Letters in 2016

Paola Bronson, Lennart Hammarström and colleagues report a genome-wide association study meta-analysis of selective IgA immunodeficiency in Europeans. They identify four new loci and a rare variant of a previously associated gene, IFIH1.

Alexandra Zhernakova, Jingyuan Fu, Cisca Wijmenga and colleagues perform genome-wide association analysis for microbiome characteristics in a cohort with fully sequenced metagenomes and detailed diet and lifestyle data. They find loci significantly associated with different microbial species, pathways and genes and examine specific gene–diet interactions.

Kenneth Croitoru, Andrew Paterson and colleagues perform genome-wide association analysis for gut microbiome composition. They identify 58 SNPs significantly associated with relative abundance of 33 taxa and replicate 4 of the associations in an independent cohort, providing further evidence that host genetics can influence the gut microbiota.

Rickard Sandberg and colleagues use allele-sensitive single-cell RNA–seq on primary mouse fibroblasts and human T cells to study clonal and dynamic monoallelic expression patterns. They find that the majority of random monoallelic expression of autosomal genes occurs transiently within individual cells rather than being stably inherited within clonally related cells.

Giacomo Cavalli, Anne-Marie Martinez and colleagues identify a large set of genes that are bound by PRC1 in the absence of H3K27me3 in Drosophila larval tissues and in differentiated human cell lines. Many of these genes, which regulate cell proliferation, signaling and polarity, are upregulated in PRC1-mutant tissues and contribute to tumor formation in Drosophila.

Shankar Balasubramanian and colleagues examine endogenous DNA G-quadruplex (G4) structures in the context of chromatin by using G4 antibody-based ChIP–seq. They find that G4 structures are enriched in nucleosome-depleted regions and the promoters and 5′ UTRs of highly transcribed genes, suggesting a relationship between chromatin state, transcriptional output and G4 status.

Mathieu Lupien and colleagues report an enrichment of somatic mutations at the ESR1 cis-regulatory region in 7% of ESR1-positive breast cancers. They find that the activity of the recurrently mutated ESR1 enhancer is also influenced by breast cancer risk–associated SNPs.

Michael Speicher and colleagues analyze plasma DNA whole-genome sequencing data from healthy donors and patients with cancer to infer nucleosome positioning on the basis of read depth coverage patterns. They use this approach to accurately predict expression of cancer driver genes from circulating tumor DNA in regions with somatic copy number gains.

Christian Fuchsberger, Gonçalo Abecasis and colleagues describe a new web-based imputation service that enables rapid imputation of large numbers of samples and allows convenient access to large reference panels of sequenced individuals. Their state space reduction provides a computationally efficient solution for genotype imputation with no loss in imputation accuracy.

Jonathan Marchini, Gonçalo Abecasis, Richard Durbin and colleagues describe the construction of a reference panel of human haplotypes from whole-genome sequencing data. They are able to use this to accurately impute genotypes at low minor allele frequency and present remote server resources for use by the community.

Murat Günel and colleagues identify recurrent mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II, in a subset of meningiomas. They find that POLR2A-mutant tumors can be distinguished on the basis of their super-enhancer and gene expression profiles, which show dysregulation of key meningeal identity genes.

Rachel Meyer and colleagues use whole-genome resequencing of 93 African rice landraces to generate a SNP map used for population analysis and a genome-wide association study for salt tolerance traits. They find 11 significant loci, some with signatures of positive selection, and evidence for a population bottleneck beginning around 15,000 years ago.

Ewan Pearson, Kathleen Giacomini and the Metformin Genetics Consortium perform a genome-wide association study for glycemic response to the antidiabetic drug metformin. They find an intronic allele of the GLUT2 glucose transporter gene that associates with greater metformin action, an effect that is more pronounced in obese individuals.

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations.

Stephen McGarvey and colleagues identify a missense variant in CREBRF strongly associated with body mass index in Samoans. This variant is rare in other populations but is common in Samoans and has a much larger effect size than other known common obesity risk variants, including variation in FTO.

Ammar Al-Chalabi, Jan Veldink and colleagues perform a genome-wide association study for amyotrophic lateral sclerosis (ALS) in 15,156 cases and 26,242 controls. They identify three new genome-wide-significant variants and establish ALS as a complex trait with a polygenic architecture, but with a distinct and important role for low-frequency variants.

Jan Veldink and colleagues show that loss-of-function variants in NEK1 are associated with susceptibility to amyotrophic lateral sclerosis (ALS). In addition to finding an excess of rare loss-of-function NEK1 variants in ALS cases, they report a significant association between a specific NEK1 missense variant (p.Arg261His) and disease risk.

Jaume Bertranpetit, Partha Majumder and colleagues analyze whole-genome sequences from Andamanese individuals and compare them to sequences from mainland Indian and other geographically diverse populations. They find evidence of ancestry from an unknown extinct hominin in South Asian populations and show that distinct Andamanese characteristics derive from strong natural selection.

Joseph Gleeson and colleagues report whole-exome sequencing of a cohort of over 1,000 individuals from the Greater Middle East, characterizing common and rare variants. They find evidence of subregional diversity and historical migrations and use the GME Variome to identify disease-causing mutations.

Nils Stein, Ehud Weiss, Tzion Fahima, Johannes Krause and colleagues report the genome sequences of 6,000-year-old barley grains obtained from desert caves in Israel. They compare these to whole-exome sequences of a modern barley diversity panel to explore domestication and migration patterns, finding evidence for prehistoric gene flow between wild and cultivated populations.