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The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism
Genomic inversions are an increasingly recognized source of genetic variation. However, a lack of reliable high-throughput genotyping assays for these structures has precluded a full understanding of an inversion's phylogenetic, phenotypic, and population genetic properties. We characterize the...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371712/ https://www.ncbi.nlm.nih.gov/pubmed/22399572 http://dx.doi.org/10.1101/gr.126037.111 |
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author | Salm, Maximilian P.A. Horswell, Stuart D. Hutchison, Claire E. Speedy, Helen E. Yang, Xia Liang, Liming Schadt, Eric E. Cookson, William O. Wierzbicki, Anthony S. Naoumova, Rossi P. Shoulders, Carol C. |
author_facet | Salm, Maximilian P.A. Horswell, Stuart D. Hutchison, Claire E. Speedy, Helen E. Yang, Xia Liang, Liming Schadt, Eric E. Cookson, William O. Wierzbicki, Anthony S. Naoumova, Rossi P. Shoulders, Carol C. |
author_sort | Salm, Maximilian P.A. |
collection | PubMed |
description | Genomic inversions are an increasingly recognized source of genetic variation. However, a lack of reliable high-throughput genotyping assays for these structures has precluded a full understanding of an inversion's phylogenetic, phenotypic, and population genetic properties. We characterize these properties for one of the largest polymorphic inversions in man (the ∼4.5-Mb 8p23.1 inversion), a structure that encompasses numerous signals of natural selection and disease association. We developed and validated a flexible bioinformatics tool that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion. This tool was applied retrospectively to diverse genome-wide data sets, revealing significant population stratification that largely follows a clinal “serial founder effect” distribution model. Phylogenetic analyses establish the inversion's ancestral origin within the Homo lineage, indicating that 8p23.1 inversion has occurred independently in the Pan lineage. The human inversion breakpoint was localized to an inverted pair of human endogenous retrovirus elements within the large, flanking low-copy repeats; experimental validation of this breakpoint confirmed these elements as the likely intermediary substrates that sponsored inversion formation. In five data sets, mRNA levels of disease-associated genes were robustly associated with inversion genotype. Moreover, a haplotype associated with systemic lupus erythematosus was restricted to the derived inversion state. We conclude that the 8p23.1 inversion is an evolutionarily dynamic structure that can now be accommodated into the understanding of human genetic and phenotypic diversity. |
format | Online Article Text |
id | pubmed-3371712 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-33717122012-12-01 The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism Salm, Maximilian P.A. Horswell, Stuart D. Hutchison, Claire E. Speedy, Helen E. Yang, Xia Liang, Liming Schadt, Eric E. Cookson, William O. Wierzbicki, Anthony S. Naoumova, Rossi P. Shoulders, Carol C. Genome Res Method Genomic inversions are an increasingly recognized source of genetic variation. However, a lack of reliable high-throughput genotyping assays for these structures has precluded a full understanding of an inversion's phylogenetic, phenotypic, and population genetic properties. We characterize these properties for one of the largest polymorphic inversions in man (the ∼4.5-Mb 8p23.1 inversion), a structure that encompasses numerous signals of natural selection and disease association. We developed and validated a flexible bioinformatics tool that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion. This tool was applied retrospectively to diverse genome-wide data sets, revealing significant population stratification that largely follows a clinal “serial founder effect” distribution model. Phylogenetic analyses establish the inversion's ancestral origin within the Homo lineage, indicating that 8p23.1 inversion has occurred independently in the Pan lineage. The human inversion breakpoint was localized to an inverted pair of human endogenous retrovirus elements within the large, flanking low-copy repeats; experimental validation of this breakpoint confirmed these elements as the likely intermediary substrates that sponsored inversion formation. In five data sets, mRNA levels of disease-associated genes were robustly associated with inversion genotype. Moreover, a haplotype associated with systemic lupus erythematosus was restricted to the derived inversion state. We conclude that the 8p23.1 inversion is an evolutionarily dynamic structure that can now be accommodated into the understanding of human genetic and phenotypic diversity. Cold Spring Harbor Laboratory Press 2012-06 /pmc/articles/PMC3371712/ /pubmed/22399572 http://dx.doi.org/10.1101/gr.126037.111 Text en © 2012, Published by Cold Spring Harbor Laboratory Press This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/. |
spellingShingle | Method Salm, Maximilian P.A. Horswell, Stuart D. Hutchison, Claire E. Speedy, Helen E. Yang, Xia Liang, Liming Schadt, Eric E. Cookson, William O. Wierzbicki, Anthony S. Naoumova, Rossi P. Shoulders, Carol C. The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism |
title | The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism |
title_full | The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism |
title_fullStr | The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism |
title_full_unstemmed | The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism |
title_short | The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism |
title_sort | origin, global distribution, and functional impact of the human 8p23 inversion polymorphism |
topic | Method |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371712/ https://www.ncbi.nlm.nih.gov/pubmed/22399572 http://dx.doi.org/10.1101/gr.126037.111 |
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