Analyses in 2017

This analysis of cancer sequencing data identifies a reduced somatic mutation rate in exons and shows that this phenomenon is due to higher mismatch-repair activity in exons as compared to introns. These findings have implications for the understanding of mutational and DNA repair processes and for studying the evolution of both tumors and species.

This study presents a new approach to estimate the tissues contributing to the genetic causality for complex traits and diseases. The method assesses tissue sharing of eQTLs among 44 tissues and then uses these tissue-sharing estimates to infer the tissues where trait-associated variants likely exert their function.

This large-scale analysis of copy number alterations (CNAs) in patient-derived xenografts (PDXs) across 24 cancer types shows that new CNAs accumulate quickly and that the specific CNAs acquired during passaging differ from those acquired during tumor evolution in patients, suggesting that PDX tumors are under distinct selection pressures from tumors in human hosts.

Steven Gazal, Alkes Price and colleagues extend stratified LD score regression to continuous annotations. They analyze summary statistics from 56 complex diseases and traits and find that SNPs with low levels of linkage disequilibrium have larger per-SNP heritability, consistent with the action of negative selection on deleterious variants that affect complex traits.

Kevin Yip and colleagues report a method for determining the target genes of enhancers in specific cells and tissues by combining global trends across many samples with sample-specific information, and considering the joint effect of multiple enhancers. They apply their method to reconstruct enhancer–target networks in 935 samples of human primary cells, tissues and cell lines.

Andrey Rzhetsky and colleagues analyze electronic medical records from over one-third of the US population to estimate disease heritability and to determine the genetic and environmental contributions to disease variance. They obtain 84 new heritability estimates and find that the genetic correlation values for disease pairs differ from their environmental correlation values.

Gil McVean and colleagues present a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Their method displays increased power to detect genetic effects over other approaches and identifies novel associations between classical HLA alleles and common immune-mediated diseases.

Matthew Robinson, Peter Visscher and colleagues use phenotypic data on 172,000 sibling pairs and phenotypic and SNP data on 150,832 unrelated individuals to estimate the heritability of body mass index across a range of experimental designs. They conclude that substantially larger sample sizes across ages and lifestyle factors will be required to understand the full genetic architecture of this trait.

Jeffrey Barrett, Tarjinder Singh and colleagues present a meta-analysis of rare coding variants and copy number variants in a large collection of schizophrenia cases and controls, combined with de novo mutation data from family trios. They find that rare, damaging variants contribute to risk of schizophrenia both with and without intellectual disability and that there is overlap between genetic risk for schizophrenia and other neurodevelopmental disorders.

Elise Robinson and colleagues present the polygenic transmission disequilibrium test (pTDT) for evaluating transmission of polygenic risk in family-based study designs. The authors apply pTDT to a cohort of autism spectrum disorder (ASD) families and find that common polygenic variation acts additively with de novo variants to contribute to ASD risk.

Michael Schatz, David Tuveson and colleagues analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas. They find recurrent noncoding regulatory mutations that correlate with differential expression of proximal genes and find that the strongest regulatory elements are more frequently mutated, suggesting a selective advantage for mutations in these regions.

Jérôme Salse and colleagues report a reconstruction of the most recent common ancestor of modern monocots and eudicots, which dates to the late Triassic era. Their results represent a resource for plant geneticists to extend findings from model species to crops.

Örjan Carlborg and colleagues analyze genotype and phenotype data from 4,390 yeast segregants from a cross between laboratory and vineyard strains to estimate how higher-order genetic interactions contribute to complex trait variation. They find networks of epistatic loci and show that accounting for these interactions leads to more accurate phenotypic predictions.

Mark Daly and colleagues use population reference samples to refine the role of de novo protein-truncating variants in neurodevelopmental disorders. They show that variants independently observed in population reference samples do not contribute substantively to neurodevelopmental risk, and they use a loss-of-function intolerance metric to identify a small subset of genes that contain the entire observed signal of associated de novo protein-truncating variants in these disorders.

Siyuan Zheng, Roel Verhaak and colleagues report an analysis of telomere lengths and somatic alterations in telomere-related pathways across 31 cancer types. Their study provides an overview of the molecular mechanisms driving TERT expression and activation of the ALT pathway, and identifies a subset of tumors with neither detectable TERT expression nor somatic alterations in ATRX or DAXX.

Serena Nik-Zainal and colleagues present a detailed analysis of somatic rearrangements in 560 breast cancers. They highlight 33 rearrangement hotspots characterized mainly by large tandem duplications and show that these hotspots are enriched in breast cancer germline susceptibility loci and breast-specific super-enhancer elements.

Peter Campbell, Hartmut Döhner and colleagues present an analysis of genetic mutations and clinical information from 1,540 patients with acute myeloid leukemia, demonstrating the utility of clinical knowledge banks for personalized medicine. They show that use of their approach could reduce the number of hematopoietic cell transplants in patients with AML by up to 25% while maintaining survival rates.

Jimmy Liu and colleagues perform genome-wide association by proxy (GWAX) in a large population cohort by replacing cases with their first-degree relatives. They apply GWAX to 12 common diseases and show its utility by identifying new risk loci for Alzheimer's disease, coronary artery disease and type 2 diabetes.

Nada Jabado, Jacek Majewski and colleagues identify mutations in multiple histone H3 genes causing recurrent p.Lys36Met alterations in head and neck squamous cell carcinomas. They show that tumors with these p.Lys36Met alterations correspond to a specific DNA methylation cluster along with tumors harboring previously described mutations in NSD1.