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Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes
Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655331/ https://www.ncbi.nlm.nih.gov/pubmed/26593880 http://dx.doi.org/10.1038/srep16972 |
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author | Lam, Tze Hau Tay, Matthew Zirui Wang, Bei Xiao, Ziwei Ren, Ee Chee |
author_facet | Lam, Tze Hau Tay, Matthew Zirui Wang, Bei Xiao, Ziwei Ren, Ee Chee |
author_sort | Lam, Tze Hau |
collection | PubMed |
description | Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within their genomic structure is unknown. Using multiple, MHC-homozygous cell lines, we demonstrate extensive sequence conservation in two common Asian MHC haplotypes: A33-B58-DR3 and A2-B46-DR9. However, characterization of phase-resolved MHC haplotypes revealed unique intra-CEH patterns of variation and uncovered 127 single nucleotide variants (SNVs) which are missing from public databases. We further show that the strong linkage disequilibrium structure within the human MHC that typically confounds precise identification of genetic features can be resolved using intra-CEH variants, as evidenced by rs3129063 and rs448489, which affect expression of ZFP57, a gene important in methylation and epigenetic regulation. This study demonstrates an improved strategy that can be used towards genetic dissection of diseases. |
format | Online Article Text |
id | pubmed-4655331 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46553312015-11-27 Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes Lam, Tze Hau Tay, Matthew Zirui Wang, Bei Xiao, Ziwei Ren, Ee Chee Sci Rep Article Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within their genomic structure is unknown. Using multiple, MHC-homozygous cell lines, we demonstrate extensive sequence conservation in two common Asian MHC haplotypes: A33-B58-DR3 and A2-B46-DR9. However, characterization of phase-resolved MHC haplotypes revealed unique intra-CEH patterns of variation and uncovered 127 single nucleotide variants (SNVs) which are missing from public databases. We further show that the strong linkage disequilibrium structure within the human MHC that typically confounds precise identification of genetic features can be resolved using intra-CEH variants, as evidenced by rs3129063 and rs448489, which affect expression of ZFP57, a gene important in methylation and epigenetic regulation. This study demonstrates an improved strategy that can be used towards genetic dissection of diseases. Nature Publishing Group 2015-11-23 /pmc/articles/PMC4655331/ /pubmed/26593880 http://dx.doi.org/10.1038/srep16972 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Lam, Tze Hau Tay, Matthew Zirui Wang, Bei Xiao, Ziwei Ren, Ee Chee Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes |
title | Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes |
title_full | Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes |
title_fullStr | Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes |
title_full_unstemmed | Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes |
title_short | Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes |
title_sort | intrahaplotypic variants differentiate complex linkage disequilibrium within human mhc haplotypes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655331/ https://www.ncbi.nlm.nih.gov/pubmed/26593880 http://dx.doi.org/10.1038/srep16972 |
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