Insertion variants missing in the human reference genome are widespread among human populations
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RESEARCH ARTICLE
Open Access
Insertion variants missing in the human reference genome are widespread among human populations Young-gun Lee1†, Jin-young Lee2†, Junhyong Kim3 and Young-Joon Kim1,2*
Abstract 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 nonreference 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 highfrequency insertion variants. The subsets of insertion variants were in high linkage disequilibrium with phenotypeassociated 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. Keywords: 1000 Genomes Project, Insertion, Structural variants
* Correspondence: [email protected] † Young-gun Lee and Jin-young Lee contributed equally to this work. 1 Department of Integrated Omics for Biomedical Science, WCU Graduate School, Yonsei University, Seoul, Republic of Korea 2 Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
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