Volume 40 Issue 10, October 2008

Mapping by admixture linkage disequilibrium (MALD) leverages differences in disease frequencies among ancestry groups to map disease-susceptibility loci on the basis of genetic admixture. Two new studies use MALD to identify variation at the MYH9 locus as a major factor for the increased risk of nondiabetic kidney disease in African Americans.

The nematode Pristionchus pacificus associates with one particular beetle and eats its rotting corpse. The report of the genome sequence of P. pacificus, the fifth nematode to be sequenced and a useful secondary nematode genetic model system, highlights genes that may have influenced the route to parasitism.

A new study identifies recessive, loss-of-function mutations in IDH3B, encoding a subunit of the NAD-specific isocitrate dehydrogenase, in individuals with retinitis pigmentosa. The lack of any obvious clinical signs in other tissues in these individuals forces a reassessment of the physiological role of this enzyme outside of the retina.

Kras, Hras or Nras mutations occur at varying frequencies across different tumors in humans for unknown reasons. A new study shows that, in mice, locus-specific regulatory elements determine whether mutations in Hras or Kras will predominate in lung and skin tumors.

William Isaacs and colleagues report evidence for a second prostate cancer risk locus in the HNF1B gene at 17q12, ∼26 kb from the previously reported risk locus in this region. The two loci are separated by a recombination hot spot and contribute independently to prostate cancer risk.

Jane Worthington and colleagues report that three SNPs, located on chromosomes 10p15, 12q13 and 22q13, are associated with susceptibility to rheumatoid arthritis. These SNPs had previously been putatively associated with rheumatoid arthritis in the genome-wide association study conducted by the Wellcome Trust Case Control Consortium.

David Hunter and colleagues report the discovery of associations between variants in FUT2 and plasma vitamin B12 levels. FUT2 encodes α,1,2-fucosyltransferase and is the classic human secretor locus that determines the secretion status of ABO blood group antigens.

Andreas Janecke and colleagues identify mutations in MYO5B, encoding the type Vb myosin motor protein, in individuals with microvillus inclusion disease, implicating myosin Vb as a key regulator of epithelial cell polarity.

David Altshuler and colleagues report the design of a hybrid SNP-CNV genotyping array (Affymetrix SNP 6.0 Array) allowing for integrated SNP and CNV detection. They describe its application to 270 HapMap samples to compile a high-resolution map of over 1,500 copy number polymorphisms, and related population-genetic analyses.

Cheryl Winkler and colleagues use admixture mapping to identify risk variants in MYH9 associated with focal segmental glomerulosclerosis and end-stage renal disease in African Americans. The risk variants are more common in populations with West African ancestry and contribute to the excess burden of end-stage kidney diseases in these populations. A similar finding is reported in an accompanying paper by Linda Kao and colleagues.

Linda Kao and colleagues use admixture mapping to identify risk variants in MYH9 associated with nondiabetic end-stage renal disease in African Americans. The risk variants are more common in populations with West African ancestry and contribute to the excess burden of end-stage kidney diseases in these populations. A similar finding is reported in an accompanying paper by Cheryl Winkler and colleagues.

Ralf Sommer and colleagues present a draft genome sequence of the nematode Pristionchus pacificus, a species that lives in association with beetles and shows a major expansion of protein-coding genes. Comparative analysis with the genomes of the ecologically distinct nematodes C. elegans and B. malayi suggests insights into the association between their genome structures and differing lifestyles.

Evan Eichler and colleagues present an analysis of how well current commercial SNP platforms accurately capture copy number variants (CNVs). Although they were able accurately predict from Illumina Human 1M genotype data many sites identified in their recent study assessing CNVs in nine human individuals with a fosmid paired-end sequence approach, they find that commonly used platforms offer limited coverage for a large fraction of CNVs.

Richard Houlston and colleagues identify variants at six loci associated with risk of chronic lymphocytic leukemia. These findings confirm that common, low-penetrance susceptibility alleles contribute to this hematological malignancy and provide new insights into disease etiology.

Hakon Hakonarson and colleagues report the identification of two new susceptibility loci for inflammatory bowel disease (IBD). One variant is near a gene encoding tumor necrosis factor receptor subfamily member 6B and is associated with increased levels of this protein in serum from individuals with IBD.

Robert Plenge and colleagues report the results of a meta-analysis of published genome-wide association studies that led to the identification of two previously unknown variants associated with rheumatoid arthritis.

Kazuhiko Yamamoto and colleagues report an association of two SNPs in CD244 with increased risk of rheumatoid arthritis. These variants promote increased expression of CD244 in luciferase reporter assays.

Thaddeus Dryja and colleagues identify homozygous loss-of-function mutations in IDH3B, encoding the beta subunit of the NAD-specific isocitrate dehydrogenase enzyme, in two families with retinitis pigmentosa. The absence of obvious clinical phenotypes outside of the retina suggests that the NADP-specific form of this enzyme can compensate for the absence of the NAD-specific form in most human tissues.

Edward Patterson and colleagues report that a missense mutation in the gene encoding dynamin 1 (DNM1) is associated with exercise-induced collapsed in Labrador retriever dogs. This is the first documented mutation in DNM1 in mammals and suggests a critical role for dynamin 1 in maintaining proper neurotransmission under conditions of high synaptic activity.

Ras family genes are common targets for somatic mutations in human cancer: KRAS is frequently mutated in lung carcinomas, whereas HRAS mutations are common in skin tumors. Allan Balmain and colleagues use genetic engineering of ras genes in mice to show that specificity for ras mutations is determined by local regulatory elements, and that Kras 4A is the major oncogenic isoform of Kras.

Matt Hurles and colleagues present a general statistical framework for copy number variation (CNV) association tests in a case-control study design. They show that existing strategies for CNV association with binary disease phenotypes are complicated by differential errors and poor clustering quality. Here they report new methods, robust to these factors, which apply likelihood ratio testing to constrained Gaussian mixture models of quantitative CNV signals in cases and controls. Their methods are assay and platform independent, and implemented in freely available CNVtools software.

David Altshuler and colleagues describe analysis for integrating genotype calling of SNPs, common copy number polymorphisms and rare CNVs, implemented in a suite of software programs collectively named Birdsuite.