Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study.

BACKGROUND: Approximately 10% of gastric cancers (GCs) are associated with strong familial clustering and can be attributed to genetic predisposition. Homologous recombination deficiency (HRD) leads to genomic instability and accumulation of genetic variations, playing an important role in the development and progression of cancer. We aimed to delineate the germline mutation characteristics of patients with HRD-mut GC in Chinese. METHODS: We retrospectively reviewed the genomic sequencing data of 1135 patients with Chinese GC. Patients harbouring at least one loss of function (LoF) germline mutations in BRCA1, BRCA2, ATM, PALB2, BRIP1, CHEK1, CHEK2, FANCA and FANCL were selected for analysis. RESULTS: 89 patients were identified with LoF germline mutations of HRD gene. Germline mutations occurred most commonly in ATM (30.33%), followed by BRIP1 (17.98%), BRCA2 (14.61%), BRCA1 (12.36%), FANCA (10.11%), PALB2 (10.11%), FANCL (6.74%), CHEK1 (3.37%) and CHEK2 (3.37%). 14 out of 89 patients with HRD-mut harboured double mutations in HRD and MMR genes, with the median age of 51.5 years. The decreasing median age would be attributed to five patients with HRD+MMR double-muts harbouring mutations in both HRD and MMR genes. The median age of onset of patients with HRD+MMR double-muts is 47, which is significantly earlier than that of Chinese patients with GC (p=0.0235). CONCLUSION: Our data suggest that carrying both HRD and MMR gene LoF germline mutations may cause early-onset GC. Germline mutations in the HRD gene should be of concern in the study of hereditary GC.

Whole-genome analysis reveals the hybrid formation of Chinese indigenous DHB pig following human migration.

Hybridization is widespread in nature and is a valuable tool in domestic breeding. The DHB (DaHuaBai) pig in South China is the product of such a breeding strategy, resulting in increased body weight compared with other pigs in the surrounding area. We analyzed genomic data from 20 Chinese pig breeds and investigated the genomic architecture after breed formation of DHB. The breed showed inconsistency in genotype and body weight phenotype, in line with selection after hybridization. By quantifying introgression with a haplotype-based approach, we proposed a two-step introgression from large-sized pigs into small-sized pigs to produce DHB, consistent with the human migration events in Chinese history. Combining with gene prioritization and allele frequency analysis, we identify candidate genes that showed selection after introgression and that may affect body weight, such as IGF1R, SRC, and PCM1. Our research provides an example of a hybrid formation of domestic breeds along with human migration patterns.

Genome-wide analysis suggests multiple domestication events of Chinese local pigs.

Chinese local pigs have abundant phenotypes as a result of different cultures and habits of Chinese populations, geographic constraints and the long history of pig domestication. A comprehensive investigation of local Chinese pigs will benefit biodiversity research and future breeding practices. However, their classification and demographic history are not yet clear. We studied 91 Chinese local pigs from 14 breeds and 15 Chinese wild boars to reveal the dispersal of Chinese pigs, genetic groups and the demographic history. Based on spatial feature analyses, we believe that the geographic landscape played an important role in the dispersal of local pigs. According to genetic studies, Chinese pigs are divided into three groups where each group appears to have a distinct background. The nucleotide diversity, observed heterozygosity, runs of homozygosity and inbreeding coefficient varied among the groups and widespread migration also existed between the groups. Furthermore, demographic models have been constructed to explain the evolutionary relationship between the groups using the approximate Bayesian computation approach. These suggested that Chinese local pigs are inherited from an extinct Sus scrofa population from ~22 000 years ago. Then, the three groups diverged from ancestors ~16 000, ~11 000 and ~8700 years ago respectively. This study advances our understanding of the genetic variation and demographic history of Chinese local pigs.

Distinct traces of mixed ancestry in western commercial pig genomes following gene flow from Chinese indigenous breeds.

Studying gene flow between different livestock breeds will benefit the discovery of genes related to production traits and provide insight into human historical breeding. Chinese pigs have played an indispensable role in the breeding of Western commercial pigs. However, the differences in the timing and volume of the contribution of pigs from different Chinese regions to Western pigs are not yet apparent. In this paper, we combine the whole-genome sequencing data of 592 pigs from different studies and illustrate patterns of gene flow from Chinese pigs into Western commercial pigs. We describe introgression patterns from four distinct Chinese indigenous groups into five Western commercial groups. There were considerable differences in the number and length of the putative introgressed segments from Chinese pig groups that contributed to Western commercial pig breeds. The contribution of pigs from different Chinese geographical locations to a given western commercial breed varied more than that from a specific Chinese pig group to different Western commercial breeds, implying admixture within Europe after introgression. Within different Western commercial lines from the same breed, the introgression patterns from a given Chinese pig group seemed highly conserved, suggesting that introgression of Chinese pigs into Western commercial pig breeds mainly occurred at an early stage of breed formation. Finally, based on analyses of introgression signals, allele frequencies, and selection footprints, we identified a ∼2.65 Mb Chinese-derived haplotype under selection in Duroc pigs (CHR14: 95.68-98.33 Mb). Functional and phenotypic studies demonstrate that this PRKG1 haplotype is related to backfat and loin depth in Duroc pigs. Overall, we demonstrate that the introgression history of domestic pigs is complex and that Western commercial pigs contain distinct traces of mixed ancestry, likely derived from various Chinese pig breeds.

Selection of Optimal Ancestry Informative Markers for Classification and Ancestry Proportion Estimation in Pigs.

Using small sets of ancestry informative markers (AIMs) constitutes a cost-effective method to accurately estimate the ancestry proportions of individuals. This study aimed to generate a small and effective number of AIMs from ∼60 K single nucleotide polymorphism (SNP) data of porcine and estimate three ancestry proportions [East China pig (ECHP), South China pig (SCHP), and European commercial pig (EUCP)] from Asian breeds and European domestic breeds. A total of 186 samples of 10 pure breeds were divided into three groups: ECHP, SCHP, and EUCP. Using these samples and a one-vs.-rest SVM classifier, we found that using only seven AIMs could completely separate the three groups. Subsequently, we utilized supervised ADMIXTURE to calculate ancestry proportions and found that the 129 AIMs performed well on ancestry estimates when pseudo admixed individuals were used. Furthermore, another 969 samples of 61 populations were applied to evaluate the performance of the 129 AIMs. We also observed that the 129 AIMs were highly correlated with estimates using ∼60 K SNP data for three ancestry components: ECHP (Pearson correlation coefficient (r) = 0.94), SCHP (r = 0.94), and EUCP (r = 0.99). Our results provided an example of using a small number of pig AIMs for classifications and estimating ancestry proportions with high accuracy and in a cost-effective manner.