Volume 43 Issue 8, August 2011

New work has identified networks of protein interactions at the transition zones of cilia. These discoveries provide insights into the molecular pathogenesis of ciliopathies and illustrate the power of linking proteomics technologies with human genetics to uncover critical disease pathways.

The human genome contains large areas with hypervariable DNA methylation that are associated with deregulation of gene expression. This epigenetic variation may be necessary for differentiation, but it also provides a mechanism for Darwinian evolution at the cellular level that may underlie age-related diseases such as cancer.

Somatic mutations in mitochondrial DNA build up in aging tissues and are thought to contribute to physiological aging. Surprisingly, it is not known if these mutations occur early or late in life. A new study looks at mechanisms of accelerated mitochondrial aging in HIV-infected individuals treated with nucleoside analog anti-retroviral drugs and offers support for an early origin of mitochondrial DNA mutations.

Han Brunner and colleagues report the identification of de novo nonsense mutations in ASXL1 in individuals with Bohring-Opitz syndrome, which is characterized by intellectual disability, distinctive facial features and multiple congenital malformations.

Meral Gunay-Aygun and colleagues report that NBEAL2 is mutated in gray platelet syndrome (GPS). GPS is a recessive platelet disorder that can lead to severe bleeding.

Cornelis Albers and colleagues identify NBEAL2 as the causative gene for gray platelet syndrome (GPS). Knockdown of this gene in zebrafish leads to spontaneous bleeding and defects in thrombocyte formation.

Walter Kahr and colleagues report mutations in NBEAL2 in gray platelet syndrome (GPS). Using RNA-seq, the authors observed abnormal pre-mRNA processing in NBEAL2 in platelets from an individual with GPS.

Alon Keinan and colleagues estimate the ratio of genetic diversity on the X chromosome to that on the autosome (X/A) on the basis of whole-genome sequencing of 69 females from the 1000 Genomes Project. They find that across populations, the X/A ratio increases with genetic distance from genes. They further find that this ratio is reduced in Europeans compared to West Africans, which may be explained by demographic history.

Jeong Sun-Seo and colleagues report whole-genome sequencing of ten Korean individuals and exome sequencing on an additional eight Korean individuals. They also performed transcriptome sequencing on 17 of these individuals. The authors identified approximately 1.83 million previously unidentified SNPs.

Ruth Loos and colleagues use genome-wide association to identify common variants influencing body fat percentage. Unexpectedly, they show that a body-fat–decreasing allele near IRS1 is associated with an impaired metabolic profile, including increased risk of type 2 diabetes and coronary artery disease.

Matthew Brown, Peter Donnelly and colleagues report results of a genome-wide association meta-analysis and follow-up study of ankylosing spondylitis. They identify three new risk variants and report a genetic interaction between ERAP1 and HLA-B27, implicating aberrant peptide handling in the pathophysiology of this disease.

Andrew Feinberg and colleagues report whole-genome bisulfite sequencing of three colon cancers and matched normal tissue and two adenomatous polyps. The authors identify large blocks of relative hypomethylation over half of the genome.

Jeremy Reiter and colleagues show that Tctn1 is a component of a transition zone complex that regulates ciliogenesis and ciliary membrane composition. They also identify a likely causal mutation in TCTN1 in two siblings with Joubert syndrome.

Rosalind Eeles and colleagues report a multistage genome-wide association study of prostate cancer, identifying seven new prostate cancer susceptibility loci.

Hongbing Shen and colleagues report a genome-wide association study for lung cancer in individuals of Han Chinese ancestry. The authors identify two new lung cancer susceptibility loci.

Kazuaki Chayama and colleagues report a genome-wide association study for progression to hepatocellular carcinoma in individuals with chronic hepatitis C. The authors identify a common variant within DEP2DC that is associated with risk of HCV-induced HCC.

David Altshuler and colleagues compare strategies to fine map the association of common variants at 9p21 with type 2 diabetes and myocardial infarction. Their study provides an empirical assessment of the performance of targeted sequencing and imputation-based approaches to comprehensively assess genetic variation in disease-associated regions.

Patrick Chinnery and colleagues analyze the effects on mitochondrial DNA of nucleoside analogue anti-retroviral (NRTIs) drugs in patients infected with HIV. The authors find that patients treated with commonly used NRTIs accumulate somatic mitochondrial DNA mutations in a process similar to normal aging.

Gavin Kelsey and colleagues report methylation landscapes in mouse oocytes, sperm and blastocysts. They find that the majority of methylated CpG islands in oocytes display incomplete demethylation in preimplantation embryos.