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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2012
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.
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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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