An Evolutionary Perspective on the Impact of Genomic Copy Number Variation on Human Health

Saitou, Marie; Gökçümen, Ömer

doi:10.1007/s00239-019-09911-6

Cited by 36 publications

(33 citation statements)

References 176 publications

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“…This result is consistent with that of a previous study that suggested that African populations retain more ancestral sequences, which can lead to the misinterpretation of the unbalanced SV loads between African and non-African populations [9]. Third, the variants exert putative functional effects by introducing structural changes to genes or by modifying regulatory elements [43,44].…”

Section: Discussionsupporting

confidence: 90%

“…A subset of ancestral sequences showed continentspecific stratification, which suggests the occurrence of recent positive selection events. These insertion variants overlapped with genes related to immunologic and metabolic functions, which are known to be adaptive among human populations and are affected by CNVs [44]. One of the strongest signals of population stratification was associated with immunologic function.…”

Section: Discussionmentioning

confidence: 99%

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Insertion variants missing in the human reference genome are widespread among human populations

Lee

Kim

et al. 2020

BMC Biol

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Background Structural variants comprise diverse genomic arrangements including deletions, insertions, inversions, and translocations, which can generally be detected in humans through sequence comparison to the reference genome. Among structural variants, insertions are the least frequently identified variants, mainly due to ascertainment bias in the reference genome, lack of previous sequence knowledge, and low complexity of typical insertion sequences. Though recent developments in long-read sequencing deliver promise in annotating individual non-reference insertions, population-level catalogues on non-reference insertion variants have not been identified and the possible functional roles of these hidden variants remain elusive. Results To detect non-reference insertion variants, we developed a pipeline, InserTag, which generates non-reference contigs by local de novo assembly and then infers the full-sequence of insertion variants by tracing contigs from non-human primates and other human genome assemblies. Application of the pipeline to data from 2535 individuals of the 1000 Genomes Project helped identify 1696 non-reference insertion variants and re-classify the variants as retention of ancestral sequences or novel sequence insertions based on the ancestral state. Genotyping of the variants showed that individuals had, on average, 0.92-Mbp sequences missing from the reference genome, 92% of the variants were common (allele frequency > 5%) among human populations, and more than half of the variants were major alleles. Among human populations, African populations were the most divergent and had the most non-reference sequences, which was attributed to the greater prevalence of high-frequency insertion variants. The subsets of insertion variants were in high linkage disequilibrium with phenotype-associated SNPs and showed signals of recent continent-specific selection. Conclusions Non-reference insertion variants represent an important type of genetic variation in the human population, and our developed pipeline, InserTag, provides the frameworks for the detection and genotyping of non-reference sequences missing from human populations.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Insertion variants missing in the human reference genome are widespread among human populations

Lee

Kim

et al. 2020

BMC Biol

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“…Most genome‐wide association studies interrogate single nucleotide variants and are generally blind to other types of variants. It is likely based on that locus‐specific and small number of genome‐wide studies that such variation may significantly increase our ability to detect the genetic basis of phenotypic variation (Eaaswarkhanth, Pavlidis, & Gokcumen, ; Resendez et al, ; Saitou & Gokcumen, ).…”

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confidence: 99%

Archaic hominin introgression into modern human genomes

Gökçümen¹

2019

American J Phys Anthropol

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“…In terms of total bases involved, CNVs encompass more nucleotide sequences and arise more frequently than SNPs [6]. Therefore, they have higher mutation probability and more signi cant potential impacts [7], such as changing gene structure and altering gene dosage and thus dramatically affect gene expression and adaptive phenotypes [8]. Additionally, some of these CNVs were even associated with several complex diseases [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide detection of CNV regions and their potential association with growth and fatness traits in Duroc pigs

Qiu

Ding²,

Zhuang

et al. 2020

Preprint

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Background: In the process of pig breeding, the average daily gain (ADG), days to 100 kg (AGE), and backfat thickness (BFT) are directly related to growth rate and fatness. However, the genetic mechanisms involved are not well understood. As an essential source of genetic diversity, copy number variation (CNV) that can affect a variety of complex traits and diseases, has gradually been thrust into the limelight. In this study, we reported the genome-wide CNVs of Duroc pigs by SNP genotyping data of 6,627 Duroc pigs. Moreover, we also performed CNV region (CNVR) based association analysis for growth and fatness traits in two Duroc populations.Results: Our study identified a total of 835 nonredundant CNVRs in American and Canadian Duroc pigs, which covered 226.73 Mb (~ 10.00%) of the pig autosomal genome. Among them, we identified 682 CNVRs in the American Duroc pigs and 424 CNVRs in the Canadian Duroc pigs, and 271 CNVRs were detected in both populations. Experimentally, 77.8% of randomly selected CNVRs were validated by quantitative PCR (qPCR). We also identified 24 significant CNVRs for growth and fatness traits though CNVR-based association analysis. Among these, six and three CNVRs in American and Canadian Duroc pigs were found to be associated with both ADG and AGE traits, respectively. Notably, four CNVRs showed both significant in ADG, AGE, and BFT, indicating that these CNVRs may play a pleiotropic role in regulating pig growth and fat deposition. Besides, further bioinformatics analysis determined a subset of potential candidate genes, such as PDGFRB, INSIG1, GPER1, PDGFA, and LPCAT1.Conclusions: The present study provides a necessary supplement to the CNV map of the Duroc genome through a large-scale population genotyping. Also, the CNVR-based association results provide a meaningful way to elucidate the genetic mechanisms of complex traits. The identified CNVRs can be used as molecular markers for genetic improvement in molecular-guided breeding of modern commercial pigs

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An Evolutionary Perspective on the Impact of Genomic Copy Number Variation on Human Health

Cited by 36 publications

References 176 publications

Insertion variants missing in the human reference genome are widespread among human populations

Insertion variants missing in the human reference genome are widespread among human populations

Archaic hominin introgression into modern human genomes

Genome-wide detection of CNV regions and their potential association with growth and fatness traits in Duroc pigs

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