccga caggactata aagataccag gcgtttcccc ctggaagctc cctcgtgcgc 12120
tctcctgttc cgaccctgcc gcttaccgga tacctgtccg cctttctccc ttcgggaagc 12180
gtggcgcttt ctcatagctc acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc 12240
aagctgggct gtgtgcacga accccccgtt cagcccgacc gctgcgcctt atccggtaac 12300
tatcgtcttg agtccaaccc ggtaagacac gacttatcgc cactggcagc agccactggt 12360
aacaggatta gcagagcgag gtatgtaggc ggtgctacag agttcttgaa gtggtggcct 12420
aactacggct acactagaag aacagtattt ggtatctgcg ctctgctgaa gccagttacc 12480
ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt 12540
ttttttgttt gcaggcagca gattacgcgc agaaaaaaag gatctcaaga agatcctttg 12600
atcttttcta cggggtctga cgctcagtgg aacgaaaact cacgttaagg gattttggtc 12660
atgaatacac ggtgcctgac tgcgttagca atttaactgt gataaactac cgcattaaag 12720
cttatcgatg ataagctgtc aaacatgaga attcttagaa aaactcatcg agcatcaaat 12780
gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa agccgtttct 12840
gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc tggtatcggt 12900
ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg tcaaaaataa 12960
ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat ggcaaaagct 13020
tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca tcaaaatcac 13080
tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga aatacgcgat 13140
cgctgttaaa aggacaatta caaacaggaa tcgaatgcaa ccggcgcagg aacactgcca 13200
gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg aatgctgttt 13260
tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata aaatgcttga 13320
tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca tctgtaacat 13380
cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg ggcttcccat 13440
acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat ttatacccat 13500
ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt tcccgttgaa 13560
tatggctcat aacacccctt gtattactgt ttatgtaagc agacagtttt attgttcatg 13620
agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt 13680
ccccgaaaag tgccacctaa attgtaagcg ttaatatttt gttaaaattc gcgttaaatt 13740
tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaaaatc ccttataaat 13800
caaaagaata gaccgagata gggttgagtg gccgctacag ggcgctccca ttcgccattc 13860
aggctgcgca actgttggga agggcgtttc ggtgcgggcc tcttcgctat tacgccagct 13920
ggcgaaaggg ggatgtgctg caaggcgatt aagttgggta acgccagggt tttcccagtc 13980
acacgcgtaa tacgactcac tatag 14005
<210> 26
<211> 13996
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co79的核苷酸序列
<400> 26
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatctctgg caccaacggc acaaagcgct tcgacaatcc 7800
tgtgttgccg tttaacgacg gcgtttactt cgccagcaca gaaaagagca acatcatccg 7860
gggctggatc ttcggcacca ccctggacag caaaacccaa agcctgctca tcgtgaacaa 7920
cgccaccaac gtggtgatca aggtgtgcga gttccagttc tgcaatgatc cttttctggg 7980
cgtgtatcac aagaacaaca agagctggat ggaaagcgag ttcagagtgt attctagcgc 8040
caacaactgc acctttgagt acgtgtccca gccctttctt atggacctgg aaggcaagca 8100
gggcaacttc aagaatctga gagaattcgt gttcaagaac attgatggct acttcaagat 8160
ctacagcaag cacaccccta tcaacctggt tcgggacctg ccacaaggct tcagcgccct 8220
ggaacctctg gtggacctgc ctatcggcat caacatcaca cggttccaaa ccctgcaccg 8280
gagctacctg acccccggcg acagcagcag cggctggacc gccggcgctg ccgcctatta 8340
cgtgggctac ctgcaaccta gaaccttcct gctgaaatac aacgagaacg gcacaatcac 8400
cgacgccgtg gactgtgccc tggaccccct gtctgagaca aagtgtaccc tgaagtcttt 8460
caccgtggag aagggcatct accagaccag caacttccgg gtgcagccta cagaatctat 8520
agtgcggttc cctaacatca ccaacctgtg tccttttggc gaggtgttca acgccactcg 8580
gttcgcctct gtctacgcct ggaaccggaa acggatctct aattgcgtgg ccgattacag 8640
cgtcctgtat aactccgcca gtttcagcac attcaagtgc tacggcgtgt cacccaccaa 8700
gctgaacgat ctgtgcttca ccaatgtgta cgccgatagt ttcgtgatcc ggggcgatga 8760
ggtgcggcag atcgcccctg gacagacagg caacatcgcc gactacaact acaagctgcc 8820
tgacgacttc acaggctgtg tgatcgcatg gaacagcaac aacctggaca gcaaggtggg 8880
cggaaactac aactacctgt acagactgtt cagaaagtcc aacctgaagc ctttcgagag 8940
agatatatct accgagatct accaggccgg cagcacaccc tgtaatggag tgaaaggctt 9000
taactgctac ttccctctgc aaagctatgg atttcaacct acatatgggg ttggctacca 9060
gccttacaga gtggtggtcc ttagcttcga gctgctccat gcccctgcca ccgtgtgcgg 9120
acctaagaag tccaccaacc tggtgaaaaa caagtgcgtg aactttaatt ttaacggcct 9180
gaccggaaca ggagtgctga cagaaagcaa caaaaagttc ctgcctttcc agcagttcgg 9240
cagagacatt gccgacacca cagatgctgt tagagacccc cagacgctgg aaatcctgga 9300
tatcaccccc tgctcttttg gcggcgtgag cgtgatcacc ccaggcacaa acacaagcaa 9360
ccaggtggct gtgctgtacc agggcgtgaa ctgtacagag gtccctgtgg caatccacgc 9420
cgatcagctg acccctacat ggcgggtgta ctccactgga tctaacgtgt tccagacaag 9480
ggccggatgc ctcatcggcg ctgagcacgt gaacaattct tacgagtgcg acatccctat 9540
tggagcgggc atctgcgcca gctaccagac acagaccaat agccctcagc aagccgctag 9600
cgtggcctcc cagagcatca tcgcctacac catgagcctg ggagccgaga actctgtggc 9660
ctacagcaac aacagcatcg ctatccctac caacttcacc atctctgtca ccaccgaaat 9720
cctgcccgtc agtatgacca aaaccagcgt cgactgcacc atgtacatat gcggcgatag 9780
caccgaatgc agcaacctgc tgctgcagta tggctccttc tgcacccaac ttaacagagc 9840
cctgactggc atcgccgtgg agcaggacaa gaatacccag gaggtgttcg cccaggtgaa 9900
gcagatctac aagacacccc cgatcaagga cttcggcggc tttaatttct ctcagatcct 9960
gccagaccca tctaaaccct ctaagcggag ctttatcgag gacctgctgt tcaacaaggt 10020
gactctggct gacgccggct tcatcaagca gtacggcgat tgcctgggcg acattgctgc 10080
tagagacctg atctgtgccc agaaattcaa cggtcttact gtgctgcctc ctctgctgac 10140
ggatgagatg atcgcccagt acaccagcgc cctgctggcc ggcaccatca catccggctg 10200
gacattcggc gccggcgcag ccctgcagat cccttttgcc atgcagatgg cctaccggtt 10260
caacggaatc ggagtgacac agaacgtgct ctacgaaaat cagaagttga tcgccaacca 10320
gttcaacagc gccatcggca agattcagga tagtctgagt tccaccgcca gcgccctggg 10380
aaagctgcag gacgtggtca atcagaatgc ccaagccctg aacaccctgg tgaagcagct 10440
gagcagcaac ttcggcgcca tcagctctgt gctgaacgac atcctgagta gactggacaa 10500
ggtggaagcc gaagtgcaga tcgacagatt gatcaccgga agactgcaaa gcctgcagac 10560
ctacgtgacc cagcagctga taagagctgc tgaaatcaga gccagcgcta atctggccgc 10620
taccaagatg agcgagtgcg ttctgggcca gtctaagaga gtggacttct gcggaaaagg 10680
ctaccacctg atgtcctttc ctcagtctgc cccccacggc gtggtgttcc tgcacgtcac 10740
atacgtgccc gctcaagaga aaaacttcac cacggcccct gccatctgtc acgacggcaa 10800
ggcccacttc cccagagagg gcgtgttcgt gagcaatggc acccactggt ttgtgactca 10860
gagaaacttc tacgagccac agattatcac cacagataac accttcgtgt ctggcaactg 10920
cgacgtggtg atcggcatcg tcaacaacac agtgtacgac ccactgcaac ctgagctgga 10980
ctcattcaag gaggaactgg ataagtactt caagaatcac accagccccg acgttgacct 11040
gggcgacatc agcggcatta acgcctctgt ggtcaacatc cagaaggaaa tcgacagact 11100
gaatgaggtg gccaagaatt tgaacgagag cctgattgat ctgcaggagc tgggcaaata 11160
cgagcagtac atcaagtggc cttggtacat ctggctgggc ttcatcgccg ggctgatcgc 11220
catcgttatg gtgacaatca tgctgtgttg catgacaagc tgttgtagct gcctgaaagg 11280
ctgctgctcc tgcggcagct gttgcaagtt tgacgaagat gacagcgagc ccgtgctgaa 11340
aggcgtcaag ctgcactaca cctgaggcgc gcccacccag cggccgcccg ctacgcccca 11400
atgatccgac cagcaaaact cgatgtactt ccgaggaact gatgtgcata atgcatcagg 11460
ctggtacatt agatccccgc ttaccgcggg caatatagca acactaaaaa ctcgatgtac 11520
ttccgaggaa gcgcagtgca taatgctgcg cagtgttgcc acataaccac tatattaacc 11580
atttatctag cggacgccaa aaactcaatg tatttctgag gaagcgtggt gcataatgcc 11640
acgcagcgtc tgcataactt ttattatttc ttttattaat caacaaaatt ttgtttttaa 11700
catttcaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaagaagagc gtttaaacac 11760
gtgatatctg gcctcatggg ccttcctttc actgcccgct ttccagtcgg gaaacctgtc 11820
gtgccagctg cattaacatg gtcatagctg tttccttgcg tattgggcgc tctccgcttc 11880
ctcgctcact gactcgctgc gctcggtcgt tcgggtaaag cctggggtgc ctaatgagca 11940
aaaggccagc aaaaggccag gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg 12000
ctccgccccc ctgacgagca tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg 12060
acaggactat aaagatacca ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt 12120
ccgaccctgc cgcttaccgg atacctgtcc gcctttctcc cttcgggaag cgtggcgctt 12180
tctcatagct cacgctgtag gtatctcagt tcggtgtagg tcgttcgctc caagctgggc 12240
tgtgtgcacg aaccccccgt tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt 12300
gagtccaacc cggtaagaca cgacttatcg ccactggcag cagccactgg taacaggatt 12360
agcagagcga ggtatgtagg cggtgctaca gagttcttga agtggtggcc taactacggc 12420
tacactagaa gaacagtatt tggtatctgc gctctgctga agccagttac cttcggaaaa 12480
agagttggta gctcttgatc cggcaaacaa accaccgctg gtagcggtgg tttttttgtt 12540
tgcaggcagc agattacgcg cagaaaaaaa ggatctcaag aagatccttt gatcttttct 12600
acggggtctg acgctcagtg gaacgaaaac tcacgttaag ggattttggt catgaataca 12660
cggtgcctga ctgcgttagc aatttaactg tgataaacta ccgcattaaa gcttatcgat 12720
gataagctgt caaacatgag aattcttaga aaaactcatc gagcatcaaa tgaaactgca 12780
atttattcat atcaggatta tcaataccat atttttgaaa aagccgtttc tgtaatgaag 12840
gagaaaactc accgaggcag ttccatagga tggcaagatc ctggtatcgg tctgcgattc 12900
cgactcgtcc aacatcaata caacctatta atttcccctc gtcaaaaata aggttatcaa 12960
gtgagaaatc accatgagtg acgactgaat ccggtgagaa tggcaaaagc ttatgcattt 13020
ctttccagac ttgttcaaca ggccagccat tacgctcgtc atcaaaatca ctcgcatcaa 13080
ccaaaccgtt attcattcgt gattgcgcct gagcgagacg aaatacgcga tcgctgttaa 13140
aaggacaatt acaaacagga atcgaatgca accggcgcag gaacactgcc agcgcatcaa 13200
caatattttc acctgaatca ggatattctt ctaatacctg gaatgctgtt ttcccgggga 13260
tcgcagtggt gagtaaccat gcatcatcag gagtacggat aaaatgcttg atggtcggaa 13320
gaggcataaa ttccgtcagc cagtttagtc tgaccatctc atctgtaaca tcattggcaa 13380
cgctaccttt gccatgtttc agaaacaact ctggcgcatc gggcttccca tacaatcgat 13440
agattgtcgc acctgattgc ccgacattat cgcgagccca tttataccca tataaatcag 13500
catccatgtt ggaatttaat cgcggcctcg agcaagacgt ttcccgttga atatggctca 13560
taacacccct tgtattactg tttatgtaag cagacagttt tattgttcat gagcggatac 13620
atatttgaat gtatttagaa aaataaacaa ataggggttc cgcgcacatt tccccgaaaa 13680
gtgccaccta aattgtaagc gttaatattt tgttaaaatt cgcgttaaat ttttgttaaa 13740
tcagctcatt ttttaaccaa taggccgaaa tcggcaaaat cccttataaa tcaaaagaat 13800
agaccgagat agggttgagt ggccgctaca gggcgctccc attcgccatt caggctgcgc 13860
aactgttggg aagggcgttt cggtgcgggc ctcttcgcta ttacgccagc tggcgaaagg 13920
gggatgtgct gcaaggcgat taagttgggt aacgccaggg ttttcccagt cacacgcgta 13980
atacgactca ctatag 13996
<210> 27
<211> 14005
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co80的核苷酸序列
<400> 27
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atctgaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatctctgg caccaacggc acaaagcgct tcgacaatcc 7800
tgtgttgccg tttaacgacg gcgtttactt cgccagcaca gaaaagagca acatcatccg 7860
gggctggatc ttcggcacca ccctggacag caaaacccaa agcctgctca tcgtgaacaa 7920
cgccaccaac gtggtgatca aggtgtgcga gttccagttc tgcaatgatc cttttctggg 7980
cgtgtatcac aagaacaaca agagctggat ggaaagcgag ttcagagtgt attctagcgc 8040
caacaactgc acctttgagt acgtgtccca gccctttctt atggacctgg aaggcaagca 8100
gggcaacttc aagaatctga gagaattcgt gttcaagaac attgatggct acttcaagat 8160
ctacagcaag cacaccccta tcaacctggt tcgggacctg ccacaaggct tcagcgccct 8220
ggaacctctg gtggacctgc ctatcggcat caacatcaca cggttccaaa ccctgctggc 8280
cctgcaccgg agctacctga cccccggcga cagcagcagc ggctggaccg ccggcgctgc 8340
cgcctattac gtgggctacc tgcaacctag aaccttcctg ctgaaataca acgagaacgg 8400
cacaatcacc gacgccgtgg actgtgccct ggaccccctg tctgagacaa agtgtaccct 8460
gaagtctttc accgtggaga agggcatcta ccagaccagc aacttccggg tgcagcctac 8520
agaatctata gtgcggttcc ctaacatcac caacctgtgt ccttttggcg aggtgttcaa 8580
cgccactcgg ttcgcctctg tctacgcctg gaaccggaaa cggatctcta attgcgtggc 8640
cgattacagc gtcctgtata actccgccag tttcagcaca ttcaagtgct acggcgtgtc 8700
acccaccaag ctgaacgatc tgtgcttcac caatgtgtac gccgatagtt tcgtgatccg 8760
gggcgatgag gtgcggcaga tcgcccctgg acagacaggc aagatcgccg actacaacta 8820
caagctgcct gacgacttca caggctgtgt gatcgcatgg aacagcaaca acctggacag 8880
caaggtgggc ggaaactaca actacctgta cagactgttc agaaagtcca acctgaagcc 8940
tttcgagaga gatatatcta ccgagatcta ccaggccggc agcacaccct gtaatggagt 9000
ggaaggcttt aactgctact tccctctgca aagctatgga tttcaaccta catatggggt 9060
tggctaccag ccttacagag tggtggtcct tagcttcgag ctgctccatg cccctgccac 9120
cgtgtgcgga cctaagaagt ccaccaacct ggtgaaaaac aagtgcgtga actttaattt 9180
taacggcctg accggaacag gagtgctgac agaaagcaac aaaaagttcc tgcctttcca 9240
gcagttcggc agagacattg acgacaccac agatgctgtt agagaccccc agacgctgga 9300
aatcctggat atcaccccct gctcttttgg cggcgtgagc gtgatcaccc caggcacaaa 9360
cacaagcaac caggtggctg tgctgtacca gggcgtgaac tgtacagagg tccctgtggc 9420
aatccacgcc gatcagctga cccctacatg gcgggtgtac tccactggat ctaacgtgtt 9480
ccagacaagg gccggatgcc tcatcggcgc tgagcacgtg aacaattctt acgagtgcga 9540
catccctatt ggagcgggca tctgcgccag ctaccagaca cagaccaata gccatcagca 9600
agccgctagc gtggcctccc agagcatcat cgcctacacc atgagcctgg gagccgagaa 9660
ctctgtggcc tacagcaaca acagcatcgc tatccctatc aacttcacca tctctgtcac 9720
caccgaaatc ctgcccgtca gtatgaccaa aaccagcgtc gactgcacca tgtacatatg 9780
cggcgatagc accgaatgca gcaacctgct gctgcagtat ggctccttct gcacccaact 9840
taacagagcc ctgactggca tcgccgtgga gcaggacaag aatacccagg aggtgttcgc 9900
ccaggtgaag cagatctaca agacaccccc gatcaaggac ttcggcggct ttaatttctc 9960
tcagatcctg ccagacccat ctaaaccctc taagcggagc tttatcgagg acctgctgtt 10020
caacaaggtg actctggctg acgccggctt catcaagcag tacggcgatt gcctgggcga 10080
cattgctgct agagacctga tctgtgccca gaaattcaac ggtcttactg tgctgcctcc 10140
tctgctgacg gatgagatga tcgcccagta caccagcgcc ctgctggccg gcaccatcac 10200
atccggctgg acattcggcg ccggcgcagc cctgcagatc ccttttgcca tgcagatggc 10260
ctaccggttc aacggaatcg gagtgacaca gaacgtgctc tacgaaaatc agaagttgat 10320
cgccaaccag ttcaacagcg ccatcggcaa gattcaggat agtctgagtt ccaccgccag 10380
cgccctggga aagctgcagg acgtggtcaa tcagaatgcc caagccctga acaccctggt 10440
gaagcagctg agcagcaact tcggcgccat cagctctgtg ctgaacgaca tcctggctag 10500
actggacaag gtggaagccg aagtgcagat cgacagattg atcaccggaa gactgcaaag 10560
cctgcagacc tacgtgaccc agcagctgat aagagctgct gaaatcagag ccagcgctaa 10620
tctggccgct accaagatga gcgagtgcgt tctgggccag tctaagagag tggacttctg 10680
cggaaaaggc taccacctga tgtcctttcc tcagtctgcc ccccacggcg tggtgttcct 10740
gcacgtcaca tacgtgcccg ctcaagagaa aaacttcacc acggcccctg ccatctgtca 10800
cgacggcaag gcccacttcc ccagagaggg cgtgttcgtg agcaatggca cccactggtt 10860
tgtgactcag agaaacttct acgagccaca gattatcacc acacataaca ccttcgtgtc 10920
tggcaactgc gacgtggtga tcggcatcgt caacaacaca gtgtacgacc cactgcaacc 10980
tgagctggac tcattcaagg aggaactgga taagtacttc aagaatcaca ccagccccga 11040
cgttgacctg ggcgacatca gcggcattaa cgcctctgtg gtcaacatcc agaaggaaat 11100
cgacagactg aatgaggtgg ccaagaattt gaacgagagc ctgattgatc tgcaggagct 11160
gggcaaatac gagcagtaca tcaagtggcc ttggtacatc tggctgggct tcatcgccgg 11220
gctgatcgcc atcgttatgg tgacaatcat gctgtgttgc atgacaagct gttgtagctg 11280
cctgaaaggc tgctgctcct gcggcagctg ttgcaagttt gacgaagatg acagcgagcc 11340
cgtgctgaaa ggcgtcaagc tgcactacac ctgaggcgcg cccacccagc ggccgcccgc 11400
tacgccccaa tgatccgacc agcaaaactc gatgtacttc cgaggaactg atgtgcataa 11460
tgcatcaggc tggtacatta gatccccgct taccgcgggc aatatagcaa cactaaaaac 11520
tcgatgtact tccgaggaag cgcagtgcat aatgctgcgc agtgttgcca cataaccact 11580
atattaacca tttatctagc ggacgccaaa aactcaatgt atttctgagg aagcgtggtg 11640
cataatgcca cgcagcgtct gcataacttt tattatttct tttattaatc aacaaaattt 11700
tgtttttaac atttcaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aagaagagcg 11760
tttaaacacg tgatatctgg cctcatgggc cttcctttca ctgcccgctt tccagtcggg 11820
aaacctgtcg tgccagctgc attaacatgg tcatagctgt ttccttgcgt attgggcgct 11880
ctccgcttcc tcgctcactg actcgctgcg ctcggtcgtt cgggtaaagc ctggggtgcc 11940
taatgagcaa aaggccagca aaaggccagg aaccgtaaaa aggccgcgtt gctggcgttt 12000
ttccataggc tccgcccccc tgacgagcat cacaaaaatc gacgctcaag tcagaggtgg 12060
cgaaacccga caggactata aagataccag gcgtttcccc ctggaagctc cctcgtgcgc 12120
tctcctgttc cgaccctgcc gcttaccgga tacctgtccg cctttctccc ttcgggaagc 12180
gtggcgcttt ctcatagctc acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc 12240
aagctgggct gtgtgcacga accccccgtt cagcccgacc gctgcgcctt atccggtaac 12300
tatcgtcttg agtccaaccc ggtaagacac gacttatcgc cactggcagc agccactggt 12360
aacaggatta gcagagcgag gtatgtaggc ggtgctacag agttcttgaa gtggtggcct 12420
aactacggct acactagaag aacagtattt ggtatctgcg ctctgctgaa gccagttacc 12480
ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt 12540
ttttttgttt gcaggcagca gattacgcgc agaaaaaaag gatctcaaga agatcctttg 12600
atcttttcta cggggtctga cgctcagtgg aacgaaaact cacgttaagg gattttggtc 12660
atgaatacac ggtgcctgac tgcgttagca atttaactgt gataaactac cgcattaaag 12720
cttatcgatg ataagctgtc aaacatgaga attcttagaa aaactcatcg agcatcaaat 12780
gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa agccgtttct 12840
gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc tggtatcggt 12900
ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg tcaaaaataa 12960
ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat ggcaaaagct 13020
tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca tcaaaatcac 13080
tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga aatacgcgat 13140
cgctgttaaa aggacaatta caaacaggaa tcgaatgcaa ccggcgcagg aacactgcca 13200
gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg aatgctgttt 13260
tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata aaatgcttga 13320
tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca tctgtaacat 13380
cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg ggcttcccat 13440
acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat ttatacccat 13500
ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt tcccgttgaa 13560
tatggctcat aacacccctt gtattactgt ttatgtaagc agacagtttt attgttcatg 13620
agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt 13680
ccccgaaaag tgccacctaa attgtaagcg ttaatatttt gttaaaattc gcgttaaatt 13740
tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaaaatc ccttataaat 13800
caaaagaata gaccgagata gggttgagtg gccgctacag ggcgctccca ttcgccattc 13860
aggctgcgca actgttggga agggcgtttc ggtgcgggcc tcttcgctat tacgccagct 13920
ggcgaaaggg ggatgtgctg caaggcgatt aagttgggta acgccagggt tttcccagtc 13980
acacgcgtaa tacgactcac tatag 14005
<210> 28
<211> 14005
<212> DNA
<213> 人工序列
<220>
<223> 构建体Co81的核苷酸序列
<400> 28
ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60
ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120
aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180
tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240
gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300
gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360
aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420
ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480
aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540
ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600
agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660
cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720
ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780
ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840
tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900
tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960
cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020
tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080
tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140
tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200
tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260
ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320
acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380
atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440
caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500
acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560
tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620
tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680
aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740
ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800
taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860
tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920
ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980
gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040
aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100
ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160
cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220
gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280
aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340
ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400
ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460
ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520
tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580
gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640
cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700
aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760
aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820
ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880
tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940
taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000
cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060
agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120
tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180
cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240
gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300
cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360
cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420
gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480
tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540
gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600
tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660
tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720
agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780
tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840
gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900
cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960
acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020
aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080
gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140
tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200
tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260
cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320
acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380
acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440
cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500
ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560
atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620
caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680
atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740
tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800
aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860
gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920
tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980
caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040
acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100
cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160
aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220
aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280
ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340
gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400
gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460
gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520
caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580
ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640
ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700
catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760
cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820
tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880
acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940
ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000
tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060
cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120
ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180
ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240
ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300
ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360
cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420
ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480
aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540
taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600
aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660
cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720
acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780
tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840
acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900
tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960
aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020
tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080
cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140
acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200
aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260
gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320
aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380
gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440
tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500
gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560
gatgttcgtg ttcctggtgc tgctgcccct cgttagcagc cagtgcgtga atttcaccac 7620
ccgcacccag ctgccaccag cctacacaaa cagcttcacc agaggagtgt attaccctga 7680
taaggtcttt agatcctccg tcctgcattc tacgcaggat ctcttcttgc cattcttcag 7740
caacgtgaca tggttccacg ccatccacgt ttctggcacc aacggcacaa agcgcttcgc 7800
caatcctgtg ttgccgttta acgacggcgt ttacttcgcc agcacagaaa agagcaacat 7860
catccggggc tggatcttcg gcaccaccct ggacagcaaa acccaaagcc tgctcatcgt 7920
gaacaacgcc accaacgtgg tgatcaaggt gtgcgagttc cagttctgca atgatccttt 7980
tctgggcgtg tactatcaca agaacaacaa gagctggatg gaaagcgagt tcagagtgta 8040
ttctagcgcc aacaactgca cctttgagta cgtgtcccag ccctttctta tggacctgga 8100
aggcaagcag ggcaacttca agaatctgag agaattcgtg ttcaagaaca ttgatggcta 8160
cttcaagatc tacagcaagc acacccctat caacctggtt cggggcctgc cacaaggctt 8220
cagcgccctg gaacctctgg tggacctgcc tatcggcatc aacatcacac ggttccaaac 8280
cctgcaccgg agctacctga cccccggcga cagcagcagc ggctggaccg ccggcgctgc 8340
cgcctattac gtgggctacc tgcaacctag aaccttcctg ctgaaataca acgagaacgg 8400
cacaatcacc gacgccgtgg actgtgccct ggaccccctg tctgagacaa agtgtaccct 8460
gaagtctttc accgtggaga agggcatcta ccagaccagc aacttccggg tgcagcctac 8520
agaatctata gtgcggttcc ctaacatcac caacctgtgt ccttttggcg aggtgttcaa 8580
cgccactcgg ttcgcctctg tctacgcctg gaaccggaaa cggatctcta attgcgtggc 8640
cgattacagc gtcctgtata actccgccag tttcagcaca ttcaagtgct acggcgtgtc 8700
acccaccaag ctgaacgatc tgtgcttcac caatgtgtac gccgatagtt tcgtgatccg 8760
gggcgatgag gtgcggcaga tcgcccctgg acagacaggc aatatcgccg actacaacta 8820
caagctgcct gacgacttca caggctgtgt gatcgcatgg aacagcaaca acctggacag 8880
caaggtgggc ggaaactaca actacctgta cagactgttc agaaagtcca acctgaagcc 8940
tttcgagaga gatatatcta ccgagatcta ccaggccggc agcacaccct gtaatggagt 9000
gaaaggcttt aactgctact tccctctgca aagctatgga tttcaaccta catatggggt 9060
tggctaccag ccttacagag tggtggtcct tagcttcgag ctgctccatg cccctgccac 9120
cgtgtgcgga cctaagaagt ccaccaacct ggtgaaaaac aagtgcgtga actttaattt 9180
taacggcctg accggaacag gagtgctgac agaaagcaac aaaaagttcc tgcctttcca 9240
gcagttcggc agagacattg ccgacaccac agatgctgtt agagaccccc agacgctgga 9300
aatcctggat atcaccccct gctcttttgg cggcgtgagc gtgatcaccc caggcacaaa 9360
cacaagcaac caggtggctg tgctgtacca gggcgtgaac tgtacagagg tccctgtggc 9420
aatccacgcc gatcagctga cccctacatg gcgggtgtac tccactggat ctaacgtgtt 9480
ccagacaagg gccggatgcc tcatcggcgc tgagcacgtg aacaattctt acgagtgcga 9540
catccctatt ggagcgggca tctgcgccag ctaccagaca cagaccaata gccctcagca 9600
agccgctagc gtggcctccc agagcatcat cgcctacacc atgagcctgg gagtcgagaa 9660
ctctgtggcc tacagcaaca acagcatcgc tatccctacc aacttcacca tctctgtcac 9720
caccgaaatc ctgcccgtca gtatgaccaa aaccagcgtc gactgcacca tgtacatatg 9780
cggcgatagc accgaatgca gcaacctgct gctgcagtat ggctccttct gcacccaact 9840
taacagagcc ctgactggca tcgccgtgga gcaggacaag aatacccagg aggtgttcgc 9900
ccaggtgaag cagatctaca agacaccccc gatcaaggac ttcggcggct ttaatttctc 9960
tcagatcctg ccagacccat ctaaaccctc taagcggagc tttatcgagg acctgctgtt 10020
caacaaggtg actctggctg acgccggctt catcaagcag tacggcgatt gcctgggcga 10080
cattgctgct agagacctga tctgtgccca gaaattcaac ggtcttactg tgctgcctcc 10140
tctgctgacg gatgagatga tcgcccagta caccagcgcc ctgctggccg gcaccatcac 10200
atccggctgg acattcggcg ccggcgcagc cctgcagatc ccttttgcca tgcagatggc 10260
ctaccggttc aacggaatcg gagtgacaca gaacgtgctc tacgaaaatc agaagttgat 10320
cgccaaccag ttcaacagcg ccatcggcaa gattcaggat agtctgagtt ccaccgccag 10380
cgccctggga aagctgcagg acgtggtcaa tcagaatgcc caagccctga acaccctggt 10440
gaagcagctg agcagcaact tcggcgccat cagctctgtg ctgaacgaca tcctgagtag 10500
actggacaag gtggaagccg aagtgcagat cgacagattg atcaccggaa gactgcaaag 10560
cctgcagacc tacgtgaccc agcagctgat aagagctgct gaaatcagag ccagcgctaa 10620
tctggccgct accaagatga gcgagtgcgt tctgggccag tctaagagag tggacttctg 10680
cggaaaaggc taccacctga tgtcctttcc tcagtctgcc ccccacggcg tggtgttcct 10740
gcacgtcaca tacgtgcccg ctcaagagaa aaacttcacc acggcccctg ccatctgtca 10800
cgacggcaag gcccacttcc ccagagaggg cgtgttcgtg agcaatggca cccactggtt 10860
tgtgactcag agaaacttct acgagccaca gattatcacc acagataaca ccttcgtgtc 10920
tggcaactgc gacgtggtga tcggcatcgt caacaacaca gtgtacgacc cactgcaacc 10980
tgagctggac tcattcaagg aggaactgga taagtacttc aagaatcaca ccagccccga 11040
cgttgacctg ggcgacatca gcggcattaa cgcctctgtg gtcaacatcc agaaggaaat 11100
cgacagactg aatgaggtgg ccaagaattt gaacgagagc ctgattgatc tgcaggagct 11160
gggcaaatac gagcagtaca tcaagtggcc ttggtacatc tggctgggct tcatcgccgg 11220
gctgatcgcc atcgttatgg tgacaatcat gctgtgttgc atgacaagct gttgtagctg 11280
cctgaaaggc tgctgctcct gcggcagctg ttgcaagttt gacgaagatg acagcgagcc 11340
cgtgctgaaa ggcgtcaagc tgcactacac ctgaggcgcg cccacccagc ggccgcccgc 11400
tacgccccaa tgatccgacc agcaaaactc gatgtacttc cgaggaactg atgtgcataa 11460
tgcatcaggc tggtacatta gatccccgct taccgcgggc aatatagcaa cactaaaaac 11520
tcgatgtact tccgaggaag cgcagtgcat aatgctgcgc agtgttgcca cataaccact 11580
atattaacca tttatctagc ggacgccaaa aactcaatgt atttctgagg aagcgtggtg 11640
cataatgcca cgcagcgtct gcataacttt tattatttct tttattaatc aacaaaattt 11700
tgtttttaac atttcaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aagaagagcg 11760
tttaaacacg tgatatctgg cctcatgggc cttcctttca ctgcccgctt tccagtcggg 11820
aaacctgtcg tgccagctgc attaacatgg tcatagctgt ttccttgcgt attgggcgct 11880
ctccgcttcc tcgctcactg actcgctgcg ctcggtcgtt cgggtaaagc ctggggtgcc 11940
taatgagcaa aaggccagca aaaggccagg aaccgtaaaa aggccgcgtt gctggcgttt 12000
ttccataggc tccgcccccc tgacgagcat cacaaaaatc gacgctcaag tcagaggtgg 12060
cgaaacccga caggactata aagataccag gcgtttcccc ctggaagctc cctcgtgcgc 12120
tctcctgttc cgaccctgcc gcttaccgga tacctgtccg cctttctccc ttcgggaagc 12180
gtggcgcttt ctcatagctc acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc 12240
aagctgggct gtgtgcacga accccccgtt cagcccgacc gctgcgcctt atccggtaac 12300
tatcgtcttg agtccaaccc ggtaagacac gacttatcgc cactggcagc agccactggt 12360
aacaggatta gcagagcgag gtatgtaggc ggtgctacag agttcttgaa gtggtggcct 12420
aactacggct acactagaag aacagtattt ggtatctgcg ctctgctgaa gccagttacc 12480
ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt 12540
ttttttgttt gcaggcagca gattacgcgc agaaaaaaag gatctcaaga agatcctttg 12600
atcttttcta cggggtctga cgctcagtgg aacgaaaact cacgttaagg gattttggtc 12660
atgaatacac ggtgcctgac tgcgttagca atttaactgt gataaactac cgcattaaag 12720
cttatcgatg ataagctgtc aaacatgaga attcttagaa aaactcatcg agcatcaaat 12780
gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa agccgtttct 12840
gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc tggtatcggt 12900
ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg tcaaaaataa 12960
ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat ggcaaaagct 13020
tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca tcaaaatcac 13080
tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga aatacgcgat 13140
cgctgttaaa aggacaatta caaacaggaa tcgaatgcaa ccggcgcagg aacactgcca 13200
gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg aatgctgttt 13260
tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata aaatgcttga 13320
tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca tctgtaacat 13380
cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg ggcttcccat 13440
acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat ttatacccat 13500
ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt tcccgttgaa 13560
tatggctcat aacacccctt gtattactgt ttatgtaagc agacagtttt attgttcatg 13620
agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt 13680
ccccgaaaag tgccacctaa attgtaagcg ttaatatttt gttaaaattc gcgttaaatt 13740
tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaaaatc ccttataaat 13800
caaaagaata gaccgagata gggttgagtg gccgctacag ggcgctccca ttcgccattc 13860
aggctgcgca actgttggga agggcgtttc ggtgcgggcc tcttcgctat tacgccagct 13920
ggcgaaaggg ggatgtgctg caaggcgatt aagttgggta acgccagggt tttcccagtc 13980
acacgcgtaa tacgactcac tatag 14005
<210> 29
<211> 45
<212> DNA
<213> 委内瑞拉马脑炎病毒(Venezuelan equine encephalitis virus)
<400> 29
gataggcggc gcatgagaga agcccagacc aattacctac ccaaa 45
<210> 30
<211> 341
<212> DNA
<213> 辛德比斯病毒(Sindbis virus)
<400> 30
ggcgcgccca cccagcggcc gcccgctacg ccccaatgat ccgaccagca aaactcgatg 60
tacttccgag gaactgatgt gcataatgca tcaggctggt acattagatc cccgcttacc 120
gcgggcaata tagcaacact aaaaactcga tgtacttccg aggaagcgca gtgcataatg 180
ctgcgcagtg ttgccacata accactatat taaccattta tctagcggac gccaaaaact 240
caatgtattt ctgaggaagc gtggtgcata atgccacgca gcgtctgcat aacttttatt 300
atttctttta ttaatcaaca aaattttgtt tttaacattt c 341
<210> 31
<211> 10
<212> DNA
<213> 人工序列
<220>
<223> 富含GC的元件
<400> 31
ccccggcgcc 10
<210> 32
<211> 7
<212> DNA
<213> 人工序列
<220>
<223> 富含GC的元件
<400> 32
ccccggc 7
<210> 33
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 富含GC的元件
<400> 33
gcgccccgcg gcgccccgcg 20
<210> 34
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 组蛋白茎环序列
<400> 34
caaaggctct tttcagagcc acca 24
<210> 35
<211> 7
<212> DNA
<213> 人工序列
<220>
<223> Kozak共有序列
<400> 35
accatgg 7
<210> 36
<211> 6
<212> DNA
<213> 人工序列
<220>
<223> Kozak共有序列
<400> 36
accatg 6
<210> 37
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> poly-a序列
<400> 37
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 36
Claims (29)
1.一种自我复制RNA,其包括与亚基因组启动子可操作地连接的编码抗原的核苷酸序列,其中所述抗原来自严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)。
2.一种单顺反子自我复制RNA,其包括与亚基因组启动子可操作地连接的编码抗原的核苷酸序列,其中所述抗原来自SARS-CoV-2。
3.根据权利要求1或2所述的自我复制RNA,其中所述抗原是刺突(S)蛋白或核衣壳(N)蛋白。
4.根据权利要求3所述的自我复制RNA,其中所述S蛋白由SEQ ID NO:1中所示的序列编码。
5.根据权利要求3所述的自我复制RNA,其中所述S蛋白是突变S蛋白。
6.根据权利要求5所述的自我复制RNA,其中:
(i)所述突变S蛋白在S1/S2边界处缺乏弗林蛋白酶切割位点,并且包括与SEQID NO:18的核苷酸682-685相对应的残基处的RRAR变为QQAA的突变;和/或
(ii)所述突变S蛋白在S2'位点处缺乏弗林蛋白酶切割位点;和/或
(iii)所述突变S蛋白包括与SEQ ID NO:18的核苷酸614相对应的残基处的D变为G的突变;和/或
(iv)所述突变S蛋白包括与SEQ ID NO:18的核苷酸986和987相对应的残基之间的两个脯氨酸残基的插入。
7.根据权利要求5或6所述的自我复制RNA,其中所述突变S蛋白由SEQ ID NO:2至7和/或SEQ ID NO:19-23中的任一个中所示的序列编码。
8.根据权利要求3所述的自我复制RNA,其中所述N蛋白由SEQ ID NO:8中所示的序列编码。
9.根据权利要求1至8中任一项所述的自我复制RNA,其中SG启动子由SEQ IDNO:9中所示的序列编码。
10.根据权利要求1至9中任一项所述的自我复制RNA,其中所述自我复制RNA来自甲病毒属(alphavirus)。
11.根据权利要求10所述的自我复制RNA,其中所述甲病毒属选自由以下组成的组:塞姆利基森林病毒(Semliki Forest virus,SFV)、辛德比斯病毒(Sindbis virus,SIN)和委内瑞拉马脑炎病毒(Venezuelan equine encephalitis virus,VEE)以及其组合。
12.根据权利要求1至11中任一项所述的自我复制RNA,其中所述RNA由SEQ ID NO:10至17中的任一个中所示的序列编码。
13.一种免疫原性组合物,其包括根据权利要求1至12中任一项所述的自我复制RNA。
14.根据权利要求13所述的免疫原性组合物,其包括多个根据权利要求1至12中任一项所述的自我复制RNA,其中每个自我复制RNA编码不同的多肽抗原序列。
15.一种药物组合物,其包括根据权利要求13或14所述的免疫原性组合物以及药学上可接受的载体。
16.根据权利要求15所述的药物组合物,其进一步包括脂质纳米颗粒(LNP)、聚合物微粒或水包油乳液。
17.根据权利要求16所述的药物组合物,其中所述自我复制RNA被包封在LNP、聚合物微粒或水包油乳液中、与LNP、聚合物微粒或水包油乳液结合或吸附在LNP、聚合物微粒或水包油乳液上。
18.根据权利要求13或14所述的免疫原性组合物或根据权利要求15至17中任一项所述的药物组合物,其用作疫苗。
19.根据权利要求13或14所述的免疫原性组合物或根据权利要求15至17中任一项所述的药物组合物,其用于治疗或预防选自由以下组成的组的疾病或病状或延缓所述疾病或病状的进展:SARS-CoV-2感染、冠状病毒疾病2019(COVID-19)、急性呼吸道疾病综合征(ARDS)以及其组合。
20.一种治疗或预防受试者的疾病或病状或延缓所述疾病或病状的进展的方法,所述方法包括向有需要的受试者施用根据权利要求13或14所述的免疫原性组合物或根据权利要求15至17中任一项所述的药物组合物。
21.一种根据权利要求1至12中任一项所述的自我复制RNA、或根据权利要求13或14所述的免疫原性组合物或根据权利要求15至17中任一项所述的药物组合物在制备用于治疗或预防有需要的受试者的疾病或病状或延缓所述疾病或病状的进展的药物中的用途。
22.根据权利要求20所述的方法或根据权利要求21所述的用途,其中所述疾病或病状选自由以下组成的组:SARS-CoV-2感染、COVID-19、ARDS以及其组合。
23.一种诱导受试者的免疫应答的方法,所述方法包括向有需要的受试者施用根据权利要求13或14所述的免疫原性组合物或根据权利要求15至17中任一项所述的药物组合物。
24.根据权利要求23所述的方法,其中所述免疫应答是体液和/或细胞介导的免疫应答。
25.一种根据权利要求1至12中任一项所述的自我复制RNA、或根据权利要求13或14所述的免疫原性组合物或根据权利要求15至17中任一项所述的药物组合物在制备用于诱导有需要的受试者的免疫应答的药物中的用途。
26.一种多核苷酸,其编码根据权利要求1至12中任一项所述的自我复制RNA。
27.根据权利要求26所述的多核苷酸,其中所述多核苷酸是重组DNA。
28.根据权利要求27所述的多核苷酸,其中所述重组DNA是质粒。
29.根据权利要求28所述的多核苷酸,其中所述质粒包括SEQ ID NO:10至17中的任一个中所示的序列。
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PCT/IB2022/051021 WO2023148527A1 (en) | 2022-02-07 | 2022-02-07 | Self-replicating rna and uses thereof |
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US11130787B2 (en) * | 2020-06-11 | 2021-09-28 | MBF Therapeutics, Inc. | Alphaherpesvirus glycoprotein d-encoding nucleic acid constructs and methods |
CN113185613B (zh) * | 2021-04-13 | 2022-09-13 | 武汉大学 | 新型冠状病毒s蛋白及其亚单位疫苗 |
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- 2022-02-07 EP EP22920982.0A patent/EP4267108A1/en active Pending
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