Analyses in 2013

Community microattribution review of the evidence for colon cancer risk conferred by constitutional variants in MLH1, MSH2, MSH6 and PMS2 has resulted in the reclassification of two-thirds of the variants reported in existing databases and led to clinical recommendations for the interpretation of 1,370 variants that do not result in obvious protein truncation.

David Altshuler and colleagues explore the genetic architecture of type 2 diabetes (T2D) using an integrated population genetics–based simulation framework calibrated with empirical data. Whereas they are able to exclude more extreme models, for example, those in which either common or rare variants explain all of the disease heritability, they find that a broad range of architecture remains consistent with current empirical data and suggest that continued large-scale sequencing and genotyping studies will be needed to more precisely characterize the genetic architecture of complex traits such as T2D.

Rameen Beroukhim and colleagues analyzed somatic structural alterations in 12 tumor types. Whole-genome doubling was found in over a third of all cancers, associated with TP53 mutation. Fifteen new significantly mutated candidate driver genes were found associated with recurrently amplified or deleted regions.

Chris Sander and colleagues have extracted significant functional events from 12 tumor types. Tumors can be classified as being driven largely by either mutation or copy number changes, and, within this division, subclasses of cross-tissue patterns of events are discerned that suggest sets of combinatorial therapies.

Naomi Wray and colleagues report an analysis of genome-wide association data sets from the Psychiatric Genomics Consortium for five psychiatric disorders. They find that common variation explains 17–29% of the variance in liability and provide further support for a shared genetic etiology for these related psychiatric disorders.

Reuben Harris and colleagues report an analysis of gene expression and mutation data for multiple tumor types. They show that the DNA cytosine deaminase APOBEC3B is upregulated and that its preferred target sequence is frequently mutated in many types of cancer

Dmitry Gordenin, Gad Getz and colleagues report an analysis of mutation patterns in cancer genomes and find evidence of mutagenesis induced by APOBEC cytidine deaminase enzymes. They find an APOBEC mutagenesis pattern in bladder, cervical, breast, head and neck, and lung cancers, representing 68% of all mutations in some samples.

John Stamatoyannopoulos, John Mattick and colleagues use DNase I–hypersensitive site maps from 86 diverse cell types to identify a subset of exons that have DNase I hypersensitivity and are accompanied by 'phantom' signals in chromatin immunoprecipitation and sequencing (ChIP-seq) resulting from cross-linking with proximal promoter- or enhancer-bound factors.

Adam Siepel and colleagues find that natural selection has exerted a significant influence on transcription factor binding sites in the human lineage using a new probabilistic method, INSIGHT. They analyzed whole-genome sequences from 54 individuals, as well as from several non-human primates, combined with chromatin immunoprecipitation and sequencing data sets to identify transcription factor binding sites and evidence of selection.

Gerald Crabtree and colleagues identify new subunits of the mSWI/SNF complex and perform a bioinformatic analysis of the mutation patterns of the mSWI/SNF complex members in human cancers. mSWI/SNF is the most frequently mutated chromatin-regulatory complex in human cancer.

Nilanjan Chatterjee and colleagues report a theoretical framework to assess the predictive performance of polygenic models for risk prediction, based on analysis of genome-wide association study data sets. Across a range of common diseases and quantitative traits, they examine how predictive performance depends on the sample size, the total heritability and the underlying effect-size distributions.