Volume 44 Issue 6, June 2012

The clinical spectrum of prostate cancer ranges from curable, local disease to widely metastatic, lethal cancer. Two new prostate cancer genome studies provide the first glimpse at both ends of this spectrum.

We usually think of an individual's cells as sharing the same genome. Challenging this notion, two new studies show that somatic mosaicism is common and can be an early herald of cancer.

A new study shows that three independent mutations in the Sh1 gene, which encodes a YABBY transcription factor, gave rise to the non-shattering seed phenotype in domesticated sorghum. This same gene may have also had a role in the domestication of other cereals, including maize and rice.

Shamil Sunyaev and colleagues present exome sequencing methods and their applications in studies to identify the genetic basis of human complex traits. They include analyses of the whole-exome sequences of 438 individuals from across several studies.

Bogdan Pasaniuc, David Reich, Alkes Price and colleagues report analyses considering the potential of genome-wide association studies (GWAS) based on extremely low-coverage sequence data sets combined with imputation using data sets from the 1000 Genomes Project. They show with simulations and real exome-sequencing data that low-coverage sequencing can increase power for GWAS relative to genotyping arrays.

Marcella Zollino and colleagues report mutations in the chromatin regulator KANSL1 in persons with 17q21.31 syndrome. This disorder is marked by distinctive facial features, moderate-to-severe intellectual disability, hypotonia and friendly behavior.

Bert DeVries and colleagues identify mutations in the chromatin regulator KANSL1 in 17q21.31 microdeletion syndrome. This syndrome is characterized by intellectual disability, hypotonia and distinctive facial features.

Cathy Laurie and colleagues detect mosaicism for large chromosomal abnormalities in peripheral blood in a subset of healthy individuals. They show that the frequency of such events increases with age and is associated with elevated risk of developing a subsequent hematological cancer.

Luis Pérez-Jurado, Stephen Chanock and colleagues detect clonal chromosomal abnormalities in peripheral blood or buccal samples from individuals in the general population. They show that the frequency of such events increases with age and is associated with elevated risk of developing subsequent hematological cancers.

Claudia Langenberg, James Meigs and colleagues apply a joint meta-analysis approach that accounts for differences in body mass index to identify variants associated with glycemic traits. They report six new loci associated with fasting insulin levels and provide insights into the genetic basis of insulin resistance.

Patrick Ellinor and colleagues report a meta-analysis of genome-wide association studies for atrial fibrillation in European populations. They identify six newly associated loci, four of which were replicated in a Japanese study.

Richard Spritz and colleagues report genome-wide association analyses identifying 13 new susceptibility loci for generalized vitiligo. Their functional pathway analysis shows that many vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components.

Nazneen Rahman and colleagues report the results of a genome-wide association study of Wilms tumor. They show that common variants at 2p24 and 11q14 influence susceptibility to this rare pediatric kidney tumor.

Levi Garraway and colleagues report exome sequencing of 112 prostate adenocarcinomas and matched normal tissues. They identify novel recurrent mutations in several genes, including MED12, FOXA1 and SPOP. They find that tumors harboring SPOP mutations lack the TMPRSS2-ERG fusion or other ETS rearrangements, supporting the hypothesis that SPOP mutation is an early driver event in prostate tumorigenesis.

Bin Tean Teh and colleagues report exome sequencing of Opisthorchis viverrini–related cholangiocarcinoma, a fatal bile duct cancer associated with liver fluke infection.

Jessica Zucman-Rossi and colleagues report exome sequencing of 24 hepatocellular carcinomas and non-tumor liver tissues and copy-number analysis of 125 tumors. They identify new recurrent mutations in ARID1A, RPS6KA3, NFE2L2 and IRF2 in HCC.

Ian Tomlinson and colleagues identify a 40-kb duplication upstream of the gene that encodes the BMP antagonist GREM1 in families with hereditary mixed polyposis syndrome. The mutation is associated with increased allele-specific and ectopic expression of GREM1.

Jaonna Jen and colleagues identify mutations in EXOSC3, encoding a core RNA exosome component, causing pontocerebellar hypoplasia type 1 (PCH1), a recessive disorder with heterogeneous defects in brain development. Nine out of 13 individuals diagnosed with PCH1 had missense, frameshift or exon-skipping mutations in EXOSC3, suggesting a critical role of RNA metabolism in normal brain development.

Bruno Reversade and colleagues show that mutations in IRX5 cause a recessive congenital disorder affecting the development of multiple organs. In follow-up studies in Xenopus laevis, they show that Irx5 influences cell migration by repressing expression of Sdf1.

Iain Drummond, Heymut Omran, Stephen King and colleagues show that CCDC103 mutations cause primary ciliary dyskinesia. Their studies suggest that CCDC103 is a core axonemal factor that helps anchor dynein motor complexes to ciliary microtubules.

A key step in domestication of cereals was loss of seed shattering. Jianming Yu and colleagues show that seed shattering is controlled by alleles at Sh1 in sorghum. The authors also identify an insertion in the ortholog of Sh1 in a shattering-resistant mutant in rice and orthologs of Sh1 located in two narrow quantitative trait locus (QTL) intervals that regulate shattering in maize. The data suggest parallel selection on Sh1 in the domestication of cereals.

Eleazar Eskin and colleagues report a new method to model the spatial structure of genetic variation, using a spatial ancestry analysis (SPA) approach for modeling of genotypes in two- or three-dimensional space. They apply this approach to a sample of 3,000 European individuals and identify SNPs that show extreme allele frequency gradients.