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The signature of long-standing balancing selection at the human defensin β-1 promoter

BACKGROUND: Defensins, small endogenous peptides with antimicrobial activity, are pivotal components of the innate immune response. A large cluster of defensin genes is located on human chromosome 8p; among them the beta defensin 1 (DEFB1) promoterhas been extensively studied since discovery that sp...

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Autores principales: Cagliani, Rachele, Fumagalli, Matteo, Riva, Stefania, Pozzoli, Uberto, Comi, Giacomo P, Menozzi, Giorgia, Bresolin, Nereo, Sironi, Manuela
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592704/
https://www.ncbi.nlm.nih.gov/pubmed/18817538
http://dx.doi.org/10.1186/gb-2008-9-9-r143
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author Cagliani, Rachele
Fumagalli, Matteo
Riva, Stefania
Pozzoli, Uberto
Comi, Giacomo P
Menozzi, Giorgia
Bresolin, Nereo
Sironi, Manuela
author_facet Cagliani, Rachele
Fumagalli, Matteo
Riva, Stefania
Pozzoli, Uberto
Comi, Giacomo P
Menozzi, Giorgia
Bresolin, Nereo
Sironi, Manuela
author_sort Cagliani, Rachele
collection PubMed
description BACKGROUND: Defensins, small endogenous peptides with antimicrobial activity, are pivotal components of the innate immune response. A large cluster of defensin genes is located on human chromosome 8p; among them the beta defensin 1 (DEFB1) promoterhas been extensively studied since discovery that specific polymorphisms and haplotypes associate with asthma and atopy, susceptibility to severe sepsis, as well as HIV and Candida infection predisposition. RESULTS: Here, we characterize the sequence variation and haplotype structure of the DEFB1 promoter region in six human populations. In all of them, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with common haplotypes separated by deep branches. Indeed, a significant departure from the expectation of evolutionary neutrality was observed in all populations and the possibility that this is due to demographic history alone was ruled out. Also, we verified that the selection signature is restricted to the promoter region and not due to a linked balanced polymorphism. A phylogeny-based estimation indicated that the two major haplotype clades separated around 4.5 million years ago, approximately the time when the human and chimpanzee lineages split. CONCLUSION: Altogether, these features represent strong molecular signatures of long-term balancing selection, a process that is thought to be extremely rare outside major histocompatibility complex genes. Our data indicate that the DEFB1 promoter region carries functional variants and support previous hypotheses whereby alleles predisposing to atopic disorders are widespread in modern societies because they conferred resistance to pathogens in ancient settings.
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spelling pubmed-25927042008-12-03 The signature of long-standing balancing selection at the human defensin β-1 promoter Cagliani, Rachele Fumagalli, Matteo Riva, Stefania Pozzoli, Uberto Comi, Giacomo P Menozzi, Giorgia Bresolin, Nereo Sironi, Manuela Genome Biol Research BACKGROUND: Defensins, small endogenous peptides with antimicrobial activity, are pivotal components of the innate immune response. A large cluster of defensin genes is located on human chromosome 8p; among them the beta defensin 1 (DEFB1) promoterhas been extensively studied since discovery that specific polymorphisms and haplotypes associate with asthma and atopy, susceptibility to severe sepsis, as well as HIV and Candida infection predisposition. RESULTS: Here, we characterize the sequence variation and haplotype structure of the DEFB1 promoter region in six human populations. In all of them, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with common haplotypes separated by deep branches. Indeed, a significant departure from the expectation of evolutionary neutrality was observed in all populations and the possibility that this is due to demographic history alone was ruled out. Also, we verified that the selection signature is restricted to the promoter region and not due to a linked balanced polymorphism. A phylogeny-based estimation indicated that the two major haplotype clades separated around 4.5 million years ago, approximately the time when the human and chimpanzee lineages split. CONCLUSION: Altogether, these features represent strong molecular signatures of long-term balancing selection, a process that is thought to be extremely rare outside major histocompatibility complex genes. Our data indicate that the DEFB1 promoter region carries functional variants and support previous hypotheses whereby alleles predisposing to atopic disorders are widespread in modern societies because they conferred resistance to pathogens in ancient settings. BioMed Central 2008 2008-09-25 /pmc/articles/PMC2592704/ /pubmed/18817538 http://dx.doi.org/10.1186/gb-2008-9-9-r143 Text en Copyright © 2008 Cagliani et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 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 Research
Cagliani, Rachele
Fumagalli, Matteo
Riva, Stefania
Pozzoli, Uberto
Comi, Giacomo P
Menozzi, Giorgia
Bresolin, Nereo
Sironi, Manuela
The signature of long-standing balancing selection at the human defensin β-1 promoter
title The signature of long-standing balancing selection at the human defensin β-1 promoter
title_full The signature of long-standing balancing selection at the human defensin β-1 promoter
title_fullStr The signature of long-standing balancing selection at the human defensin β-1 promoter
title_full_unstemmed The signature of long-standing balancing selection at the human defensin β-1 promoter
title_short The signature of long-standing balancing selection at the human defensin β-1 promoter
title_sort signature of long-standing balancing selection at the human defensin β-1 promoter
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592704/
https://www.ncbi.nlm.nih.gov/pubmed/18817538
http://dx.doi.org/10.1186/gb-2008-9-9-r143
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