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A recombination hotspot in a schizophrenia-associated region of GABRB2

Ng, SK and Lo, WS and Pun, FW and Zhao, C and Yu, Z and Chen, J and Tong, KL and Xu, Z and Tsang, SY and Yang, Q and Yu, W and Nimgaonkar, V and Stöber, G and Harano, M and Xue, H (2010) A recombination hotspot in a schizophrenia-associated region of GABRB2. PLoS ONE, 5 (3).

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Abstract

Background: Schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the β2 subunit of GABAA receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs) and containing schizophrenia-associated SNPs and haplotypes. Methodology/Principal Findings:In the present study, the possible occurrence of recombination in this 'S1-S29' segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (Hd) over mutation rate (θ), was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD) analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia. Conclusions/Significance: The co-occurrence of hotspot recombination and positive selection in the S1-S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and hotspot recombination, two interacting factors both affecting genetic diversity, merit close scrutiny with respect to the etiology of common complex disorders. © 2010 Ng et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ng, SK
Lo, WS
Pun, FW
Zhao, C
Yu, Z
Chen, J
Tong, KL
Xu, Z
Tsang, SY
Yang, Q
Yu, W
Nimgaonkar, Vnimga@pitt.eduNIMGA
Stöber, G
Harano, M
Xue, H
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorCordaux, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 8 March 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0009547
Schools and Programs: Graduate School of Public Health > Human Genetics
Refereed: Yes
MeSH Headings: Case-Control Studies; Cohort Studies; Female; Genotype; Haplotypes; Humans; Linkage Disequilibrium; Male; Models, Genetic; Point Mutation; Polymorphism, Single Nucleotide; Receptors, GABA-A--genetics; Recombination, Genetic; Schizophrenia--genetics; Sequence Analysis, DNA
Other ID: NLM PMC2833194
PubMed Central ID: PMC2833194
PubMed ID: 20221451
Date Deposited: 03 Aug 2012 18:45
Last Modified: 22 Jun 2021 13:56
URI: http://d-scholarship.pitt.edu/id/eprint/13335

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