CN105969856B - A kind of unicellular exon sequencing tumour somatic mutation detection method - Google Patents
A kind of unicellular exon sequencing tumour somatic mutation detection method Download PDFInfo
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Abstract
The present invention provides a kind of unicellular exons, and tumour somatic mutation detection method is sequenced, and includes the following steps, (1) calculates the false positive rate of unicellular genome mutation；(2) the allelic loss rate in the sequencing of unicellular sample is calculated；(3) somatic mutation is excavated, somatic mutation is filtered；(4) heterogeneity of slender intercellular is analyzed.The present invention passes through the calculating to unicellular mutational site false positive rate, allelic loss rate, filter the somatic mutation in tumour, and analyze the heterogeneity between unicellular, the present invention proves the reliability of sequencing result according to the false positive situation of unicellular genome mutation, it is able to detect the reliability of unicellular experimental technique, multifunctional analysis can be carried out to subsequent result.
Description
Technical field
The invention belongs to gene sequencing fields, more particularly, to a kind of unicellular exon sequencing tumour somatic mutation inspection
Survey method.
Background technique
We can only pay close attention to one piece of whole genome situation of tissue in past genomics research, but it is thousands of on
Ten thousand cells mix and are studied, and can obscure us to brain, hematological system, immune system, and its form these systems
Cell between heterogeneous (heterogeneity) understanding.Can genome situation for each cell progress it is slow
Slowly, this is because the DNA in a cell is simply placed in the level of pik (picograms) grade, so few amount much reaches not
To the minimum loading demand of existing sequenator.So far from 2013, a variety of unicellular sequencing amplification techniques (such as: multiple displacement
Amplification technique MDA, the multiple cyclic annular amplification cycles technology MALBAC that anneals) gradually improve and be able to let us to the base of a cell
Because of a group analysis for progress system.It is sequenced by unicellular amplification technique in conjunction with existing exon, is deep into a tumour cell
Level carry out the pathogenic variation detection of disease, excavating different intercellular relationships is a hot spot direction from now on.In this base
The design of somatic mutation parser on plinth is a very crucial problem.
Existing mutation detection methods can detecte the mutational site in all samples, but the reliability in these sites
Analysis is but seldom optimized for unicellular data.Two problems mainly faced in the detection of unicellular mutational site, one
A is false positive results, the other is allelic loss.False positive results refer to can not detect in tissue mixing sequencing
Site, really detect in unicellular, error when this result may be due to sequencing causes.Allelic loss is
It is expanded in unicellular amplification only for one in allele, another is not expanded, so as to cause one
Homozygosis, the heterozygosis situation in mutational site change.According to the false positive of different data and allelic loss situation, unicellular mutation
As a result screening conditions will suitably change, to ensure its accuracy.Therefore, it is necessary to design and develop a kind of unicellular exon sequencing
Tumour somatic mutation detection method, according to somatic mutation result and abrupt climatic change as a result, the unicellular mutation position of weight analysis
False positive, the allelic loss rate of point, using for the somatic mutation in single celled screening conditions filtering tumour.
Summary of the invention
In view of this, the present invention is directed to propose tumour somatic mutation detection method is sequenced in a kind of unicellular exon, with
The somatic mutation of high reliability is obtained, the unicellular somatic mutation screening of high reliability needs to refer to false positive, equipotential base
Because of Loss Rate, determined in conjunction with the filter result of individual cells sample.
In order to achieve the above objectives, the technical scheme of the present invention is realized as follows:
A kind of unicellular exon sequencing tumour somatic mutation detection method, includes the following steps,
(1) false positive rate of unicellular genome mutation is calculated；
(2) the allelic loss rate in the sequencing of unicellular sample is calculated；
(3) somatic mutation is excavated, somatic mutation is filtered；
(4) heterogeneity of slender intercellular is analyzed.
Further, in the step (1), by tissue sequencing and unicellular sequencing acquisition in tissue samples and unicellular
Mutational site information in sample is defined on the true positives that sport having been found that in tissue sequencing and unicellular sequencing first and is mutated
(TP mutation), the discovery in tissue sequencing but the mutation for not having discovery in unicellular is false negative mutation (FN
It mutation), is false positive mutation (FP in the mutation that unicellular middle discovery is not found in tissue sequencing still
Mutation), the site that mutation is not identified as in tissue sequencing is that true positives are mutated (TN mutation), according to upper
It states data and calculates false positive rate FPR=FP/ (FP+TN).
Further, specifically comprise the following steps in the step (2),
(a1) being defined on site of the frequency of mutation less than 95% in group organization data first is heterozygosity mutation；
(b1) site that all known common SNP are heterozygosity mutation in the tissue is extracted；
(c1) according to the heterozygosity mutational site extracted in tissue, look for its it is corresponding it is unicellular in whether to become homozygosity prominent
Become (frequency of mutation be greater than or equal to 95%), and calculates the ratio for becoming homozygous mutation in unicellular, which is etc.
Position gene Loss Rate, allelic loss rate is higher, and the reliability in mutational site is lower.
Further, the step (3) specifically comprises the following steps,
(a2) position analysis of the short sequential covering depth more than or equal to 5 is mutated position first in tumor tissues sequencing result
Point, the site using the mutational site frequency in tumor sample more than or equal to 10% is as candidate collection；
(b2) secondly by cancer/sequencing result of blood sample in analyze the mutation that short sequential covering depth is more than or equal to 5
Site, site of the mutational site frequency less than or equal to 5% is germinal mutation in check sample；
(c2) difference on the frequency to judge the mutational site in tumor sample and check sample is examined by Fisher accuracy
The opposite sex, the big site of difference is somatic mutation；
(d2) somatic mutation occurred in several unicellular repetitions is determined according to false positive rate, allelic loss rate
It is reliable somatic mutation, in the case where unicellular packet number is less, mutational site at least will repeat in 2 cells
It is existing.
Further, in the step (4), the otherness in each sample between mutated-genotype is analyzed,
(1) calculating intercellular Jaccard distance, calculation formula two-by-two according to the following formula is
Wherein, A is all mutational site frequency informations of cell A, and B is all mutational site frequency informations of cell B, root
According to Jaccard distance, the big heterogeneity of iuntercellular distance is strong, otherwise heterogeneous weak；
(2) it to unicellular carry out principal component analysis, calculates unicellular composed by the first principal component and Second principal component,
Position in plane, the close iuntercellular catastrophe in position is similar, heterogeneous weak, conversely, catastrophe difference is big heterogeneous strong.
Compared with the existing technology, tumour somatic mutation detection method is sequenced in a kind of unicellular exon of the present invention
Have the advantage that the present invention by the calculating to unicellular mutational site false positive rate, allelic loss rate, filters tumour
In somatic mutation, and analyze the heterogeneity between unicellular.
The present invention proves the reliability of sequencing result according to the false positive situation of unicellular genome mutation first.It is unicellular
The finiteness due to technology is sequenced, it usually all can be than organizing the false positive of sequencing result high.The vacation sun of our known universe data
Property is higher, and the reliability in mutational site is lower, needs to integrate the result of multiple cells to screen reliable somatic mutation site.
Existing mutation detection methods can detecte the mutational site in all samples, but not provide the analysis of false positive situation, nothing
The total quality situation of method grasp data.
Secondly, the present invention is able to detect the reliability of unicellular experimental technique, the allelic loss in unicellular amplification
The genotype (homozygous, heterozygosis) that will lead to mutational site changes, this will lead to the mutation erroneous judgement of some heterozygosity into homozygosis
Property mutation, cause to mutation harm erroneous judgement.
Third, ratio of the somatic mutation in all mutation is less, due to the sequencing number of each sample in unicellular
It is sequenced according to amount than tissue small, when fine screen is wanted by assuming that examining to exclude incredible site.And according to false positive and equipotential
Gene Loss Rate determines that the somatic mutation occurred in several unicellular repetitions is reliable somatic mutation.Unicellular
In the case that packet number is less, default mutational site will at least repeat in 2 cells.
Finally for the carry out heterogeneity analysis of more tissue monocytes data, it is prominent that the present invention can not only screen body cell
Become, but result can be analyzed to follow-up study and carry out certain multifunctional analysis.
Detailed description of the invention
The attached drawing for constituting a part of the invention is used to provide further understanding of the present invention, schematic reality of the invention
It applies example and its explanation is used to explain the present invention, do not constitute improper limitations of the present invention.In the accompanying drawings:
Fig. 1 is a kind of stream of unicellular exon sequencing tumour somatic mutation detection method described in the embodiment of the present invention
Cheng Tu；
Fig. 2 is single celled false positive rate in different tissues sample described in the embodiment of the present invention；
Fig. 3 is single celled allelic loss rate in different tissues sample described in the embodiment of the present invention；
Fig. 4 is the number of unicellular same sense mutation and nonsynonymous mutation in each sample described in the embodiment of the present invention；
Fig. 5 is the genetypic distance distribution map of slender intercellular in different tissues sample described in the embodiment of the present invention；
Fig. 6 is that slender intercellular PCA analyzes result figure in different tissues sample described in the embodiment of the present invention.
Specific embodiment
It should be noted that in the absence of conflict, the feature in embodiment and embodiment in the present invention can phase
Mutually combination.
In the description of the present invention, it is to be understood that, term " center ", " longitudinal direction ", " transverse direction ", "upper", "lower",
The orientation or positional relationship of the instructions such as "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outside" is
It is based on the orientation or positional relationship shown in the drawings, is merely for convenience of description of the present invention and simplification of the description, rather than instruction or dark
Show that signified device or element must have a particular orientation, be constructed and operated in a specific orientation, therefore should not be understood as pair
Limitation of the invention.In addition, term " first ", " second " etc. are used for description purposes only, it is not understood to indicate or imply phase
To importance or implicitly indicate the quantity of indicated technical characteristic.The feature for defining " first ", " second " etc. as a result, can
To explicitly or implicitly include one or more of the features.In the description of the present invention, unless otherwise indicated, " multiple "
It is meant that two or more.
In the description of the present invention, it should be noted that unless otherwise clearly defined and limited, term " installation ", " phase
Even ", " connection " shall be understood in a broad sense, for example, it may be being fixedly connected, may be a detachable connection, or be integrally connected；It can
To be mechanical connection, it is also possible to be electrically connected；It can be directly connected, can also can be indirectly connected through an intermediary
Connection inside two elements.For the ordinary skill in the art, above-mentioned term can be understood by concrete condition
Concrete meaning in the present invention.
The present invention will be described in detail below with reference to the accompanying drawings and embodiments.
As shown in Figure 1, tumour somatic mutation detection is sequenced for a kind of unicellular exon described in the embodiment of the present invention
The flow chart of method.
The present invention is by the full sequencing of extron group data instance after the amplification of unicellular MDA method, in 3 each tumor tissues
Tissue sequencing and unicellular sequencing have been done in (Tissue1, Tissue2, Tissue3) respectively, and has used blood sample as normal control.
Sequencing of extron group flow processing result is counted as shown in table 4.1,
Firstly, calculating the false positive rate of unicellular data, it is reliable that the false positive of unicellular genome mutation embodies sequencing
Property.By tissue sequencing and unicellular sequencing, we can obtain the mutational site information in tissue samples and unicellular sample.
In general, we, which are defined on the true positives that sport having been found that in tissue sequencing and unicellular sequencing, is mutated (TP mutation), In
Discovery in tissue sequencing but the mutation for not having discovery in unicellular is false negative mutation (FN mutation), unicellular
The mutation that middle discovery is not found in tissue sequencing still is false positive mutation (FP mutation), and true negative mutation is then
The site (TN mutation) of mutation is not identified as in tissue sequencing.False sun can be calculated according to aforementioned four data
Property rate FPR=FP/ (FP+TN), herein it is however emphasized that calculate when TN be tissue sequencing in be not identified as mutation site, and
It is not the site that mutation is not identified as in unicellular.Unicellular false positive is higher, and the reliability in each mutational site is lower,
Need to integrate the result of multiple cells to screen reliable somatic mutation site.Fig. 2 illustrates slender in three tumor tissues
The false positive ratio that cytoplasmic process becomes has in i.e. single celled all mutational sites about between 5/20000 to ten thousand/10000ths
20000 to ten thousand/10000ths/fifth is that pseudomutation；
Secondly, calculating single celled allelic loss rate, allelic loss rate embodies unicellular amplification method
Reliability, the genotype (homozygous, heterozygosis) that allelic loss will lead to mutational site change, this will lead to subsequent
By the mutation erroneous judgement of some heterozygosity at homozygous mutant in analysis.The extent of injury that heterozygosity is mutated in biology is than homozygosis
Property mutation it is low.The Loss Rate of allele must be obtained by the unicellular comparison with group organization data.It is typically defined in tissue
Site of the frequency of mutation less than 95% is heterozygosity mutation in data, and it is homozygous mutant that frequency, which is more than or equal to 95%, extracts institute
Known common SNP is the site of heterozygosity mutation in the tissue；According to the heterozygosity mutational site extracted in tissue, it is looked for
It is corresponding it is unicellular in whether become homozygous mutant (frequency of mutation be greater than or equal to 95%), and calculate and become in unicellular
The ratio of homozygous mutation, the ratio are allelic loss rate；Fig. 3 illustrates the unicellular equipotential in three tumor samples
For gene Loss Rate between 20% to 60%, this illustrates that having 20% to 60% in all unicellular homozygous mutations is false homozygosis,
If necessary to exclude false homozygote status need to count at least three it is unicellular in the somatic mutation site that all occurs；
Again, somatic mutation site is filtered, mutation with a high credibility is screened, obtains the somatic mutation of each sample,
Each sample nonsynonymous mutation number and total number are counted, ratio of the somatic mutation in all mutation is less, unicellular
In be sequenced than tissue small due to the sequencing data amount of each sample, when fine screen, is wanted by assuming that examining to exclude incredible position
Point.
Condition is as follows:
1. the short sequential covering depth of sequencing in tumor sample and check sample is greater than equal to 5.
2. the mutational site frequency in check sample is less than or equal to 5%.
3. the mutational site frequency in tumor sample is more than or equal to 10%.
It is examined by Fisher accuracy to judge that it is very big that the frequency in the mutational site in tumor sample and check sample has
Difference, and the p value of hypothesis testing is corrected, it is determined according to false positive rate and allelic loss rate several unicellular
The somatic mutation occurred in repeating is reliable somatic mutation.
Same sense mutation and nonsynonymous mutation ratio in each sample is as shown in fig. 4, it can be seen that each unicellular sample
In the ratio of somatic mutation that finds at 20 or so, wherein same sense mutation sum is higher than nonsynonymous mutation；
According to above-mentioned analysis, it can be seen that the allelic loss rate in the sample is higher, in the reliable body cell of determination
When mutation, it is ensured that all occur during this mutation is at least unicellular at 3 to 4.Next prominent according to finally determining body cell
Become the heterogeneous implementations of cell as a result, analysis organization internal, analyzes the otherness in each sample between mutated-genotype, calculate
Intercellular Jaccard distance, calculation formula are two-by-two
Wherein, A is all mutational site frequency informations of cell A, and B is all mutational site frequency informations of cell B, root
According to Jaccard distance, the big heterogeneity of iuntercellular distance is strong, otherwise weak, the base of slender intercellular in different tissues sample of heterogeneity
Because type range distribution is as shown in Figure 5；To unicellular carry out principal component analysis, calculate it is unicellular first principal component and second it is main at
Position in plane composed by point, the close iuntercellular catastrophe in position is similar, heterogeneous weak, conversely, catastrophe difference
Big heterogeneous strong, slender intercellular PCA analysis result is as shown in Figure 6 in different tissues sample；It can be found that these three types of cells is prominent
Displacement point has very big difference.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (3)
1. tumour somatic mutation detection platform is sequenced in a kind of unicellular exon, it is characterised in that: the detection platform is used for
Somatic mutation is screened, detection platform has a characteristic that
(1) false positive rate of unicellular genome mutation is calculated；
The mutational site information in tissue samples and unicellular sample is obtained by tissue sequencing and unicellular sequencing, it is fixed first
What justice had been found that in tissue sequencing and unicellular sequencing sports true positives mutation (TP mutation), in tissue sequencing
It was found that but not having the mutation of discovery in unicellular is false negative mutation (FN mutation), unicellular middle discovery still
The mutation not found in tissue sequencing is false positive mutation (FP mutation), is not identified as in tissue sequencing
The site of mutation is that true negative is mutated (TN mutation), calculates false positive rate FPR=FP/ (FP+TN) according to above-mentioned data,
False positive rate is higher, and the reliability in mutational site is lower；
(2) the allelic loss rate in the sequencing of unicellular sample is calculated；
Being defined on site of the frequency of mutation less than 95% in group organization data first is heterozygosity mutation, if heterozygosity mutational site
The frequency of mutation be greater than or equal to 95% be homozygous mutant, extract heterozygosity mutational site, and look for its it is corresponding it is unicellular in
Whether become homozygous mutant, and calculate the ratio for becoming homozygous mutant in unicellular, which is that allele is lost
Mistake rate, allelic loss rate is higher, and the reliability in mutational site is lower；
(3) somatic mutation is excavated, somatic mutation is filtered；
(4) heterogeneity of slender intercellular is analyzed.
2. tumour somatic mutation detection platform is sequenced in a kind of unicellular exon according to claim 1, feature exists
In: (3) specifically comprise the following steps,
(a2) position analysis mutational site of the short sequential covering depth more than or equal to 5 first in tumor tissues sequencing result, will
Site of the mutational site frequency more than or equal to 10% in tumor sample is as candidate collection；
(b2) secondly by cancer/sequencing result of blood sample in analyze the mutational site that short sequential covering depth is more than or equal to 5,
Site of the mutational site frequency less than or equal to 5% is germinal mutation in check sample；
(c2) difference on the frequency for examining to judge the mutational site in tumor sample and check sample by Fisher accuracy is anisotropic,
The big site of difference is somatic mutation；
(d2) being according to the somatic mutation that false positive rate, the determination of allelic loss rate occur in several unicellular repetitions can
The somatic mutation leaned on, in the case where unicellular packet number is less, mutational site will at least repeat in 2 cells.
3. tumour somatic mutation detection platform is sequenced in a kind of unicellular exon according to claim 1, feature exists
In: in (4), the otherness in each sample between mutated-genotype is analyzed,
(1) calculating intercellular Jaccard distance, calculation formula two-by-two according to the following formula is
Wherein, A is all mutational site frequency informations of cell A, and B is all mutational site frequency informations of cell B, according to
Jaccard distance, the big heterogeneity of iuntercellular distance is strong, otherwise heterogeneous weak；
(2) to unicellular carry out principal component analysis, the unicellular plane composed by first principal component and Second principal component, is calculated
On position, the close iuntercellular catastrophe in position is similar, heterogeneous weak, conversely, catastrophe difference is big heterogeneous strong.
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| CN106778075A (en) * | 2016-12-29 | 2017-05-31 | 安诺优达基因科技(北京)有限公司 | A kind of device for detecting blood disease correlation somatic mutation |
| CN109943635A (en) * | 2017-12-21 | 2019-06-28 | 安诺优达基因科技(北京)有限公司 | A kind of device for FLT3-ITD quantitative detection |
| CN110093417B (en) * | 2018-01-31 | 2021-03-02 | 北京大学 | Method for detecting tumor single cell somatic mutation |
| CN111199776B (en) * | 2018-11-16 | 2023-03-28 | 深圳华大生命科学研究院 | Method and device for evaluating analysis quality of tumor genome sequencing data and application |
| CN113628682B (en) * | 2021-08-11 | 2023-10-24 | 上海小海龟科技有限公司 | T790M and C797S cis-trans mutation type identification and calculation method |
| CN116230082B (en) * | 2022-12-06 | 2024-05-14 | 序科码医学检验实验室(广州)有限公司 | Label-free multi-sample mixed single cell sequencing method based on sample genotype data resolution |
| CN116564405B (en) * | 2023-04-19 | 2023-12-15 | 江苏先声医学诊断有限公司 | Average-disorder-based genome sequencing mutation site filtering method |
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| CN104160391A (en) * | 2011-09-16 | 2014-11-19 | 考利达基因组股份有限公司 | Determining variants in a genome of a heterogeneous sample |
| CN104462869A (en) * | 2014-11-28 | 2015-03-25 | 天津诺禾致源生物信息科技有限公司 | Method and device for detecting somatic cell SNP |
| CN104662168A (en) * | 2012-06-21 | 2015-05-27 | 香港中文大学 | Mutational analysis of plasma dna for cancer detection |
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| CN104160391A (en) * | 2011-09-16 | 2014-11-19 | 考利达基因组股份有限公司 | Determining variants in a genome of a heterogeneous sample |
| CN104662168A (en) * | 2012-06-21 | 2015-05-27 | 香港中文大学 | Mutational analysis of plasma dna for cancer detection |
| CN104462869A (en) * | 2014-11-28 | 2015-03-25 | 天津诺禾致源生物信息科技有限公司 | Method and device for detecting somatic cell SNP |
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