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Structural variants in the Chinese population and their impact on phenotypes, diseases and population adaptation.

ABSTRACT: A complete characterization of genetic variation is a fundamental goal of human genome research. Long-read sequencing has improved the sensitivity of structural variant discovery. Here, we conduct the long-read sequencing-based structural variant analysis for 405 unrelated Chinese individuals, with 68 phenotypic and clinical measurements. We discover a landscape of 132,312 nonredundant structural variants, of which 45.2% are novel. The identified structural variants are of high-quality, with an estimated false discovery rate of 3.2%. The concatenated length of all the structural variants is approximately 13.2% of the human reference genome. We annotate 1,929 loss-of-function structural variants affecting the coding sequence of 1,681 genes. We discover rare deletions in HBA1/HBA2/HBB associated with anemia. Furthermore, we identify structural variants related to immunity which differentiate the northern and southern Chinese populations. Our study describes the landscape of structural variants in the Chinese population and their contribution to phenotypes and disease.

SUBMITTER: Wu Z

PROVIDER: S-EPMC8586011 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Structural variants in the Chinese population and their impact on phenotypes, diseases and population adaptation.

Wu Zhikun Z Jiang Zehang Z Li Tong T Xie Chuanbo C Zhao Liansheng L Yang Jiaqi J Ouyang Shuai S Liu Yizhi Y Li Tao T Xie Zhi Z

Nature communications 20211111 1

A complete characterization of genetic variation is a fundamental goal of human genome research. Long-read sequencing has improved the sensitivity of structural variant discovery. Here, we conduct the long-read sequencing-based structural variant analysis for 405 unrelated Chinese individuals, with 68 phenotypic and clinical measurements. We discover a landscape of 132,312 nonredundant structural variants, of which 45.2% are novel. The identified structural variants are of high-quality, with an ...[more]

PMID: 34764282

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Project description:Structural variants play an important role in evolutionary processes. Besides, they constitute a large source of inter individual genetic variation that might represent a major factor in the aetiology of complex, multifactorial traits. Their importance in adaptation is becoming increasingly evident in literature. Yet, the characterization of the genomic landscape of structural variants in local breeds remains scarce to date. Herein, we investigate patterns and gene annotation of structural variants in the Creole cattle from Guadeloupe breed using whole genome sequences from 23 bulls representative of the population. In total, we detected 32821 ascertained SV defining 15258 regions, representing ~ 17% of the Creole cattle genome. Among these, 6639 regions have not been previously reported in the Database of Genomic Variants archive. Average number of structural variants detected per individual in the studied population is in the same order of magnitude of that observed in indicine populations and higher than that reported in taurine breeds. We observe an important within-individual variability where approximately half of the detected structural variants have low frequency (MAF < 0.25). Most of the detected structural variants (55%) occurred in intergenic regions. Genic structural variants overlapped with 7793 genes and the predicted effect of most of them is ranked as "modifier". Among the structural variants that were predicted to have a high functional impact on the protein, a 5.5 Kb in length, highly frequent deletion on chromosome 2, affects ALPI, a gene associated with the interaction between gut microbiota and host immune system. The 6639 newly identified structural variants regions include three deletions and three duplications shared by more than 80% of individuals that are significantly enriched for genes related to tRNA threonylcarbamoyladenosine metabolic process, important for temperature adaptation in thermophilic organisms, therefore suggesting a potential role in the thermotolerance of Creole cattle from Guadeloupe cattle to tropical climate. Overall, highly frequent structural variants that are specific to the Creole cattle population encompass olfactory receptor and immunity genes as well as genes involved in muscle tone, muscle development and contraction. Beyond mapping and characterizing structural variants in the Creole cattle from Guadeloupe breed, this study provides valuable information for a better understanding of the potential role of chromosomal rearrangements in adaptive traits in cattle.

Project description:ObjectivesIdentifying drivers of complex traits from the noisy signals of genetic variation obtained from high-throughput genome sequencing technologies is a central challenge faced by human geneticists today. We hypothesize that the variants involved in complex diseases are likely to exhibit non-neutral evolutionary signatures. Uncovering the evolutionary history of all variants is therefore of intrinsic interest for complex disease research. However, doing so necessitates the simultaneous elucidation of the targets of natural selection and population-specific demographic history.MethodsHere we characterize the action of natural selection operating across complex disease categories, and use population genetic simulations to evaluate the expected patterns of genetic variation in large samples. We focus on populations that have experienced historical bottlenecks followed by explosive growth (consistent with many human populations), and describe the differences between evolutionarily deleterious mutations and those that are neutral.ResultsGenes associated with several complex disease categories exhibit stronger signatures of purifying selection than non-disease genes. In addition, loci identified through genome-wide association studies of complex traits also exhibit signatures consistent with being in regions recurrently targeted by purifying selection. Through simulations, we show that population bottlenecks and rapid growth enable deleterious rare variants to persist at low frequencies just as long as neutral variants, but low-frequency and common variants tend to be much younger than neutral variants. This has resulted in a large proportion of modern-day rare alleles that have a deleterious effect on function and that potentially contribute to disease susceptibility.ConclusionsThe key question for sequencing-based association studies of complex traits is how to distinguish between deleterious and benign genetic variation. We used population genetic simulations to uncover patterns of genetic variation that distinguish these two categories, especially derived allele age, thereby providing inroads into novel methods for characterizing rare genetic variation driving complex diseases.

Dataset Information

Structural variants in the Chinese population and their impact on phenotypes, diseases and population adaptation.

Publications

Structural variants in the Chinese population and their impact on phenotypes, diseases and population adaptation.

Similar Datasets

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