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Conserved KIR allele-level haplotypes are altered by microvariation in individuals with European ancestry.

ABSTRACT: NK cell immunoglobulin-like receptor (KIR) haplotype-specific DNA fragments were sequenced to identify centromeric and telomeric allele-level haplotype structures and their frequencies from 76 unrelated individuals with European ancestry. Analysis was simplified by redefining the 5' boundary of the centromeric KIR gene cluster to include only exons 7-9 of KIR3DL3. Three consensus allele-level haplotypes were identified for a centromeric gene presence/absence structure designated as Cen-A1. KIR3DL3*00201 (exons 7-9)?KIR2DL3*001?KIR2DL1*00302 was the most frequent (37.5%) centromeric structure. Single consensus haplotypes were observed for haplotype structures Cen-B1 and Cen-B2. Six Tel-A1 and two Tel-B1 consensus haplotypes were observed; the most prevalent (23.0%) was KIR2DL4*00102?KIR3DL1*002?KIR2DS4*00101?KIR3DL2*002. A small number of nucleotide substitutions (?3) in the coding regions of the functional KIR genes created microvariants of the consensus haplotypes. Eight less common haplotype structures were also detected. Four carried hybrid genes formed during gene deletion events, two carried an insertion with a 2DL5/3DP1 fusion gene and two included a very large insertion. These data show that the KIR gene complex is composed of a limited number of conserved allele-level centromeric and telomeric haplotypes that have diversified by mutation, recombination within a locus and unequal crossing over.

SUBMITTER: Hou L

PROVIDER: S-EPMC3536055 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Conserved KIR allele-level haplotypes are altered by microvariation in individuals with European ancestry.

Hou L L Chen M M Ng J J Hurley C K CK

Genes and immunity 20110728 1

NK cell immunoglobulin-like receptor (KIR) haplotype-specific DNA fragments were sequenced to identify centromeric and telomeric allele-level haplotype structures and their frequencies from 76 unrelated individuals with European ancestry. Analysis was simplified by redefining the 5' boundary of the centromeric KIR gene cluster to include only exons 7-9 of KIR3DL3. Three consensus allele-level haplotypes were identified for a centromeric gene presence/absence structure designated as Cen-A1. KIR3D ...[more]

PMID: 21796155

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Project description:BackgroundProctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity.MethodsWe investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369).ResultsIn prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.ConclusionsWe report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual's susceptibility to developing radiotoxicity.

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Conserved KIR allele-level haplotypes are altered by microvariation in individuals with European ancestry.

Publications

Conserved KIR allele-level haplotypes are altered by microvariation in individuals with European ancestry.

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