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Accurate measurement of gene copy number for human alpha-defensin DEFA1A3

BACKGROUND: Multi-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technic...

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Autores principales: Khan, Fayeza F, Carpenter, Danielle, Mitchell, Laura, Mansouri, Omniah, Black, Holly A, Tyson, Jess, Armour, John AL
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046698/
https://www.ncbi.nlm.nih.gov/pubmed/24138543
http://dx.doi.org/10.1186/1471-2164-14-719
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author Khan, Fayeza F
Carpenter, Danielle
Mitchell, Laura
Mansouri, Omniah
Black, Holly A
Tyson, Jess
Armour, John AL
author_facet Khan, Fayeza F
Carpenter, Danielle
Mitchell, Laura
Mansouri, Omniah
Black, Holly A
Tyson, Jess
Armour, John AL
author_sort Khan, Fayeza F
collection PubMed
description BACKGROUND: Multi-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technical difficulty of large-scale but accurate typing of genomic copy number. The copy-variable alpha-defensin locus DEFA1A3 on human chromosome 8 commonly varies between 4 and 10 copies per diploid genome, and presents considerable challenges for accurate high-throughput typing. RESULTS: In this study, we developed two paralogue ratio tests and three allelic ratio measurements that, in combination, provide an accurate and scalable method for measurement of DEFA1A3 gene number. We combined information from different measurements in a maximum-likelihood framework which suggests that most samples can be assigned to an integer copy number with high confidence, and applied it to typing 589 unrelated European DNA samples. Typing the members of three-generation pedigrees provided further reassurance that correct integer copy numbers had been assigned. Our results have allowed us to discover that the SNP rs4300027 is strongly associated with DEFA1A3 gene copy number in European samples. CONCLUSIONS: We have developed an accurate and robust method for measurement of DEFA1A3 copy number. Interrogation of rs4300027 and associated SNPs in Genome-Wide Association Study SNP data provides no evidence that alpha-defensin copy number is a strong risk factor for phenotypes such as Crohn’s disease, type I diabetes, HIV progression and multiple sclerosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-14-719) contains supplementary material, which is available to authorized users.
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spelling pubmed-40466982014-06-06 Accurate measurement of gene copy number for human alpha-defensin DEFA1A3 Khan, Fayeza F Carpenter, Danielle Mitchell, Laura Mansouri, Omniah Black, Holly A Tyson, Jess Armour, John AL BMC Genomics Methodology Article BACKGROUND: Multi-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technical difficulty of large-scale but accurate typing of genomic copy number. The copy-variable alpha-defensin locus DEFA1A3 on human chromosome 8 commonly varies between 4 and 10 copies per diploid genome, and presents considerable challenges for accurate high-throughput typing. RESULTS: In this study, we developed two paralogue ratio tests and three allelic ratio measurements that, in combination, provide an accurate and scalable method for measurement of DEFA1A3 gene number. We combined information from different measurements in a maximum-likelihood framework which suggests that most samples can be assigned to an integer copy number with high confidence, and applied it to typing 589 unrelated European DNA samples. Typing the members of three-generation pedigrees provided further reassurance that correct integer copy numbers had been assigned. Our results have allowed us to discover that the SNP rs4300027 is strongly associated with DEFA1A3 gene copy number in European samples. CONCLUSIONS: We have developed an accurate and robust method for measurement of DEFA1A3 copy number. Interrogation of rs4300027 and associated SNPs in Genome-Wide Association Study SNP data provides no evidence that alpha-defensin copy number is a strong risk factor for phenotypes such as Crohn’s disease, type I diabetes, HIV progression and multiple sclerosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-14-719) contains supplementary material, which is available to authorized users. BioMed Central 2013-10-20 /pmc/articles/PMC4046698/ /pubmed/24138543 http://dx.doi.org/10.1186/1471-2164-14-719 Text en © Khan et al.; licensee BioMed Central Ltd. 2013 This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Methodology Article
Khan, Fayeza F
Carpenter, Danielle
Mitchell, Laura
Mansouri, Omniah
Black, Holly A
Tyson, Jess
Armour, John AL
Accurate measurement of gene copy number for human alpha-defensin DEFA1A3
title Accurate measurement of gene copy number for human alpha-defensin DEFA1A3
title_full Accurate measurement of gene copy number for human alpha-defensin DEFA1A3
title_fullStr Accurate measurement of gene copy number for human alpha-defensin DEFA1A3
title_full_unstemmed Accurate measurement of gene copy number for human alpha-defensin DEFA1A3
title_short Accurate measurement of gene copy number for human alpha-defensin DEFA1A3
title_sort accurate measurement of gene copy number for human alpha-defensin defa1a3
topic Methodology Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046698/
https://www.ncbi.nlm.nih.gov/pubmed/24138543
http://dx.doi.org/10.1186/1471-2164-14-719
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