CN102876793B - Application of single nucleotide polymorphism rs2058660 to detecting susceptibility gene of leprosy - Google Patents
Application of single nucleotide polymorphism rs2058660 to detecting susceptibility gene of leprosy Download PDFInfo
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Abstract
The invention discloses application of single nucleotide polymorphism rs2058660 to detecting a susceptibility gene of leprosy. One technical scheme includes application of a substance for detecting rs2058660 polymorphism or genotype in a personal genome to preparing a product for detecting single nucleotide polymorphism related to the leprosy. The substance for detecting rs2058660 polymorphism can be combined with other substances (such as a substance for detecting other single nucleotide polymorphism related to the leprosy) to prepare a product for screening lepers.
Description
Technical field
The present invention relates to the application of single nucleotide polymorphism rs2058660 in detecting leprosy tumor susceptibility gene.
Background technology
Single nucleotide polymorphism (single nucleotide polymorphism, SNP) refers to the variation of genome single core thuja acid, and it is the most small variation unit, is to displacement, transversion, insertion or lack formed variant form by single core thuja acid.Single nucleotide polymorphism is highdensity genetic marker on genome, and the SNP quantity of having found in human genome surpasses 30,000,000.As third generation genetic marker SNP One's name is legion, densely distributed, be easy to detect, because of but desirable gene type target.SNP somatotype detects at disease genome (as disease susceptibility), in the researchs such as Drug Discovery (drug effect, drug metabolism difference and untoward reaction) and Swarm Evolution, is significant.
At present existing several different methods can be used for SNP and detects, as DNA sequencing, Restriction fragment length polymorphism, single strand conformation polymorphism, sex change high performance liquid chromatography, SNP chip.Wherein, SNP chip comprises chip based on nucleic acid hybridization reaction, the chip based on single base extension, the chip based on allele-specific primers extension, the chip based on " single stage method " reaction, the chip based on primer ligation, the chip based on restriction enzyme reaction, the chip based on protein D NA association reaction, and the chip (Zhang little Yan etc. based on fluorescence molecule DNA association reaction.By genechip detection single nucleotide polymorphism reaction principle.Chinese biological engineering magazine.2005,25(11):52～56）。
Leprosy be a kind of chronic infectious disease ， developing country due to being infected by Mycobacterium leprae this remain a serious health problem, annual global neopathy number of cases is 250000.Main infringement skin and peripheral nerve, and cause the nerve function lesion of non-reversibility and chronic teratogenesis to be disabled.This has been proved to be in the environmental factors in the groove of leprosy and host genetic factor and has played vital effect, estimates that inherited genetic factors is up to 57%.
The scheme of the World Health Organization is divided into tuberculosis type and knurl type the clinical manifestation of leprosy, and respectively corresponding Th1(is cell-mediated) and Th2(body fluid mediate) immunne response of the human body of tissue.The multifarious clinical manifestation of leprosy reflects that human body is to two of allogenic disease substance kinds of distinct immunne responses, and this just illustrates the importance of genetic predisposition in leprosy morbidity.The result of genetic research shows that heredity is all relevant with the disease progression of vulnerability to leprosy and its clinical subtype.
Summary of the invention
Technical problem to be solved by this invention is to provide the new purposes of single nucleotide polymorphism rs2058660 aspect leprosy.
New purposes provided by the present invention is following 1)-9) at least one:
1) detect polymorphism or the application of genotypic material in the product of the preparation detection single nucleotide polymorphism relevant to leprosy of rs2058660 in human genome;
2) detect the application in the product of characterization or the assistant identification single nucleotide polymorphism relevant to leprosy of the polymorphism of rs2058660 in human genome or genotypic material;
3) detect polymorphism or the application of genotypic material in preparation examination leper product of rs2058660 in human genome;
4) polymorphism or the genotypic material that detect rs2058660 in human genome detect the application in leprosy susceptibility product in preparation;
5) application of the single nucleotide polymorphism in human genome in the product of preparation detection leprosy tumor susceptibility gene, wherein, described single nucleotide polymorphism is that refSNP ID is the DNA sequence polymorphism of rs2058660;
6) application of the single nucleotide polymorphism in human genome in the product of characterization or assistant identification leprosy tumor susceptibility gene, wherein, described single nucleotide polymorphism is that refSNP ID is the DNA sequence polymorphism of rs2058660;
7) application of the polymorphism of rs2058660 in preparation examination leper product in human genome;
8) in human genome, the polymorphism of rs2058660 detects the application in leprosy susceptibility product in preparation;
9) comprising the product that detects the material of rs2058660 polymorphism in human genome, is a)-d) in any product:
A) detect the product of the single nucleotide polymorphism relevant to leprosy,
The product of the single nucleotide polymorphism that b) evaluation or assistant identification are relevant to leprosy,
C) examination leper product,
D) detect leprosy susceptibility product.
In an embodiment of the present invention, described leprosy is specially Chinese han population and ethnic minority's leprosy.
Rs2058660 is the SNP site of two equipotential polymorphisms on human chromosome 2q12.1, and this variation is conversion (C/T is G/A on its complementary strand).Described rs2058660 genotype is CC, CT or TT.Described CC is that rs2058660 site is the homozygous of C, and described TT is that rs2058660 site is the homozygous of T, and described CT is that rs2058660 site is the heterozygous of T and C.In described detection human genome, the polymorphism of rs2058660 or genotype specifically can be the Nucleotide kind that detects rs2735591.
Experiment showed, that rs2058660 is 4.57 * 10 in the P value of the case colony being comprised of 5503 lepers and the case-control colony that is comprised of 4971 normal peoples
-19, relative risk is 1.30, illustrates that rs2058660 is the single nucleotide polymorphism relevant to leprosy.
Experiment showed, that, in three genotype of rs2058660, the ratio of the genotypic individuality of TT in normal people colony is 21.0%, is starkly lower than the ratio 30.6% in leper colony.In actual applications, material and other material (as detected other the material of relevant single nucleotide polymorphism with the leprosy) gang that detects the polymorphism of rs2058660 can be prepared to examination leper's product.
Wherein, in detection human genome, the material of the polymorphism of rs2058660 can be required reagent and/or the instrument of polymorphism of determining rs2058660 by following at least one method: DNA sequencing, Restriction fragment length polymorphism, single strand conformation polymorphism, sex change high performance liquid chromatography and SNP chip.Wherein, SNP chip comprises chip based on nucleic acid hybridization reaction, the chip based on single base extension, the chip based on allele-specific primers extension, the chip based on " single stage method " reaction, the chip based on primer ligation, the chip based on restriction enzyme reaction, the chip based on protein D NA association reaction, and the chip based on fluorescence molecule DNA association reaction.
Described product can be reagent or test kit, also can be the combined prod of reagent or test kit and instrument, as the combined prod being formed by primer and DNA sequencer, and the combined prod being formed by PCR reagent and DNA sequencing reagent and DNA sequencer.
In one embodiment of the present of invention, adopt PCR primer amplification to comprise the genomic DNA fragment of rs2058660, the pcr amplification product obtaining of take is template, adopt single-basic extension primer to carry out single base extension, sequence to the extension products obtaining detects, and determines polymorphism and the genotype of rs2058660.Described PCR primer does not have particular requirement in sequence, as long as can amplify the genomic DNA fragment that comprises rs2058660, specifically can be the single stranded DNA shown in sequence 3 and sequence 4.Described extension primer designs according to rs2058660 upstream in human genome (not comprising this SNP site), front 1 Nucleotide of last 1 Nucleotide correspondence of described extension primer rs2058660 in human genome, as as described in extension primer specifically can be the single stranded DNA as shown in the sequence 6 in sequence table, certainly also the single stranded DNA shown in sequence 6 can be extended to an above Nucleotide according to the downstream sequence of rs2058660 in human genome, or according to above Nucleotide of the downstream sequence disappearance of rs2058660 in human genome, as long as can make 3 ' end of this single-basic extension primer extend the Nucleotide in rs2058660 site.
The present invention finds that in a sample from Chinese population (5503 leper with 4971 healthy persons) rs2058660 is the single nucleotide polymorphism relevant to leprosy.Material and other material (as detected other the material of relevant single nucleotide polymorphism with the leprosy) gang that detects the polymorphism of rs2058660 can be prepared to examination leper's product.
Accompanying drawing explanation
Fig. 1 is the associated region of rs2058660.
The left side longitudinal axis is shown as the P value of SNP, and the right side longitudinal axis is shown as recombination fraction, and transverse axis shows its physical location.In each region, SNP and this relation conefficient (r2) of testing positive SNP site rs2058660 are used different colours mark, arrow indication be P value minimum SNP site in the positive SNP rs2058660 of this experiment, region and the SNP that in the past reported, the minimum SNP site rs1916307 of P value, the report site rs3771166 relevant to asthma all tested positive SNP site rs2058660 onrelevant with this in the past, and site rs917997, the rs13015714 relevant to celiac disease and positive site be associated (r by force
2> 0.8).The estimation of recombination fraction is based on China in thousand human genomes and Japanese population sample.The gene annotating in figure comes from (http://genome.ucsc.edu/).
Fig. 2 is the associated region of rs6871626.
The left side longitudinal axis is shown as the P value of SNP, and the right side longitudinal axis is shown as recombination fraction, and transverse axis shows its physical location.In each region, SNP and this are tested the relation conefficient (r of positive SNP site rs6871626
2) use different colours mark, arrow indication be P value minimum SNP site in the positive SNP rs6871626 of this experiment, region and the SNP that in the past reported, the site rs1422877 that P value is minimum and the rs10045431 relevant to Crohn disease, the rs2546890 that multiple sclerosis is relevant, the rs2546890 that psoriatic is relevant, rs3213094, rs2082412, the rs12188300 that arthropathic psoriasis is relevant, the relevant rs6556416 of ankylosing spondylitis all with positive SNP site rs6871626 onrelevant (r
2< 0.01).The estimation of recombination fraction is based on China in thousand human genomes and Japanese population sample.The gene annotating in figure comes from (http://genome.ucsc.edu/).
Embodiment
Following embodiment is convenient to understand better the present invention, but does not limit the present invention.Experimental technique in following embodiment, if no special instructions, is ordinary method.
In following embodiment, material used, reagent etc., if no special instructions, all can obtain from commercial channels.
Embodiment 1, rs2058660 are the single nucleotide polymorphism relevant to leprosy
Within 2009, contriver place research group adopts genome-wide association study (GWAS) in Chinese han population, to find 7 tumor susceptibility gene (CCDC122 of leprosy, C13orf31, NOD2, TNFSF15, HLA-DR, RIPK2 and LRRK2), wherein 5 genes are set up a signal path (Zhang centered by NOD2, F.R., Huang, W., Chen, S, M., Sun, L.D., Liu, H., Li, Y., Cui, Y., Yan, X.X., Yang, H.T., Yang, R.D.et al. (2009) Genomewide association study of leprosy.N.Engl.J.Med., 361, 2609-2618.), within 2011, after GWAS, found again 2 vulnerability to leprosy genes (IL23R and RAB32) (Zhang, F., Liu, H., Chen, S., Low, H., Sun, L., Cui, Y., Chu, T., Li, Y., Fu, X., Yu, Y.etal. (2011) Identification of two new loci at IL23R and RAB32that influence).The Complex Diseases that leprosy concurs as a plurality of minor genes of a class, 9 susceptibility locis finding are at present only the tips of the iceberg of its tumor susceptibility gene spectrum, more vulnerability to leprosy gene waits further discovery.
The selection of candidate gene and SNP
Contriver by the GWAS official website (http://www.genome.gov/26525384) of PUBMED, has consulted 12 CD(Crohn's diseases) GWAS research and 2 UC(ulcerative colitiss) GWAS study.Therefrom select 155 of being positioned on 118 genes and CD or UC or SNPs(p<5.0 * 10 that both are relevant
-8).Get rid of 7 SNP and 15 SNPs that are positioned on 5 known vulnerability to leprosy genes (NOD2, TNFSF15, IL23R, C13ORF31 and LRRK2) that are positioned at MHC region.Remaining 133 SNPs, comprise the related SNP s of 75 CD, 54 SNPs that UC is relevant, 41 IBD(MIM266600) (CD and UC) relevant SNPs.These are named a person for a particular job and are verified in 4 independent samples from Chinese population.
Ethics statement
This research has been passed through Ethics Committee of Dermatology and Venereology research institution of Shandong Academy of Medical Sciences and has been ratified, and all lepers and normal healthy controls person have all signed Informed Consent Form.
Research object
From four independent samples of Chinese population, in these four independent samples, have 4971 lepers, 5503 normal healthy controls persons.They are the independent individual of consanguinity-less relation.The information exchanges such as clinical classification, family history situation and age of onset are crossed case history collection.Sample standard deviation is by the Quality Control of sample.(clinical foundation comprises claw hand, reel foot and pathology foundation etc.) made a definite diagnosis in leper's the diagnosis at least expert of You Liangming Dermatology Department simultaneously.Normal healthy controls person all personally discusses disease medical history without leprosy family history and other.
Wherein, leprosy in China patient's Case definition be meet in following 4 more than 2 or 2, or meet the 3rd person and establish diagnosis: 1, skin damages with sensory disturbance and closes sweat, or has numb district; 2, peripheral nerve is got involved, and shows as the thick companion's corresponding function of nerve trunk obstacle; 3, skin damage tissue slice or tissue juice smear are found leprosy bacillus; 4, pathology visible features sexually revises.
Normal healthy controls person's Case definition: without leprosy medical history and other transmissible disease medical histories, without other autoimmune disorder medical history and family history.
Table 1 has shown the essential information of sample 1-4.
Table 1,4971 leprosy in China patients and 5503 normal healthy controls persons' basic condition
asample is from Shandong, Anhui and the Wuhan province in Chinese East China
bsample is from Shandong, Anhui and the Jiangsu Province in Chinese East China
csample is from Yunnan, Guizhou and the Fujian Province of In South China
dsample is from Yunnan, Guizhou and the Fujian Province of In South China.
The present invention's application Sequenom MassARRAY SNP genotyping technique (San Diego, USA) is analyzed the genotype of 4 groups of independence leprosy samples.In first stage, 133 SNPs of 1504 lepers from north of China and 1502 normal healthy controls persons have been carried out to gene type, wherein 119 successful somatotypes of quilt.The p value of 19 SNPs is less than 0.05, comprises the SNPs of 9 CD, the SNPs of the SNPs of 8 UC and 2 IBD.In subordinate phase, 19 above-mentioned SNPs are independently verified in Chinese population at another.This crowd is divided into 3 groups: 1) from 1154 lepers and 2605 normal healthy controls persons of Northern Han Nationality; 2) from 1165 lepers and 648 normal healthy controls persons of Han nationality in southern China; 3) from 1148 lepers and 748 normal healthy controls person's (Zhuangs: 358 lepers and 323 normal healthy controls persons of southern china ethnic minority; Miao ethnic group: 277 lepers and 190 collators; The Yi nationality, distributed over Yunnan, Sichuan and Guizhou: 366 lepers and 182 normal healthy controls persons; Other nationality: 147 lepers and 53 normal healthy controls persons).
In 4 groups of independent samples (p>0.05 of its genetic heterogeneity), found 2 new relevant SNPs, be positioned at the rs2058660 and the rs6871626 that is positioned at 5q33.3 of 2q12.1.Comprehensive analysis after all samples (4971 lepers and 5503 normal healthy controls persons), show that the p value of 2 SNPs is respectively 4.57 * 10
-19with 3.95 * 10
-18, OR value is respectively 1.30 and 0.75.
Table 2.rs2058660 is in the association analysis result of 4 independent samples and whole samples
aallelotrope for assessment of OR value.
bin four independent samples, detect allelic average frequency.
Table 3.rs6871626 is in the association analysis result of 4 independent samples and whole samples
aallelotrope for assessment of OR value.
bin four independent samples, detect allelic average frequency.
Then contriver has studied relevant evidence (the Zhang FR of two genes in the GWAS data centralization of previously having delivered at these two new locus near zones, Liu H, Chen S, Low H, Sun L, Cui Y, Chu T, Li Y, Fu X, Yu Y, et al. (2011) .Identification of two new loci at IL23R and RAB32that influence susceptibility to leprosy.Nat Genet.43,1247-1251).In order to cover to greatest extent this genovariation, invention people application imports GWAS data set from the heritable variation data set of thousand human genome plans, thousand human genome plans comprise and come from Africa (246 sample), and America (181 sample), Asia (286 samples) and Europe (379 sample) amount to the individuality of the dissimilar ancestor of 1092 samples.Guarantee idiotype probability < 90%, the importing < 80% of SNP, MAF<5%, the individuality of miss rate > 1% is left out in next step analysis.In a word, there are 6593 samples (706 lepers and 5587 contrasts are individual) and 1,987,713SNP to be still retained in correlation analysis by quality control.
Rs2058660 is positioned at the linkage disequilibrium region of a 480kb of 2q12.1, and it comprises 5 gene IL1RL1, IL18RAP, IL18R1, SLC9A4 and SLC9A2 (Fig. 1).IL1RL1, IL18RAP and IL18R1 are parts that is positioned at the cytokine receptor bunch in 2q12 region, IL1RL1 coding IL33 acceptor, IL18RAP and IL18R1 coding IL18 acceptor.IL33 in Th2 cell and mastocyte, and stimulates the generation of Th2 relevant cell factor as part selective expression.
Rs6871626 is positioned at mono-of 5q33.3 and only has the LD region (Fig. 2) that 40kb is very little, only has the function of a gene (LOC285627) to there is no clearly in this region.Yet IL12B is positioned near this LD region, and it is strong biology candidate gene.The p40 subunit of IL12B coding heterodimer interleukin I L-12 and IL-23.These two site prompting IL18RAP/IL18R1 of Rs2058660 and Rs6871626 and IL12B, as the new tumor susceptibility gene of leprosy, have participated in the regulate process of IFN-r transcriptional expression in leprosy.
Wherein, the method for gene type is as follows:
133 SNPs adopt Sequenom MassArray (San Diego, USA) platform validation, and each sample is approximately used 15ngDNA.First extract the genomic dna of peripheral blood, after stdn, sample DNA comprises the genomic DNA fragment in SNP site through multi-PRC reaction amplification, amplified production carries out the extension of the single chain of SNP locus specificity, and extension products desalination is also transferred on the chip in 384 holes.Mass spectrograph (MALDI-TOF MS) carries out allelic detection, adopts Sequenom Mass ARRAY somatotype software to analyze detected result.
1, whole blood sample collection
In informed consent, and sign in the situation of written consent book and gather research object peripheric venous blood 5ml, be positioned over EDTANa
2in anticoagulant tube, putting-80 ℃ of refrigerator-freezers stores for future use.
2, DNA concentration standard comprises the steps:
1) utilize every a standardized sample DNA concentration and the OD ratio (A260/A280, A260/A230) of needing of NanoDrop-1000 concentration tester Accurate Determining.
2) set up electrical form, the DNA numbering that each sample aperture that is ranked need to add.
Carry out the sample of Sequenom MassArray somatotype, on every 96 orifice plates, leave blank and repeated sample contrast.
3), according to the order of electrical form, add the DNA that measures concentration.
For the sample that carries out Sequenom MassArray somatotype, requiring experimental concentration is 12-30ng/ μ l, generally take 18ng/ μ l as good.And A260/A280 ratio between 1.5-2.0, A260/230 is between 1.5-2.3, as DNA concentration adds appropriate FG3 higher than 18ng/ul, by concentration mark to 18ng/ul; If DNA concentration is lower than 12ng/ul, again from blood, extract qualified DNA.Concentration directly adds between 12-18ng/ μ l.
After centrifugal, stick viscosity masking foil, and put on the information such as sample plane label, sample type, source place with marker pen.
4) on dull and stereotyped whizzer, centrifugal 3 minutes of 3000g, deposit in-20 ℃ standby.
3, multiplex PCR
Wherein, in multiplex PCR, amplification comprises that the primer of genomic DNA fragment of rs6871626 is as follows:
Sequence 1 in ACGTTGGATGGCAGAGAAAGTTACCTGTCC(sequence table) and
In multiplex PCR, amplification comprises that the primer of genomic DNA fragment of rs2058660 is as follows:
Sequence 3 in ACGTTGGATGCAGCCCCATTAGCAGTAAAT(sequence table) and
Sequence 4 in ACGTTGGATGAGCTCCACTTAACACCAGTC(sequence table).
4, the extension of the single chain of SNP locus specificity
Wherein, extend primer according to upstream, SNP site in human genome (not comprising this SNP site) design, front 1 Nucleotide in last 1 Nucleotide correspondence of described extension primer this SNP site in human genome.The sequence of the extension primer of rs6871626 is the sequence 5 in TGTCCTTCATCACTTGG(sequence table).The sequence of the extension primer of rs2058660 is the sequence 6 in TGGCCCCATTAGCAGTAAATGCCCTTT(sequence table).
5, data quality control
1) SNP of somatotype is carried out to call rate calculating, remove the SNP of call rate<95% or the SNPs of gene frequency <0.01;
2) SNP is carried out to genetic equilibrium check, remove P≤0.001 of Hardy-Weinberg balance check in the SNP(check sample that departs from the law of genetic equilibrium).
3) in Sequenom MassArray system, check the somatotype dendrogram of SNP, remove dendrogram and divide heap unclear SNP.
4) sample Quality Control: the sample of directly removing somatotype failure.
Sample by Quality Control and SNP are carried out to statistical study.
6, data statistic analysis
Utilize Plink1.07 software in case group and control group, to do gene phenotype correlation analysis to somatotype success the SNP by Quality Control, with Cochran-Armitage trend, check the genotype of each sample and the cognation of phenotype, then by the comprehensive genotype of all samples and the dependency of phenotype analyzed of Cochran-Mantel-Haenszel.With Q, check to evaluate the heterogeneity between individuality, in this experiment, using p<0.05 as inspection level.Multiple logistic regression analysis is for detection of the independence of the signal in region.It 0.05 is inspection level divided by the SNP number by quality control that inspection level α be take.Q check, for assessment of the significance of genetic heterogeneity, is less than 0.05 to P value after SNP correct detection and has been considered as remarkable genetic heterogeneity.
The genotype of rs6871626 and phenotype association study result are as shown in table 4, show that rs6871626 is the single nucleotide polymorphism relevant to leprosy.
Genotype and the phenotype association study result of table 4.rs6871626
The genotype of rs2058660 and phenotype association study result are as shown in table 5, show that rs2058660 is the single nucleotide polymorphism relevant to leprosy.
Genotype and the phenotype association study result of table 5.rs2058660
Claims (4)
1. amplification comprises the PCR primer and the application of single-basic extension primer in the product of the preparation detection single nucleotide polymorphism relevant to leprosy of the genomic DNA fragment of rs2058660.
2. the application of PCR primer and the single-basic extension primer of genomic DNA fragment that amplification comprises rs2058660 in the product of characterization or the assistant identification single nucleotide polymorphism relevant to leprosy.
3. amplification comprises PCR primer and the application of single-basic extension primer in preparation examination leper product of the genomic DNA fragment of rs2058660.
4. amplification comprises that PCR primer and the single-basic extension primer of the genomic DNA fragment of rs2058660 detect the application in leprosy susceptibility product in preparation.
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| SG11201607938UA (en) * | 2014-03-27 | 2016-10-28 | Genentech Inc | Methods for diagnosing and treating inflammatory bowel disease |
| CN104293947B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs58600253 is detecting the application in susceptibility gene of leprosy |
| CN104293948B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs2221593 is detecting the application in susceptibility gene of leprosy |
| CN104293949B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs73058713 is detecting the application in susceptibility gene of leprosy |
| CN104293950B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs77061563 is detecting the application in susceptibility gene of leprosy |
| CN104293946B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs663743 is detecting the application in susceptibility gene of leprosy |
| CN104293952B (en) * | 2014-10-10 | 2016-06-29 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs10817758 application in detection susceptibility gene of leprosy |
| CN111304323A (en) * | 2019-12-31 | 2020-06-19 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | SNP markers related to evaluation of NK/T cell lymphoma onset risk and application thereof |
| CN111647659A (en) * | 2020-06-30 | 2020-09-11 | 北京泱深生物信息技术有限公司 | New application of LOC285627 |
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