Volume 48 Issue 8, August 2016

A new study tracks the distribution of bivalent H3K4me3/H3K27me3 chromatin in male germ cells of six vertebrate species. The results have big implications for understanding the mechanisms that specify animal development.

Analysis of a large whole-genome sequencing data set of 36,441 high-quality de novo mutations (DNMs) that arose in 816 family trios provides an unprecedented view into the landscape of DNMs in the germ line. This work both refines and challenges some of the views previously held on the nature and origin of DNMs.

Two new studies confirm that Plasmodium vivax populations are more diverse than Plasmodium falciparum and identify signs of recent selection at many loci, including those for drug resistance. P. vivax shows a trend of regional adaptations that poses challenges to global efforts to control and eliminate this major cause of relapsing malaria.

Li Ding, Feng Chen and colleagues report a pan-cancer analysis using a new computational tool, HotSpot3D, to identify mutational hotspots in the encoded three-dimensional protein structure, which suggest their functional involvement in cancer. They use a mutation–drug cluster analysis to predict more than 800 potentially druggable mutations.

Andrea Califano, Mariano Alvarez and colleagues present an approach, VIPER, for inferring protein activity in single cancer samples based on expression of a protein's downstream targets. The authors use VIPER to predict aberrant protein activity independent of mutational status and validate drug sensitivity predictions using in vitro assays.

Helga Salvesen, Rameen Beroukhim, Scott Carter and colleagues study the evolutionary landscape of endometrial cancer by performing whole-exome sequencing of complex atypical hyperplasias, primary tumors and metastases. They identify recurrent alterations in primary tumors and suggest that driver events are generally shared by primary and metastatic tumors.

Aarno Palotie and colleagues present results of a large genome-wide association study of migraine. They identified significant associations at 38 distinct loci and found enrichment for genes expressed in vascular and smooth muscle tissues.

Nathan Pankratz, Santhi Ganesh and colleagues use exome chip data to identify rare and common variants influencing blood cell traits. They report associations at several loci, including a rare missense variant in S1PR4 associated with circulating neutrophil counts, and present functional studies supporting a role for S1PR4 in neutrophil recruitment and resolution in response to tissue injury.

Sharon Kolk, Tjitske Kleefstra and colleagues identify loss-of-function mutations in SIN3A in individuals with intellectual disability and other clinical features. They further show that knockdown of Sin3a in developing mouse brain results in reduced cortical neurogenesis, altered neuronal identity and aberrant cortical projections, identifying this MeCP2-interacting protein as a key regulator of cortical development.

David Page and colleagues examine genes with bivalent chromatin modifications in male germ cells from five mammalian species and chicken. They find that the set of bivalently marked genes shared by all species represent evolutionarily ancient morphogenesis regulators, whereas genes showing lineage-specific bivalent marks act downstream of these core regulators.

Douglas Higgs and colleagues functionally test the α-globin super-enhancer in mice by genetically deleting its constituent enhancers. They find that the individual regulatory elements seem to act independently and in an additive way with respect to hematological phenotype, gene expression, and chromatin structure and conformation.

Lothar Hennighausen and colleagues identify 440 mammary-specific super-enhancers in mouse and focus on the STAT5-regulated Wap gene. Genetic dissection of the Wap super-enhancer suggests an internal hierarchy, as mutations in one of the constituent enhancers incapacitate the entire regulatory region.

Jonathan Flint, Richard Mott and colleagues employ low-coverage (0.15×) sequencing and their new imputation method STITCH to perform genome-wide association analysis for complex traits in an outbred mouse population. They find >250 QTLs for 92 phenotypes and obtain gene-level mapping resolution for around 20% of the loci.

Abraham Palmer and colleagues use genotyping by sequencing to perform genome-wide association studies on CFW mice for behavioral, physiological and gene expression traits. They find many QTLs and incorporate expression QTL analysis to prioritize specific genes at loci of interest that underlie different complex traits.

Makoto Matsuoka and colleagues use a whole-genome sequencing-based approach to perform genome-wide association analysis for important agronomic traits in rice. Using phenotypically diverse rice with low interrelationships, they rapidly identify novel genes associated with heading date, plant height and panicle number per plant, validating candidates with transgenic experiments.

Christian Gilissen, John Niederhuber and colleagues examine de novo mutations with parent-of-origin information from whole-genome sequencing datasets from 816 parent–offspring trios. They find maternal and paternal specific mutation signatures that are more prominent with increased age of the parent as well as clustered mutation signatures with no parental bias.

Timothy Vyse, Yong Cui, Wanling Yang and colleagues report a meta-analysis of genome-wide association studies for systemic lupus erythematosus (SLE) including European and Chinese individuals. They identify ten new loci associated with SLE and find evidence for increased genetic risk of disease among individuals of non-European ancestry.

Li Yu, Ya-Ping Zhang, Chung-I Wu and colleagues report the de novo genome of the black snub-nosed monkey Rhinopithecus bieti and the genomic sequences of four other Rhinopithecus species, including three high-altitude and two lowland species. The species- and population-level genomic analyses as well as the transcriptomic analysis and functional assays find adaptive signatures associated with adaptation to high altitude.

Jane Carlton, Daniel Neafsey and colleagues report a population genomics analysis of 182 Plasmodium vivax isolates from 11 countries. They find evidence of regional adaptation and signatures of selection at genes involved in antimalarial drug resistance.

Dominic Kwiatkowski and colleagues report a population genomic analysis of 228 clinical samples of Plasmodium vivax from 13 countries, with an emphasis on Southeast Asia. They analyze patterns of genetic structure within individual infections and find evidence for regional adaptation at the population level.

Richard Mott, Simon Myers and colleagues present a new imputation method, STITCH, which does not require genotyping arrays or high-quality reference panels. They use STITCH to accurately impute genotypes in both outbred laboratory mice and a sample human population directly from low-coverage (<2×) sequencing data.