CN116994651A - Method and device for determining source of chromosome copy number deficiency - Google Patents
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Abstract
The invention discloses a method and a device for determining the source of chromosome copy number deficiency, wherein the method comprises the following steps: obtaining variation data about chromosome copy number deficiency and obtaining family point mutation data corresponding to the variation data; calculating point mutation proportion parameters of the mutation data and the family point mutation data about the number of point mutations based on mutation types corresponding to the family point mutation data; and determining the family source of the chromosome copy number deletion according to the numerical value of the point mutation proportion parameter. According to the invention, variation data about chromosome copy number deficiency can be obtained, family point mutation data related to the chromosome is extracted according to the chromosome copy number deficiency data, the ratio of the family point mutation data to the point mutation number in the chromosome copy number deficiency data is calculated, and the variation sources are determined by comparing the ratios of different mutation types, so that the possibility of mismatching caused by judgment according to the whole deficiency area is reduced, and the detection precision and accuracy are improved.
Description
Technical Field
The invention relates to the technical field of chromosome detection, in particular to a method and a device for determining the source of chromosome copy number deficiency.
Background
Along with the development of technology, the gene detection technology is becoming usual, and the application scene is becoming wide. For example, detection of chromosome copy number deficiency can be used to discover variation of large fragment DNA sequence in genome early, thereby providing basis for diagnosis and treatment of diseases.
The current detection method for chromosome copy number deficiency mainly uses CNV-seq, CMA, MLPA or other methods for detecting CNV to determine gene fragments with copy number deficiency in the chromosome, but the methods can only detect whether copy number abnormality exists or not, and can not obtain variation sources and other related information of CNV. In a simple identification of the origin of the copy number deleted chromosome, the deleted gene segments can be base pair matched with all the male parent gene segments and all the female parent gene segments, respectively, to determine whether the deleted gene segments are specifically from the male parent gene or the female parent gene. Because the number of the gene fragments of the male parent and the female parent which need to be matched is large, and all the bases on the complete chromosome fragment are generally long, the same base occupies most of the fragment, and can be matched with an irrelevant base pair during detection, more messy information is generated, the result judgment is influenced, and the detection accuracy is reduced.
Disclosure of Invention
The invention provides a method and a device for determining the source of chromosome copy number deficiency, wherein the method can extract family point mutation data related to a chromosome according to the chromosome copy number deficiency data, determine mutation sources based on the mutation number in the family point mutation data and the mutation number of the copy number mutation data, and further reduce the mismatching result so as to improve the detection precision and accuracy.
A first aspect of embodiments of the present invention provides a method of source determination regarding chromosome copy number loss, the method comprising:
obtaining variation data about chromosome copy number deficiency and obtaining family point mutation data corresponding to the variation data;
calculating point mutation proportion parameters of the mutation data and the family point mutation data about the number of point mutations based on mutation types corresponding to the family point mutation data;
and determining the family source of the chromosome copy number deletion according to the numerical value of the point mutation proportion parameter.
In a possible implementation manner of the first aspect, the point mutation proportion parameter includes: a first ratio value;
the calculating the mutation ratio parameters of the mutation data and the family point mutation data about the point mutation number based on the mutation types corresponding to the family point mutation data comprises the following steps:
And when the mutation type corresponding to the family point mutation data is the homozygous mutation of the male parent, calculating the ratio of the number of the homozygous mutation contained in the mutation data to the number of the homozygous mutation contained in the family point mutation data and related to the homozygous mutation of the male parent to obtain a first ratio value.
In a possible implementation manner of the first aspect, the point mutation proportion parameter further includes: a second ratio value;
the calculating the mutation data and the point mutation proportion parameter of the family point mutation data about the point mutation number based on the mutation type corresponding to the family point mutation data further comprises:
and when the mutation type corresponding to the family point mutation data is the wild mutation of the male parent, calculating the ratio of the number of the wild mutation contained in the mutation data to the number of the point mutation contained in the family point mutation data and related to the wild mutation of the male parent to obtain a second ratio value.
In a possible implementation manner of the first aspect, the point mutation proportion parameter further includes: a third ratio value;
the calculating the mutation data and the point mutation proportion parameter of the family point mutation data about the point mutation number based on the mutation type corresponding to the family point mutation data further comprises:
And when the mutation type corresponding to the family point mutation data is female parent homozygous mutation, calculating the ratio of the number of the homozygous mutation contained in the mutation data to the number of the point mutation related to the female parent homozygous mutation contained in the family point mutation data to obtain a third ratio value.
In a possible implementation manner of the first aspect, the point mutation proportion parameter further includes: a fourth ratio value;
the calculating the mutation data and the point mutation proportion parameter of the family point mutation data about the point mutation number based on the mutation type corresponding to the family point mutation data further comprises:
and when the mutation type corresponding to the family point mutation data is female parent wild mutation, calculating the ratio of the point mutation number of the wild mutation contained in the mutation data to the point mutation number of the family point mutation data about the female parent wild mutation to obtain a fourth ratio value.
In a possible implementation manner of the first aspect, the determining a family source of the chromosome copy number deletion according to the magnitude of the point mutation proportion parameter includes:
if the first ratio value is greater than the third ratio value and the second ratio value is greater than the fourth ratio value, determining that the source of the family of the chromosome copy number deletion is female parent deletion;
And if the first proportion value is smaller than the third proportion value and the second proportion value is smaller than the fourth proportion value, determining that the family source of the chromosome copy number deletion is a male parent deletion.
In a possible implementation manner of the first aspect, after the step of determining that the source of the chromosome copy number deleted family is maternal deletion, the method further includes:
if the first proportion value and the second proportion value are both larger than a first preset value, determining that only chromosomes in the mutation data are derived from a male parent;
and if the first proportion value or the second proportion value is smaller than a first preset value, determining that only chromosomes in the mutation data tend to originate from a male parent.
In a possible implementation manner of the first aspect, after the step of determining that the source of the family with the chromosome copy number deletion is a male parent deletion, the method further includes:
if the third proportion value and the fourth proportion value are both larger than a second preset value, determining that only chromosomes in the variation data are derived from female parents;
if the third ratio or the fourth ratio is smaller than a second preset value, determining that only chromosomes in the mutation data tend to originate from a female parent.
In a possible implementation manner of the first aspect, the obtaining family point mutation data corresponding to the mutation data includes:
acquiring a plurality of family sequencing original data corresponding to the variation data, and preprocessing each family sequencing original data to obtain family processing data, wherein the preprocessing comprises the following steps: data cleaning, data quality control, data comparison, mutation detection and data filtering, wherein each family sequencing original data is the gene data of the family member corresponding to the mutation data;
combining the point mutation data contained in the family processing data, and extracting a union set of the combined data to obtain a point mutation data set;
and carrying out data screening on the point mutation data set according to the mutation fragments corresponding to the mutation data to obtain family point mutation data.
A second aspect of an embodiment of the present invention provides a source determining apparatus for chromosome copy number deletion, the apparatus comprising:
the acquisition data module is used for acquiring variation data about chromosome copy number deficiency and acquiring family point mutation data corresponding to the variation data;
the point mutation proportion calculation module is used for calculating point mutation proportion parameters of the mutation data and the family point mutation data about the number of point mutations based on mutation types corresponding to the family point mutation data;
And the family source determining module is used for determining the family source of the chromosome copy number deletion according to the numerical value of the point mutation proportion parameter.
Compared with the prior art, the source determining method and device for chromosome copy number deletion provided by the embodiment of the invention have the beneficial effects that: according to the invention, mutation data about chromosome copy number deficiency can be obtained, family point mutation data related to the chromosome is extracted according to the chromosome copy number deficiency data, the ratio of the family point mutation data to the number of point mutations in the chromosome copy number deficiency data is calculated, and the mutation sources are determined by comparing the ratios of different mutation types, so that the possibility of mismatching caused by judgment according to the whole deficiency area is reduced, and the detection precision and accuracy are improved.
Drawings
FIG. 1 is a flow chart of a method for determining a source of a chromosome copy number deficiency according to an embodiment of the present invention;
FIG. 2 is a graph showing the copy numbers of all genes on a fragment according to one embodiment of the present invention;
FIG. 3 is a statistical diagram of scale values according to an embodiment of the present invention;
FIG. 4 is a flowchart illustrating a method for determining a source of a chromosome copy number deficiency according to an embodiment of the present invention;
FIG. 5 is a schematic diagram of a source determining device related to chromosome copy number deficiency according to an embodiment of the present application.
Detailed Description
The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
In order to solve the above problems, a method for determining the origin of chromosome copy number deletion according to the present application will be described and illustrated in detail by the following specific examples.
Referring to fig. 1, a flow chart of a method for determining a source of a chromosome copy number deficiency according to an embodiment of the application is shown.
In one embodiment, the method is applicable to a computer system, and the abnormal gene data can be input into the computer system, and the computer system is used for detecting and analyzing the abnormal gene data or gene fragments to determine the specific source of the abnormal gene data.
Wherein, as an example, the method for determining the origin of the chromosome copy number deletion may include:
s11, obtaining mutation data about chromosome copy number deletion and obtaining family point mutation data corresponding to the mutation data.
In one embodiment, the mutation data regarding the deletion of the chromosome copy number may include a mutation fragment to be detected (specifically, a mutation gene fragment) and a mutation type (possibly a hybridization type, a homozygosity type, etc.). The family point mutation data may be data of variation points included in each family member corresponding to the variation data. Wherein, family members may be family members of a direct family relatives.
Because there may be a plurality of each family member corresponding to the mutation data, if gene data of all family members are collected for detection, the amount of data to be processed is large, and the time consumption is long.
In order to reduce the amount of data processed and increase the processing efficiency, step S11 may include the following sub-steps, as an example:
s111, acquiring a plurality of family sequencing original data corresponding to the variation data, and preprocessing each family sequencing original data to obtain family processing data, wherein the preprocessing comprises the following steps: data cleaning, data quality control, data comparison, mutation detection and data filtering, wherein each family sequencing original data is gene data of a family member corresponding to the mutation data.
In an alternative embodiment, family sequencing raw data for a number of family members may be obtained, which may be genetic data for the family members.
In genetic inheritance, the influence of the alternate genes is smaller, in order to further reduce the amount of processed data, in a preferred embodiment, family sequencing original data of a father parent corresponding to the mutation data (namely family sequencing original data of a father parent and family sequencing original data of a mother) can be obtained, mutation sources are judged according to differences between mutation fragments and all point mutation information of three families of the father parent and the mother parent, so that the inheritance characteristics of chromosomes and the characteristic of wide distribution of point mutations can be reserved, and meanwhile, the fixed characteristics shown by different copy number mutation types can be relied on, so that judgment of results is completed, and the detection accuracy is improved.
In an embodiment, after obtaining the family sequencing original data of the male parent and the family sequencing original data of the female parent, the steps of data cleaning, data quality control, sequencing data comparison, mutation detection, mutation information filtering, mutation data annotation and the like can be sequentially performed on the obtained family sequencing original data and the obtained family sequencing original data respectively to form family processing data.
Alternatively, the processed family sequencing raw data may be converted into a family point variation information summary table containing variation information of all members of the family for subsequent processing.
In one embodiment, all the point mutation information of the family members can be recorded in a family point mutation information summary table, wherein the information includes mutation conditions of the point mutation (including base information before and after mutation), quality values of the point mutation, heterozygous conditions of the point mutation, counting information of the point mutation (recording the number of sequencing fragments with mutation at the current mutation site and the number of sequencing fragments covering the current site), and the proportion of the point mutation (the proportion of the number of sequencing fragments with mutation at the current base site to the number of sequencing fragments covering the current site), and the point mutation information is necessary information for subsequently judging the source of copy number mutation.
And S112, merging the point mutation data contained in the family processing data, and extracting a union set of the merged data to obtain a point mutation data set.
In one embodiment, after preprocessing is completed, point mutation data of family processing data of a male parent can be extracted, point mutation data of family processing data of a female parent can be extracted, and then mutation data of the two point mutation data are combined to form a data set. And extracting the same point mutation data in the two family processing data in the data set, namely obtaining the union of the two data to form a point mutation data set.
And S113, carrying out data screening on the point mutation data set according to the mutation fragments corresponding to the mutation data to obtain the family point mutation data.
In order to further reduce the amount of processed data, the mutation fragments contained in the mutation data can be obtained, then the same fragments are screened in the point mutation data set according to the mutation fragments, and the same mutation fragments obtained by screening are formed into a data set to form the family point mutation data.
In yet another alternative embodiment, the point mutation data set includes point mutation information owned by both the male parent and the female parent, and after all the point mutation information is obtained, the point mutations whose quality values do not satisfy the minimum threshold value may be filtered, so as to reduce the number of unnecessary or useless point mutation information.
Specifically, the user can preset the segment to be judged, then analyze the position of the preset segment, and screen out all the point mutation information of the family members in the segment according to the position. And after screening to obtain the point mutation information of all members of the family on the current fragment, starting to judge the mutation sources of different types.
In yet another alternative embodiment, in the screening of point mutations, it may be considered to delete point mutations of the same mutation type (i.e., point mutations are identical and are all homozygous, wild-type or homozygous) of family members in order to make the results more prone.
In addition, in some cases, it is also possible to find new chromosomal copy number variation segments by comprehensively analyzing all the point mutation information contained on a specific chromosomal segment of all members of the family.
S12, calculating point mutation proportion parameters of the mutation data and the family point mutation data about the number of point mutations based on mutation types corresponding to the family point mutation data.
In one embodiment, after obtaining the family point mutation data, the mutation type of the mutation data may be obtained.
Because the family point mutation data comprises the point mutation data of the male parent and the point mutation data of the female parent, the mutation type corresponding to the family point mutation data can comprise the mutation type of the male parent or the mutation type of the female parent. Correspondingly, the mutation type corresponding to the mutation data can also be obtained.
And then, calculating the ratio of the mutation data to the number of the point mutations of the same mutation type of the family point mutation data according to the mutation type corresponding to the family point mutation data and the mutation type corresponding to the mutation data to obtain the point mutation ratio parameter.
In an alternative embodiment, the point mutation ratio parameter includes: a first scale value, a second scale value, a third scale value, and a fourth scale value;
As an example, step S12 may include the following sub-steps:
s121, when the mutation type corresponding to the family point mutation data is homozygous mutation of the male parent, calculating the ratio of the number of homozygous mutation points contained in the mutation data to the number of homozygous mutation points contained in the family point mutation data and related to the homozygous mutation points of the male parent, so as to obtain a first ratio value.
S122, when the mutation type corresponding to the family point mutation data is the wild mutation of the male parent, calculating the ratio of the number of the wild mutation contained in the mutation data to the number of the point mutation contained in the family point mutation data and related to the wild mutation of the male parent, and obtaining a second ratio value.
And S123, when the mutation type corresponding to the family point mutation data is female parent homozygous mutation, calculating the ratio of the number of homozygous mutation contained in the mutation data to the number of female parent homozygous mutation contained in the family point mutation data to obtain a third ratio value.
And S124, when the mutation type corresponding to the family point mutation data is female parent wild mutation, calculating the ratio of the number of the wild mutation contained in the mutation data to the number of the point mutation of the family point mutation data relative to the female parent wild mutation to obtain a fourth ratio value.
In one embodiment, the mutation data to be detected has a fragment mutation type of heterozygous deletion, and the fragment has only a single copy of a chromosome, i.e., only one chromosome. This means that the gene and base on this fragment are all single copy, resulting in a majority of the mutation types on this fragment by the proband being homozygous or wild type. Meanwhile, the single-copy fragment is only from one of parents, so that the source of the missing fragment is judged, the source of the single-copy chromosome fragment is judged, and the user (called a prover) of the mutation data has less point mutation information of the single-copy chromosome of the single-copy fragment, so that the judgment of the source of the copy number missing mutation can be started from the parent and the mother of the single-copy chromosome fragment.
For both parents, there are typically many heterozygous mutations in a chromosome fragment, and the bases that make the mutation may be distributed on either chromosome. When the prover inherits these heterozygous mutation sites from the parent, the prover obtains only one chromosome from the four chromosomes of both parents due to the copy number deletion on this fragment, resulting in the heterozygous mutation of the parent also appearing only as a wild-type mutation and a homozygous mutation on the genome of the prover. The proportions of these wild-type and homozygous mutations are random, and therefore point variation, which is a heterozygous mutation by parents, cannot be used to judge the source.
When a parent is selected as a wild mutant or a homozygous mutant, respectively, since the chromosome of the prover is derived from one of them, the mutation type of the prover should be consistent with the mutation type of one of them, which itself has only a chromosomal genetic origin, but have no obvious correlation with the mutation type of the other.
For example, assuming that a certain heterozygous deletion of the prover originates from the father, then the only chromosome of the prover should originate from its mother, then when screening only all wild-type mutants or homozygous mutants of the mother, the mutation type of the prover should also appear mostly as wild-type mutants and homozygous mutants, respectively.
In an alternative calculation mode, the specific calculation operations of the first scale value, the second scale value, the third scale value and the fourth scale value are as follows:
assuming that the mutation type of the father is homozygote mutation, counting the point mutation number h1 of which the father and the forensics are homozygote mutation, and calculating the point mutation proportion p1=h1/f 1 of which the forensics are homozygote mutation when the father is homozygote mutation to obtain a first proportion value;
assuming that the mutation type of the father is wild mutation, counting the number f2 of all the point mutations of which the father is wild mutation, counting the number w1 of the point mutations of which the father is wild mutation, and calculating the point mutation proportion p2=w1/f 2 of which the father is wild mutation when the father is wild mutation, so as to obtain a second proportion value;
Assuming that the mutation type of the mother is homozygous mutation, counting the number m1 of all the point mutations of which the mother is homozygous mutation, counting the number h2 of the point mutations of which the mother and the precursor are homozygous mutation, and calculating the point mutation proportion p3=h2/m 1 of the point mutations of which the precursor is homozygous mutation when the mother is homozygous mutation, so as to obtain a third proportion value;
assuming that the mutation type of the mother is a wild mutation, counting the number m2 of all the point mutations of which the mother is the wild mutation, counting the number w2 of the point mutations of which the mother and the precursor are both the wild mutation, and calculating the point mutation ratio p4=w2/m 2 of which the precursor is the wild mutation when the mother is the wild mutation, thereby obtaining a fourth ratio value.
S13, determining the family source of the chromosome copy number deletion according to the numerical value of the point mutation proportion parameter.
After calculating the point mutation proportion parameter, the chromosome copy number of the foreigner can be judged to be deleted according to the numerical value of the point mutation proportion parameter, and the chromosome mutation is specifically from the father (father) or the mother (mother).
In one embodiment, step S13 may include the sub-steps of:
s131, if the first proportion value is larger than the third proportion value and the second proportion value is larger than the fourth proportion value, determining that the family source of the chromosome copy number deletion is female parent deletion.
The first ratio value is that the mutation types of father and forensics are homozygous mutations; the second ratio value is that the mutation types of father and forensics are all wild mutations; the third ratio is homozygous mutation for both the mother and the precursor, and the fourth ratio is wild mutation for both the mother and the precursor.
If the first ratio is greater than the third ratio and the second ratio is greater than the fourth ratio, indicating that the ratio of homozygous to wild-type point mutation inherited by the father is greater than that of the mother, the deleted fragment or variant gene is from the mother or the mother.
In an embodiment, after step S131, the method may further include:
s21, if the first proportion value and the second proportion value are both larger than a first preset value, determining that only chromosomes in the mutation data are derived from the male parent.
S22, if the first proportion value or the second proportion value is smaller than a first preset value, determining that only chromosomes in the mutation data tend to originate from a male parent.
In some cases, since genetic recombination may cause both parents to inherit some segments to the forensics, if it is further confirmed that the segment variation is only derived from one party, a threshold of a ratio value, such as a first preset value, needs to be set.
Under the test condition, the source of the variation of the section can be accurately judged as the other party as long as the first proportion value and the second proportion value are both larger than the first preset value.
For example, if the first ratio value and the second ratio value are both greater than the first preset value, it is determined that the source of the chromosome copy number deletion family is female parent deletion, and it is determined that only the chromosome in the mutation data is derived from male parent.
If the first ratio is greater than the first preset value or the second ratio is greater than the first preset value, determining that the source of the chromosome copy number deletion family is female parent deletion, and determining that only the chromosome in the mutation data tends to be derived from male parent.
And S132, if the first proportion value is smaller than the third proportion value and the second proportion value is smaller than the fourth proportion value, determining that the family source of the chromosome copy number deletion is father deletion.
Similarly, the first ratio is that the mutation types of father and forensics are homozygous mutations; the second ratio value is that the mutation types of father and forensics are all wild mutations; the third ratio is homozygous mutation for both the mother and the precursor, and the fourth ratio is wild mutation for both the mother and the precursor.
If the first ratio is less than the third ratio and the second ratio is less than the fourth ratio, indicating that the ratio of homozygous and wild-type point mutations inherited by the mother is greater than that of the father, the deleted fragment or variant gene is from the father or the father.
In an embodiment, after step S132, the method may further include:
s31, if the third proportion value and the fourth proportion value are both larger than a second preset value, determining that only chromosomes in the variation data are derived from female parents.
S32, if the third proportion value or the fourth proportion value is smaller than a second preset value, determining that only chromosomes in the variation data tend to originate from a female parent.
In some cases, since genetic recombination may cause both parents to inherit some segments to the forensics, if it is further confirmed that the segment variation is only derived from one party, a threshold of a ratio value, such as a second preset value, needs to be set.
Under the test condition, the source of the variation of the section can be accurately judged as the other party as long as the third proportion value and the fourth proportion value are both larger than the second preset value.
For example, if the third and fourth ratio values are both greater than the second preset value, it may be determined that the source of the chromosome copy number deletion is female parent deletion, and it may be determined that only the chromosome in the mutation data is derived from male parent.
If the third ratio is greater than the second preset value or the fourth ratio is greater than the second preset value, determining that the source of the chromosome copy number deficiency family is female parent deficiency, and determining that only the chromosome in the mutation data tends to be derived from the female parent.
S133, if the first ratio is not greater than the third ratio and the second ratio is greater than the fourth ratio, or if the first ratio is not less than the third ratio and the second ratio is less than the fourth ratio, determining the family source of the chromosome copy number deficiency.
Specifically, based on the calculated above result, the determination logic of the determination program: since the mutation type of the chromosome fragment should be almost the same as that of the chromosome of the genetic source, the result should be judged according to the magnitude relation between the first ratio p1 and the third ratio p3 and the second ratio p2 and the fourth ratio p 4.
In the judgment, it is necessary to satisfy that the ratio of homozygosity inherited from one parent to wild-type point mutation is larger than that from the other parent, and for example, the source of the deletion cannot be judged if the homozygosity inherited from the parent is higher but the wild-type inherited from the mother is higher. After the judgment of satisfying the magnitude relation, it can be considered that the deleted fragment tends to originate from the party with lower p-value of both homozygosity and wild-type, but in some cases, both parents may inherit some segments to the forensics due to genetic recombination, so if the fragment variation is further confirmed to originate from only one party, it is necessary to set a threshold value (a first preset value and a second preset value) of p-value, and in the test case, it is found that the source of variation of this segment can be accurately judged as the other party as long as the homozygosity ratio and the wild-type ratio from the party are both greater than the first preset value or the second preset value.
Alternatively, the first preset value and the second preset value may be the same or different.
In an embodiment, the first preset value and the second preset value may be 0.8.
Referring to FIG. 2, a flowchart of the operation of a method for determining the origin of a chromosome copy number deficiency according to an embodiment of the present invention is shown.
Specifically, the mutation data such as the position of the mutation fragment to be detected or judged and the mutation type of the mutation fragment to be judged can be obtained, and standard family sequencing original data of a person to be detected can be obtained, and preprocessing operations such as data cleaning, quality control, comparison, mutation detection, data filtering and the like are performed on the family sequencing original data; combining the point mutation data of family members, and taking the union of all the point mutation data; screening all family point mutation data on the fragments from the union according to the positions of the variant fragments; when the father is homozygous mutation, calculating the proportion P1 of the precursor being homozygous mutation; when the father is wild mutation, calculating the proportion P2 of the precursor as the wild mutation; when the mother is homozygous mutant, calculating the proportion P3 of the precursor being homozygous mutant; when the mother is a wild mutation, the proportion P4 of the precursor to the wild mutation is calculated. When P1 > P3 and P2 > P4, it can be stated that the source of the deletion is mother, on the basis that if P1 and P2 are both greater than the preset value (0.8), it is stated that only the chromosome is derived from the father, and if P1 or P2 is less than the preset value, it is stated that only the chromosome tends to be derived from the father. When P3 > P1 and P4 > P2, it can be stated that the source of the deletion is the father, on the basis that if P3 and P4 are both greater than the predetermined value (0.8), it is stated that only the chromosome is derived from the mother, and if P3 or P4 is less than the predetermined value, it is stated that only the chromosome tends to be derived from the mother.
Referring to FIG. 3, a schematic diagram showing the copy numbers of all genes on a fragment according to an embodiment of the present invention is shown.
In one example, in a pair of copy number heterozygous deletion test cases, the copy number of all genes on the fragment is shown in FIG. 3, and the fragment is 5.19M long (blue part is heterozygous deletion fragment), which contains many genes, and the deletion source of the heterozygous deletion fragment is detected.
The ratio values obtained after statistics are respectively as follows:
the father is the point mutation number 133 of the homozygous mutation, the father and the forensics are the point mutation number 107 of the homozygous mutation, and the first ratio value p1 is 0.8;
the father is the point mutation number 182 of the wild mutation, the father and the forensics are the point mutation number 44 of the wild mutation, and the second ratio p2 is 0.24;
point mutation number 182 for homozygous mutation for mother, point mutation number 181 for homozygous mutation for both mother and forensics, at which point the third ratio p3 is 0.99;
the mother was the wild-mutated point mutation number 72, and both the mother and the precursor were the wild-mutated point mutation number 59, at which point the fourth ratio p4 was 0.82.
Referring to fig. 4, a statistical schematic diagram of the scale values provided by an embodiment of the present invention is shown.
According to the obtained ratio values, a ratio comparison chart of four cases is drawn as shown in the following fig. 4.
Referring to fig. 4, according to the proportion distribution in the figure, it is obvious that the third proportion p3> the first proportion p1, the fourth proportion p4> the second proportion p2, and the third proportion p3> the fourth proportion p4> the preset value 0.8, so that the determination of the source of heterozygous deleted fragments is performed according to the determination logic, and it is considered that only one chromosome of the forensic in the region is inherited from the mother, and the deleted fragments are derived from the father.
In an alternative embodiment, the operational procedure for determining the source of the CNV may be used after the explicit determination and verification of the existence of the CNV is obtained by conventional methods (e.g., the methods of CNV-seq, CMA, etc.). When the verified CNV is of a missing type, a flow of judging the source of copy number missing is used.
In practical application, the invention can analyze the mutation of the whole chromosome segment by using the comprehensive information of all the point mutations of family members in the copy number mutation section, and the theoretical basis is the wide distribution of the point mutations and the genetic characteristics of the point mutations inherited from parents along with the chromosome segment.
Meanwhile, the invention can more accurately explain the reason of fragment variation formation aiming at different characteristics of different types.
In addition, the invention can be also suitable for the current gene detection field, combines the sequencing data of the whole exon or whole genome sequencing commonly used in gene detection, can use the current flow to assist in analyzing clinical data besides main mutation detection, and makes expectations for the occurrence probability of diseases, thereby effectively improving the accuracy and reliability of diagnosis.
In this embodiment, the present invention provides a method for determining a source of chromosome copy number deficiency, which has the following advantages: according to the invention, mutation data about chromosome copy number deficiency can be obtained, family point mutation data related to the chromosome is extracted according to the chromosome copy number deficiency data, the ratio of the family point mutation data to the number of point mutations in the chromosome copy number deficiency data is calculated, and the mutation sources are determined by comparing the ratios of different mutation types, so that the possibility of mismatching caused by judgment according to the whole deficiency area is reduced, and the detection precision and accuracy are improved.
The embodiment of the invention also provides a source determining device related to chromosome copy number deficiency, and referring to fig. 5, a schematic structural diagram of the source determining device related to chromosome copy number deficiency according to an embodiment of the invention is shown.
Wherein, as an example, the source determining means for chromosome copy number deletion may include:
an acquisition data module 501, configured to acquire mutation data related to chromosome copy number deletion, and acquire family point mutation data corresponding to the mutation data;
a point mutation ratio calculating module 502, configured to calculate a point mutation ratio parameter of the mutation data and the family point mutation data with respect to the number of point mutations based on a mutation type corresponding to the family point mutation data;
the family source determining module 503 is configured to determine a family source of the chromosome copy number deletion according to the magnitude of the point mutation proportion parameter.
Optionally, the point mutation ratio parameter includes: a first ratio value;
the point mutation proportion calculation module is further used for:
and when the mutation type corresponding to the family point mutation data is the homozygous mutation of the male parent, calculating the ratio of the number of the homozygous mutation contained in the mutation data to the number of the homozygous mutation contained in the family point mutation data and related to the homozygous mutation of the male parent to obtain a first ratio value.
Optionally, the point mutation ratio parameter further includes: a second ratio value;
The point mutation proportion calculation module is further used for:
and when the mutation type corresponding to the family point mutation data is the wild mutation of the male parent, calculating the ratio of the number of the wild mutation contained in the mutation data to the number of the point mutation contained in the family point mutation data and related to the wild mutation of the male parent to obtain a second ratio value.
Optionally, the point mutation ratio parameter further includes: a third ratio value;
the point mutation proportion calculation module is further used for:
and when the mutation type corresponding to the family point mutation data is female parent homozygous mutation, calculating the ratio of the number of the homozygous mutation contained in the mutation data to the number of the point mutation related to the female parent homozygous mutation contained in the family point mutation data to obtain a third ratio value.
Optionally, the point mutation ratio parameter further includes: a fourth ratio value;
the point mutation proportion calculation module is further used for:
and when the mutation type corresponding to the family point mutation data is female parent wild mutation, calculating the ratio of the point mutation number of the wild mutation contained in the mutation data to the point mutation number of the family point mutation data about the female parent wild mutation to obtain a fourth ratio value.
Optionally, the family source determining module is further configured to:
if the first ratio value is greater than the third ratio value and the second ratio value is greater than the fourth ratio value, determining that the source of the family of the chromosome copy number deletion is female parent deletion;
and if the first proportion value is smaller than the third proportion value and the second proportion value is smaller than the fourth proportion value, determining that the family source of the chromosome copy number deletion is a male parent deletion.
Optionally, the family source determining module is further configured to:
if the first proportion value and the second proportion value are both larger than a first preset value, determining that only chromosomes in the mutation data are derived from a male parent;
and if the first proportion value or the second proportion value is smaller than a first preset value, determining that only chromosomes in the mutation data tend to originate from a male parent.
Optionally, the family source determining module is further configured to:
if the third proportion value and the fourth proportion value are both larger than a second preset value, determining that only chromosomes in the variation data are derived from female parents;
if the third ratio or the fourth ratio is smaller than a second preset value, determining that only chromosomes in the mutation data tend to originate from a female parent.
Optionally, the data acquisition module is further configured to:
acquiring a plurality of family sequencing original data corresponding to the variation data, and preprocessing each family sequencing original data to obtain family processing data, wherein the preprocessing comprises the following steps: data cleaning, data quality control, data comparison, mutation detection and data filtering, wherein each family sequencing original data is the gene data of the family member corresponding to the mutation data;
combining the point mutation data contained in the family processing data, and extracting a union set of the combined data to obtain a point mutation data set;
and carrying out data screening on the point mutation data set according to the mutation fragments corresponding to the mutation data to obtain family point mutation data.
It will be clearly understood by those skilled in the art that, for convenience and brevity, the specific working process of the apparatus described above may refer to the corresponding process in the foregoing method embodiment, which is not described herein again.
Further, an embodiment of the present application further provides an electronic device, including: a memory, a processor and a computer program stored on the memory and executable on the processor, which when executed implements the method of source determination regarding chromosome copy number loss as described in the above embodiments.
Further, an embodiment of the present application also provides a computer-readable storage medium storing a computer-executable program for causing a computer to execute the source determining method regarding chromosome copy number deletion as described in the above embodiment.
While the foregoing is directed to the preferred embodiments of the present application, it will be appreciated by those skilled in the art that changes and modifications may be made without departing from the principles of the application, such changes and modifications are also intended to be within the scope of the application.
Claims (10)
1. A method of determining a source of a chromosome copy number deletion, the method comprising:
obtaining variation data about chromosome copy number deficiency and obtaining family point mutation data corresponding to the variation data;
calculating point mutation proportion parameters of the mutation data and the family point mutation data about the number of point mutations based on mutation types corresponding to the family point mutation data;
and determining the family source of the chromosome copy number deletion according to the numerical value of the point mutation proportion parameter.
2. The method of claim 1, wherein the point mutation ratio parameters comprise: a first ratio value;
The calculating the mutation ratio parameters of the mutation data and the family point mutation data about the point mutation number based on the mutation types corresponding to the family point mutation data comprises the following steps:
and when the mutation type corresponding to the family point mutation data is the homozygous mutation of the male parent, calculating the ratio of the number of the homozygous mutation contained in the mutation data to the number of the homozygous mutation contained in the family point mutation data and related to the homozygous mutation of the male parent to obtain a first ratio value.
3. The method of claim 2, wherein the point mutation ratio parameters further comprise: a second ratio value;
the calculating the mutation data and the point mutation proportion parameter of the family point mutation data about the point mutation number based on the mutation type corresponding to the family point mutation data further comprises:
and when the mutation type corresponding to the family point mutation data is the wild mutation of the male parent, calculating the ratio of the number of the wild mutation contained in the mutation data to the number of the point mutation contained in the family point mutation data and related to the wild mutation of the male parent to obtain a second ratio value.
4. The method of claim 3, wherein the point mutation scaling parameters further comprise: a third ratio value;
the calculating the mutation data and the point mutation proportion parameter of the family point mutation data about the point mutation number based on the mutation type corresponding to the family point mutation data further comprises:
and when the mutation type corresponding to the family point mutation data is female parent homozygous mutation, calculating the ratio of the number of the homozygous mutation contained in the mutation data to the number of the point mutation related to the female parent homozygous mutation contained in the family point mutation data to obtain a third ratio value.
5. The method of claim 4, wherein the point mutation scaling parameters further comprise: a fourth ratio value;
the calculating the mutation data and the point mutation proportion parameter of the family point mutation data about the point mutation number based on the mutation type corresponding to the family point mutation data further comprises:
and when the mutation type corresponding to the family point mutation data is female parent wild mutation, calculating the ratio of the point mutation number of the wild mutation contained in the mutation data to the point mutation number of the family point mutation data about the female parent wild mutation to obtain a fourth ratio value.
6. The method according to claim 5, wherein determining the source of the chromosome copy number deletion family based on the magnitude of the point mutation ratio parameter comprises:
if the first ratio value is greater than the third ratio value and the second ratio value is greater than the fourth ratio value, determining that the source of the family of the chromosome copy number deletion is female parent deletion;
and if the first proportion value is smaller than the third proportion value and the second proportion value is smaller than the fourth proportion value, determining that the family source of the chromosome copy number deletion is a male parent deletion.
7. The method for determining the origin of a chromosomal copy number deletion as defined in claim 6, wherein after said step of determining the source of the chromosome copy number deletion as the maternal deletion, the method further comprises:
if the first proportion value and the second proportion value are both larger than a first preset value, determining that only chromosomes in the mutation data are derived from a male parent;
and if the first proportion value or the second proportion value is smaller than a first preset value, determining that only chromosomes in the mutation data tend to originate from a male parent.
8. The method for determining the origin of a chromosomal copy number deletion as defined in claim 6, wherein after said step of determining the origin of the chromosome copy number deletion as a male parent deletion, the method further comprises:
if the third proportion value and the fourth proportion value are both larger than a second preset value, determining that only chromosomes in the variation data are derived from female parents;
if the third ratio or the fourth ratio is smaller than a second preset value, determining that only chromosomes in the mutation data tend to originate from a female parent.
9. The method for determining a source of a chromosome copy number deletion as claimed in any one of claims 1 to 8, wherein said obtaining family point mutation data corresponding to said mutation data comprises:
acquiring a plurality of family sequencing original data corresponding to the variation data, and preprocessing each family sequencing original data to obtain family processing data, wherein the preprocessing comprises the following steps: data cleaning, data quality control, data comparison, mutation detection and data filtering, wherein each family sequencing original data is the gene data of the family member corresponding to the mutation data;
Combining the point mutation data contained in the family processing data, and extracting a union set of the combined data to obtain a point mutation data set;
and carrying out data screening on the point mutation data set according to the mutation fragments corresponding to the mutation data to obtain family point mutation data.
10. A source determining device for chromosome copy number deletion, the device comprising:
the acquisition data module is used for acquiring variation data about chromosome copy number deficiency and acquiring family point mutation data corresponding to the variation data;
the point mutation proportion calculation module is used for calculating point mutation proportion parameters of the mutation data and the family point mutation data about the number of point mutations based on mutation types corresponding to the family point mutation data;
and the family source determining module is used for determining the family source of the chromosome copy number deletion according to the numerical value of the point mutation proportion parameter.
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