Method for detecting diplophile and application thereof

Abstract

The invention discloses a method for detecting monophilic disomes and application of the method. According to the method, on the basis of given family whole genome low-depth sequencing data, a sliding window is set in a whole genome to count and compare contribution rate differences of male parents and female parents to fetal (subline) genetic materials in the window, so that UPD detection is realized. According to the method, the UPD abnormity of the whole chromosome can be accurately identified, local UPD (segment UPD) in the chromosome and the breakpoint position of the UPD can be identified, and the parent source of the UPD can be automatically judged.

Description

Technical Field

[0001] The present invention relates to the technical field of prenatal diagnostic cytogenetic testing, and particularly relates to a method for detecting uniparental disomy and its application. Background Art

[0002] Human cells are diploid, with one set of genomes from the paternal parent and the other set from the maternal parent. Uniparental disomy (UPD) abnormality refers to the situation where a pair of homologous chromosomes or a part of homologous chromosomes simultaneously originate from the same parent. According to literature reports, the incidence of UPD is usually 1 / 3500 - 1 / 5000, but there are also literatures indicating that the incidence of UPD in live births can reach 1 / 2000. Although most UPDs are not pathogenic, if UPD occurs in the imprinted gene region, it may lead to severe birth defects. Common pathogenic-related UPDs are located on chromosomes 6, 7, 11, 14, 15, and 20. The most representative region among them is 15q11 - 13, and upd(15)mat and upd(15)pat in this region correspond to Prader - Willi syndrome (PWS syndrome) caused by paternal imprinted gene deletion and Angelman syndrome (AS syndrome) caused by maternal imprinted gene deletion, respectively.

[0003] According to the occurrence mechanism of UPD, UPD is usually divided into three subtypes: isodisomy (isoUPD), heterodisomy (hetUPD), and mosaic UPD (partial isoUPD). Among them, HetUPD is caused by non-disjunction occurring in meiosis I, and the affected individual will inherit two homologous chromosomes of the chromosome from the same father / mother; IsoUPD is caused by non-disjunction occurring in meiosis II, and the affected individual will inherit two identical copies of one homologous chromosome from one of the parents; Mosaic UPD is caused by non-disjunction occurring after crossover in meiosis I or meiosis II, which will result in the dominant manifestation of the alternating appearance of hetUPD and isoUPD on the same chromosome. It should be noted that there are continuous regions of homozygosity (ROHs) in isoUPD and mosaic UPD. Therefore, when only analyzing the proband on the CMA platform and the ROH-seq analysis method in Chinese Patent Application No. CN202010896507.5 infer whether there is UPD on the chromosome by detecting the ROH region of the sample, but these two methods cannot detect hetUPD, and the detection effect for mosaic UPD is related to the length of ROH, and there are possibilities of false positives and false negatives (see Table 1).

[0004] Based on the existing UPD detection principle, the UPD detection techniques can be divided into three categories: the detection method based on ROH to hint UPD, the detection method based on the detection of imprinting gene defects to hint UPD, and the detection method directly targeting UPD itself. However, as shown in Table 1 below, there are certain limitations in the currently existing UPD detection techniques.

[0005] Table 1 Comparison Table of UPD Detection Techniques

[0006]

[0007]

[0008] Specifically, the first type of UPD detection method, which takes the detection of large genomic homozygous regions (ROH) to hint UPD abnormalities as the core, can detect genomic homozygous regions within the whole genome and accurately identify isodisomic UPD (isoUPD). However, due to the limitations of the detection mechanism of this type of method itself, it cannot detect heterodisomic UPD (hetUPD) of the whole chromosome, and there may be cases of missed detection of mixed UPD; in addition, genomic homozygous regions can also be caused by other reasons such as parental kinship, and the results of this type of method only hint at a high risk of UPD, so additional technologies need to be combined for confirmation. Moreover, this type of method cannot identify the parental origin of UPD. The second type of UPD detection method based on methylation analysis to hint UPD abnormalities is limited by its limited detection sites and cannot detect UPD abnormalities in un-covered regions, and cannot accurately hint at the breakpoint position of UPD. Currently, there are also many defects in the detection techniques directly targeting UPD itself. For example, QF-PCR is limited to analyzing whole-genome UPD due to fewer detectable sites and cannot accurately identify UPD abnormalities within the chromosome. The family-based CMA method has limitations of high detection cost and low throughput. Although Chinese Patent CN 202110726077.7 discloses a method for detecting chromosomal uniparental disomy based on low-depth sequencing of families, this method only supports the detection of UPD of the whole chromosome, cannot detect fragmented UPD within the chromosome, fails to provide an accurate UPD interval, and cannot confirm the origin of UPD.

[0009] Therefore, developing a UPD detection method that can effectively overcome all the above problems will provide strong technical support for clinical research, diagnosis, and treatment related to UPD. Summary of the Invention

[0010] The present invention aims to solve at least one of the above-mentioned technical problems in the prior art. For this purpose, the object of the present invention is to provide a method for detecting uniparental disomy and its application. The method in the present invention realizes high-precision UPD detection at low cost. Based on the given low-depth whole-genome sequencing data of a pedigree, by setting a sliding window in the whole genome to statistically compare the difference in the contribution rate of paternal and maternal genetic materials to the fetus (offspring) within the window, UPD detection is achieved. It can not only accurately identify the UPD abnormalities of the whole chromosome, but also identify the local UPD (segmentUPD) within the chromosome and the breakpoint positions of UPD, and automatically determine the parental origin of UPD.

[0011] In the first aspect of the present invention, there is provided a method for identifying the origin of UPD in an offspring, comprising the following steps:

[0012] (1) Construct a pedigree DNA library and perform low-depth whole-genome sequencing at a sequencing depth of 0.1 - 0.5×. Align the sequencing results with the reference genome, remove repetitive sequences and low-quality (MAQ < 10) sequences to obtain a database set;

[0013] (2) Screen biallelic SNP sites with a minor allele frequency between 0.01 and 0.5 from the database set for single-base mutation detection to obtain the genotype composition information of each SNP site;

[0014] (3) Classify the SNPs according to the genotype composition information of each SNP site, calculate the allele frequencies of the father and mother, and combine the genotype detection results of the offspring to calculate the heritability of the father and mother;

[0015] (4) Divide the human genome into windows according to the heritability of the father and mother, count the number of SNP sites in each group, and calculate the ratio of the genetic contribution degrees of the father and mother for each window;

[0016] (5) According to the ratio of genetic contribution degrees (logOR) in the test offspring sample, determine the UPD abnormality (i.e., whether UPD exists) and its origin.

[0017] In the present invention, the theoretical construction basis of the above method is: Uniparental disomy (UPD) is a situation where an individual inherits two copies of a chromosome from one of the parents, that is, the genetic material in the UPD region all originates from a certain parent, and there are significant differences in the contribution degrees of the father and mother to the offspring's genetic material. Therefore, based on this fact, the inventor divides the genome into N analysis windows through an algorithm model, and then quantitatively processes the differences in the contribution degrees of the father / mother in each window, and realizes UPD detection in the whole-genome range through statistical analysis of the quantitative results.

[0018] In the present invention, whole-genome low-depth data is used as the basis, and the average coverage depth of each SNP locus is only 0.1-0.5×. In this case, the inventor pioneered the introduction of the measure logOR of the parental genetic contribution ratio to overcome the defect that the genotype (i.e., the composition of alleles) of each SNP locus cannot be judged due to the low average coverage depth, and achieved low-cost detection. The measure logOR is a pioneering quantitative index used to quantitatively analyze the contribution of genetic materials passed from the father and mother to the offspring in each analysis window, so as to evaluate and detect UPD of the offspring in a new way.

[0019] In some embodiments of the present invention, the judgment criterion for the source of UPD is as follows:

[0020] When the genetic contribution ratio of the test offspring sample ≥ 1, it is considered that the UPD comes from the father, which is paternal UPD;

[0021] When the genetic contribution ratio of the test offspring sample ≤ -1, it is considered that the UPD comes from the mother, which is maternal UPD;

[0022] When -1 < the genetic contribution ratio of the test offspring sample < 1, there is no UPD, and the source is not considered.

[0023] In some embodiments of the present invention, the pedigree includes a father, a mother, and an offspring pedigree.

[0024] In some embodiments of the present invention, the construction of the pedigree DNA library is carried out by using conventional library construction methods in the art.

[0025] In some embodiments of the present invention, the process of library construction includes but is not limited to: DNA fragmentation of the sample genomic DNA, and successively performing end repair, adapter addition, PCR enrichment, library quantification, and library quality inspection on the fragmented DNA fragments.

[0026] In some embodiments of the present invention, the average sequencing depth of whole-genome low-depth sequencing is 0.15×.

[0027] In some embodiments of the present invention, the comparison in step (1) is carried out using the BWA alignment software.

[0028] In some embodiments of the present invention, the comparison parameters in step (1) are bwamem -t20 -B1 -O1 -L1 -T -M reference.

[0029] In some embodiments of the present invention, in step (3), the classification criteria for SNPs are as follows:

[0030] The first type of SNP: SNPs that contain only the reference allele (labeled as AA in the present invention);

[0031] The second type of SNP: SNPs that contain only the minor allele (labeled as BB in the present invention);

[0032] The third type of SNP: SNPs that have both the reference allele and the minor allele (labeled as AB in the present invention).

[0033] In some embodiments of the present invention, the reference allele is the allele on the human reference genome of the hg19 version.

[0034] In some embodiments of the present invention, in step (3), the calculation formulas for the allele frequencies of the male parent and the female parent are as shown in Table 2 of the specification, where AA represents the first type of SNP, BB represents the second type of SNP, and AB represents the third type of SNP.

[0035] In some embodiments of the present invention, in step (3), the calculation formulas for the heritability of the male parent and the female parent are as shown in Table 3 of the specification, where AA represents the first type of SNP, BB represents the second type of SNP, and AB represents the third type of SNP.

[0036] In some embodiments of the present invention, in step (4), window partitioning is performed in a sliding window partitioning manner, and the size of the window can be adjusted according to the average coverage rate of the whole-genome low-depth sequencing depth.

[0037] In some embodiments of the present invention, in step (4), each window includes 2000 SNP loci, and the length of each window is about 1 Mb.

[0038] In some embodiments of the present invention, in step (4), the calculation formula for the genetic contribution ratio odds ratio is:

[0039]

[0040] Genetic contribution ratio odds ratio = log2OR

[0041] In the formula,

[0042] M pa and N pa represent the number of SNPs in the corresponding categories after the male parent is classified based on M categories with a heritability greater than 0.25 and N categories with a heritability less than 0.25;

[0043] M ma and N ma represent the number of SNPs in the corresponding categories after the female parent is classified based on M categories with a heritability greater than 0.25 and N categories with a heritability less than 0.25.

[0044] In some embodiments of the present invention, before calculating the genetic contribution ratio odds ratio (logOR) in the sample of the subsystem to be tested, it is block-segmented using the Circular Binary Segmentation (CBS) algorithm, and the logOR value of each block is calculated independently.

[0045] The second aspect of the present invention provides an application of the method described in the first aspect of the present invention in UPD detection.

[0046] In some embodiments of the present invention, the UPD detection includes determining whether UPD exists qualitatively, UPD typing, and determining the location of UPD.

[0047] In some embodiments of the present invention, the judgment criterion for qualitatively determining whether UPD exists is as follows:

[0048] When the logOR of the sample to be tested satisfies -1 < logOR < 1, it is determined that no UPD occurs in the sample to be tested (negative);

[0049] When the logOR of the sample to be tested satisfies logOR ≥ 1, it is determined that paternal UPD exists in the sample to be tested;

[0050] When the logOR of the sample to be tested satisfies logOR ≤ -1, it is determined that maternal UPD exists in the sample to be tested;

[0051] In some embodiments of the present invention, the method for determining the location of UPD is as follows:

[0052] By measuring the window where UPD exists, the position of the chromosome where the window is located is correspondingly obtained, so as to obtain the location of UPD.

[0053] The third aspect of the present invention provides a product that writes or executes the method described in the first aspect of the present invention.

[0054] In some embodiments of the present invention, the product includes a computer-readable carrier and a detection system.

[0055] In some embodiments of the present invention, the detection system includes a detection end and an analysis end.

[0056] In some embodiments of the present invention, the analysis end carries a computer-readable carrier of the method described in the first aspect of the present invention, or executes the steps in the UPD-seq detection method of the method described in the first aspect of the present invention.

[0057] The beneficial effects of the present invention are:

[0058] 1. The UPD-seq detection method in the present invention has the advantages of high throughput and low cost compared with traditional methods such as CMA and CNV-seq commonly used in the art, and is more accurate in detecting copy numbers of low-level mosaics.

[0059] 2. Compared with UPD screening methods such as ROH detection, the UPD-seq detection method in the present invention can identify hetUPD (full-type identification: accurately identify all three types of UPD, namely isoUPD, mixed-type UPD, and heterUPD) and the parental origin of UPD, without false positive results, and can also detect fragmented UPD within a chromosome, providing an accurate UPD interval (breakpoint position of segmentUPD within a chromosome) and clarifying the parental origin of UPD. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 It is a technical roadmap of UPD-seq in the present invention.

[0061] Figure 2 It is a comparison chart of the detection results of the SNP-array, a comparative method involved in the present invention (UPD-tools software).

[0062] Figure 3 It is a comparison chart of the detection results of UPD-seq (B) and traditional ROH-seq (A) in the present invention for Case A (upd(3)mat).

[0063] Figure 4 It is a comparison chart of the detection results of UPD-seq (B) and traditional ROH-seq (A) in the present invention for Case B (upd(16)mat).

[0064] Figure 5 It is a comparison chart of the detection results of UPD-seq (B) and traditional ROH-seq (A) in the present invention for Case C (upd(15)mat).

[0065] Figure 6 It is a comparison chart of the detection results of UPD-seq (B) and traditional ROH-seq (A) in the present invention for Case D (Segment upd(1)pat; arr[hg19]1p36.33p36.12(888,658 - 22,067,338)×2upd). DETAILED DESCRIPTION OF THE INVENTION

[0066] The content of the present invention will be further described in detail through specific embodiments below. Unless otherwise specified, the raw materials, reagents or devices used in the examples and comparative examples can be obtained from conventional commercial channels or can be obtained by methods of the prior art. Unless otherwise specified, the test or measurement methods are conventional methods in this field.

[0067] Construction and analysis of UPD-seq detection method

[0068] The specific steps are as follows:

[0069] (1) Low-depth whole-genome library construction and sequencing (~0.15×) for pedigrees:

[0070] Collect training set samples (DNA samples of father, mother, and child pedigrees), construct libraries respectively according to the conventional library construction methods in this field. After the library construction is completed, perform low-depth whole-genome sequencing with an average sequencing depth of 0.15×.

[0071] Among them, the specific library construction process in this embodiment is as follows: Extract genomic DNA of the sample and perform DNA fragmentation by enzymatic digestion. Perform end repair, adapter ligation, PCR enrichment, library quantification, and library quality inspection on the fragmented DNA in sequence to obtain the constructed library. After confirming that there are no problems with the library quality inspection, perform low-depth whole-genome sequencing according to the above average sequencing depth requirements.

[0072] (2) Data preprocessing:

[0073] Use the BWA alignment software to align the sequencing reads obtained from low-depth whole-genome sequencing with the human reference genome (the human reference genome version is hg19, and the alignment parameters are bwamem -t20 -B1 -O1 -L1 -T -M reference), and remove the duplicate sequences and low-quality alignment (MAQ < 10) results.

[0074] (3) Screen SNP sites:

[0075] Screen biallelic SNP sites with minor allele frequency (MAF value) between 0.01 and 0.5 as the analysis targets from the preprocessed data. In this embodiment, a total of 6.2 million SNP sites are obtained.

[0076] (4) Detect single-nucleotide variants SNV:

[0077] Perform single-nucleotide variant detection on the obtained SNP sites to obtain the genotype composition information of each SNP site.

[0078] (5) Calculate allele frequencies:

[0079] Due to the insufficient coverage rate of each locus, it is actually difficult to determine the true genotype of each SNP. In this regard, after single-base variant detection, based on the detection results, SNP loci are further classified into three categories:

[0080] SNPs that contain only the reference allele (denoted as the A allele) are classified as AA;

[0081] SNPs that contain only the minor allele (denoted as the B allele) are classified as BB;

[0082] SNPs that have both A and B alleles are labeled as AB.

[0083] Based on the classification, calculate the frequencies of the A or B alleles carried by the parents respectively.

[0084] The specific calculation method can be referred to Table 2.

[0085] Table 2 Probability calculation formula for the frequencies of alleles carried by the male parent / female parent

[0086]

[0087] In the above formula, p A and p B respectively represent the allele frequencies of the A and B alleles in the overall sample;

[0088] p Apa and p Bpa respectively represent the probabilities of the A or B alleles owned by the male parent;

[0089] p Ama and p Bma respectively represent the probabilities of the A or B alleles owned by the female parent.

[0090] (6) Calculate the heritabilities of the male parent and the female parent:

[0091] Based on the allele frequencies of the male parent and the female parent obtained in the above step (5), combined with the genotype detection results of the fetus (offspring), calculate the heritabilities I pa and I pa .

[0092] Table 3 Heritability calculation formula for the male parent and the female parent

[0093]

[0094] (7) Divide the analysis window and calculate the number of SNP loci:

[0095] The human genome is divided into analysis windows with a fixed number of SNPs using a sliding window method. The size of the analysis window can be adjusted according to the average coverage of the low-depth whole-genome sequencing depth. In this embodiment, each window includes 2,000 SNP loci, and the length of each window is approximately 1 Mb.

[0096] The SNP loci are divided into two groups, and the number of SNP loci in each group in each analysis window is calculated. Among them, the grouping is based on the heritability of the parental / maternal SNP loci obtained in the above steps, with M class having a heritability greater than 0.25 and N class having a heritability less than 0.25. Then, the number of SNPs in which the parent / mother is classified into each category is calculated separately. The number of SNP loci of the father in groups M and N is denoted as M pa and N pa , and the number of SNP loci of the mother in groups M and N is denoted as M ma and N ma .

[0097] (8) Based on the calculated number of SNP loci obtained in the above steps, the ratio of the paternal and maternal genetic contribution degrees (logOR value) of each analysis window is calculated using the following formula.

[0098]

[0099] logOR = log2OR

[0100] (9) The entire genome of the sample to be tested is segmented into multiple blocks using the circular binary segmentation (CBS) algorithm (using the segment function with parameter alpha = 0.0001), and the average logOR value of each block is calculated using the formula in step (8) above.

[0101] (10) Qualitatively determine UPD and judge the source of UPD based on the average logOR value obtained in step (9):

[0102] For segments with logOR ≥ 1, they are classified as paternal UPD; for segments with logOR ≤ -1, they are classified as maternal UPD.

[0103] Among them, for segments with the characteristic of -1 < logOR < 1, they are classified as negative (i.e., no UPD occurs).

[0104] At the same time, by determining which block the UPD comes from, it is possible to correspondingly determine which segment the UPD comes from, thereby realizing the localization of UPD.

[0105] The technical flow chart of the UPD-seq detection method in this embodiment is as Figure 1 shown.

[0106] Validation of the effectiveness of the UPD-seq detection method

[0107] In this embodiment, in order to prove the effectiveness of the UPD-seq detection method in the above embodiment and its advantages over the traditional methods in the prior art, the UPD detection results based on the low-depth sequencing method and the chip method SNP-array were compared.

[0108] In this embodiment, the samples used for testing were 4 samples with confirmed UPD types.

[0109] In this embodiment, the usage method of the UPD-seq detection method was the same as that in the above embodiment. For the chip method SNP-array used for comparison, CMA analysis was performed using the Affymetrix CytoScan 750K array. The specific detection steps were as follows: The parental-maternal-offspring genomic samples were simultaneously detected using a whole-genome high-resolution SNP microarray, and then the raw data obtained was processed using the ChAS 3.0 software. The specific operations were carried out according to the manufacturer's instructions (Affymetrix, Inc.). Finally, the genotype data of the parental-maternal-offspring trios was analyzed using the UPDTools software (analysis parameters: regions with ≥10 ME numbers, sliding window size ≥100 SNPs, minimum fraction of ME ≥1%), and the UPD detection results of the SNP-array pedigree were obtained.

[0110] Meanwhile, the method in Chinese Patent CN202010896507.5 was used as a comparative method to analyze the above samples. The results are shown in Table 4 and Figures 2 to 6 as follows.

[0111] Table 4 Detection results of the UPD-seq detection method in the above embodiment

[0112]

[0113] From the above results, it can be found that for the samples in 4 different cases, the UPD-seq method in the embodiments of the present invention can detect all the labeled UPDs, and the sensitivity is 100%. In addition, the specificity of UPD-seq also reaches 100%, and no false positive results of unlabeled UPDs are detected. Moreover, UPD-seq can correctly identify the sources of UPDs in all samples, and at the same time correctly classify the three types of UPDs: isoUPD (case A), mixed UPD (Case B and D), and heterUPD (Case C), and detect the fragmented UPD (segment UPD) within the chromosome (Case D). For the fragmented UPD in Case D, the SNP-array family detection result is the paternal UPD in the region of 1p36.33p36.12(888,658-22,067,338)×2, while the detection result of UPD-seq is the paternal UPD in the region of 1p36.33p36.12(55299_24519094)×2, and the two detection results are consistent with a high breakpoint consistency.

[0114] In addition, it can also be found that the ROH-seq analysis method in CN202010896507.5 cannot effectively detect the hetUPD on chromosome 15 in Case C (such as Figure 5 ), while the UPD-seq method in the embodiments of the present invention can detect the maternal UPD on chromosome 15. Thus, it can be seen that the UPD-seq method in the embodiments of the present invention has a broader application direction and a more accurate detection effect compared with the ROH-seq analysis method in CN202010896507.5.

[0115] In summary, the UPD-seq method (which can also be called the family whole-genome low-depth UPD-seq detection method) in the embodiments of the present invention can detect all three types of UPDs (isoUPD, mixed UPD, and heterUPD), can accurately determine the breakpoint positions of Segment UPD within the chromosome, correctly identify the parental sources of UPDs, and can be used as an alternative to the conventional CMA UPD detection in the field to achieve low-cost and high-precision UPD detection.

[0116] Product written with the UPD-seq detection method

[0117] A computer-readable carrier, which writes the UPD-seq detection method in the above embodiments.

[0118] A detection system, including a detection end and an analysis end. Among them, the analysis end carries a computer-readable carrier written with the UPD-seq detection method in the above embodiments and executes the steps in the UPD-seq detection method in the above embodiments.

[0119] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A method for identifying the origin of UPD in a sub-lineage, comprising the following steps: (1) Construct a pedigree DNA library and perform whole-genome sequencing at a sequencing depth of 0.1 - 0.5×. Align the sequencing results with the reference genome, remove repetitive sequences and sequences with MAQ < 10 to obtain a database set; (2) Screen the biallelic SNP sites with minor allele frequencies between 0.01 and 0.5 from the database set for single-base variant detection to obtain the genotype composition information of each SNP site; (3) Classify the SNPs according to the genotype composition information of each SNP site, calculate the allele frequencies of the paternal and maternal parents, and combine the genotype detection results of the offspring to calculate the heritability of the paternal and maternal parents; (4) Divide the human genome into windows according to the heritability of the paternal and maternal parents, count the number of SNP sites in each group, and calculate the odds ratio of the genetic contribution degrees of the paternal and maternal parents for each window; (5) Determine the UPD source according to the odds ratio of the genetic contribution degree in the test offspring sample.

2. The method according to claim 1, characterized in that, The judgment criteria for UPD source are as follows: When the odds ratio of the genetic contribution degree of the test offspring sample ≥ 1, it is considered that UPD is from the paternal parent, which is paternal UPD; When the odds ratio of the genetic contribution degree of the test offspring sample ≤ -1, it is considered that UPD is from the maternal parent, which is maternal UPD; When -1 < the odds ratio of the genetic contribution degree of the test offspring sample < 1, there is no UPD, and the source is not considered.

3. The method according to claim 1, characterized in that, In step (3), the classification criteria for SNPs are as follows: The first type of SNP: SNPs that only contain the reference allele; The second type of SNP: SNPs that only contain the minor allele; The third type of SNP: SNPs that have both the reference allele and the minor allele.

4. The method according to claim 3, characterized in that, The reference allele is the allele on the human reference genome of hg19 version.

5. The method according to claim 1, characterized in that, In step (3), the calculation formulas for the allele frequencies of the paternal and maternal parents are shown in Table 2 of the specification, where AA represents the first type of SNP, BB represents the second type of SNP, and AB represents the third type of SNP.

6. The method according to claim 1, characterized in that, In step (3), the calculation formulas for the heritability of the paternal and maternal parents are shown in Table 3 of the specification, where AA represents the first type of SNP, BB represents the second type of SNP, and AB represents the third type of SNP.

7. The method according to claim 1, characterized in that, In step (4), the calculation formula for the odds ratio of the genetic contribution degree is: Odds ratio of genetic contribution degree = log2OR In the formula, M pa and N pa represent the number of SNPs in the corresponding categories after the male parent is classified based on Class M with a heritability greater than 0.25 and Class N with a heritability less than 0.25; M ma and N ma represent the number of SNPs in the corresponding categories after the female parent is classified based on Class M with a heritability greater than 0.25 and Class N with a heritability less than 0.

25.

8. Use of the method according to any one of claims 1 - 7 in UPD detection.

9. The use according to claim 8, characterized in that, The UPD detection includes determining whether UPD exists qualitatively, UPD typing, and determining the location of UPD.

10. A product, characterized in that, The product writes or executes the method described in any one of claims 1 to 7, and the product includes a computer-readable carrier and a detection system.

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