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

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 identif...

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Autores principales: Lee, Young-gun, Lee, Jin-young, Kim, Junhyong, Kim, Young-Joon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666470/
https://www.ncbi.nlm.nih.gov/pubmed/33187521
http://dx.doi.org/10.1186/s12915-020-00894-1
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author Lee, Young-gun
Lee, Jin-young
Kim, Junhyong
Kim, Young-Joon
author_facet Lee, Young-gun
Lee, Jin-young
Kim, Junhyong
Kim, Young-Joon
author_sort Lee, Young-gun
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s12915-020-00894-1.
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spelling pubmed-76664702020-11-16 Insertion variants missing in the human reference genome are widespread among human populations Lee, Young-gun Lee, Jin-young Kim, Junhyong Kim, Young-Joon BMC Biol Research Article 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. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s12915-020-00894-1. BioMed Central 2020-11-13 /pmc/articles/PMC7666470/ /pubmed/33187521 http://dx.doi.org/10.1186/s12915-020-00894-1 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Lee, Young-gun
Lee, Jin-young
Kim, Junhyong
Kim, Young-Joon
Insertion variants missing in the human reference genome are widespread among human populations
title Insertion variants missing in the human reference genome are widespread among human populations
title_full Insertion variants missing in the human reference genome are widespread among human populations
title_fullStr Insertion variants missing in the human reference genome are widespread among human populations
title_full_unstemmed Insertion variants missing in the human reference genome are widespread among human populations
title_short Insertion variants missing in the human reference genome are widespread among human populations
title_sort insertion variants missing in the human reference genome are widespread among human populations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666470/
https://www.ncbi.nlm.nih.gov/pubmed/33187521
http://dx.doi.org/10.1186/s12915-020-00894-1
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