title: A recombination hotspot in a schizophrenia-associated region of GABRB2.
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 beta(2) subunit of GABA(A) receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs) and containing schizophrenia-associated SNPs and haplotypes.
  
  
  RESULTS
  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 (H(d)) over mutation rate (theta), 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
  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.
authors.affiliation: Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: Siu-Kin
authors.initials: SK
authors.lastname: Ng
authors.forename: Wing-Sze
authors.initials: WS
authors.lastname: Lo
authors.forename: Frank W
authors.initials: FW
authors.lastname: Pun
authors.forename: Cunyou
authors.initials: C
authors.lastname: Zhao
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Yu
authors.forename: Jianhuan
authors.initials: J
authors.lastname: Chen
authors.forename: Ka-Lok
authors.initials: KL
authors.lastname: Tong
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Xu
authors.forename: Shui-Ying
authors.initials: SY
authors.lastname: Tsang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yang
authors.forename: Weichuan
authors.initials: W
authors.lastname: Yu
authors.forename: Vishwajit
authors.initials: V
authors.lastname: Nimgaonkar
authors.forename: Gerald
authors.initials: G
authors.lastname: Stöber
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Harano
authors.forename: Hong
authors.initials: H
authors.lastname: Xue
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008957:Models, Genetic; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics*; D011995:Recombination, Genetic; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C495710:GABRB2 protein, human; D011963:Receptors, GABA-A