Letters in 2017

Didier Trono and colleagues show that both human DUX4 and mouse Dux are expressed before zygotic genome activation (ZGA) and lead to activation of ZGA-associated genes. Dux knockout in mouse embryonic stem cells prevents cycling through a 2-cell-like state, and zygotic depletion of Dux impairs embryonic development.

Fei Lu, Punna Ramu and colleagues construct a cassava haplotype map (HapMapII) by using deep-sequencing data from 241 accessions and identify over 28 million segregating variants. They find that clonal propagation has led to fixation of deleterious mutations, which have been ineffectively purged, owing to limited recombination

Kaoru Ito, Yoichiro Kamatani, Toshihiro Tanaka and colleagues report a genome-wide association study for atrial fibrillation in the Japanese population. They identify six new loci, five of which are not associated with atrial fibrillation in individuals of European ancestry, suggesting that they may be specific to the Japanese population.

Patrick Ellinor and colleagues report meta-analyses of common and rare variant association studies for atrial fibrillation across multiple populations. They identify 12 new loci, some of which implicate genes in atrial electrical and mechanical function.

Jacob George and colleagues examine whether the association of the IFNL3–IFNL4 region with hepatic inflammation and fibrosis is mediated by IFN-λ3 or IFN-λ4. They find greater hepatic inflammation, fibrosis progression rate and hepatic infiltration of immune cells in individuals with the risk haplotype that produces IFN-λ3 but not IFN-λ4.

Michael Taylor, Marco Marra and colleagues analyze spatial tumor heterogeneity in 9 medulloblastomas, 16 high-grade gliomas and 10 renal cell carcinomas, using a combination of transcriptomic and genomic profiling of multiregional biopsies. They find that medulloblastomas have spatially homogeneous transcriptomes, whereas somatic mutations that affect genes suitable for targeted therapeutics are spatially heterogeneous.

Kenneth Olsen, Ana Caicedo and colleagues analyze whole-genome sequences of two strains of weedy relatives of cultivated rice. They find that weedy rice strains are primarily descended from domesticated ancestors and that few genetic differences accompanied the emergence of weediness traits.

Shamil Sunyaev, David Beier and colleagues report an analysis of the fitness effects of heterozygous protein-truncating variants from the Exome Aggregation Consortium. They find that high heterozygous selection coefficients are enriched in Mendelian disease-associated genes and essential mouse genes, suggesting that this coefficient can be used to prioritize candidate disease-associated genes from clinical exome-sequencing data.

Beatrice Melin, Richard Houlston, Melissa Bondy and colleagues report results of a large-scale genome-wide association study of glioma. They identify five new risk loci for glioblastoma and eight new risk loci for non-glioblastoma tumors, highlighting distinct genetic etiologies for these two glioma subtypes.

Kari Stefansson, Unnur Styrkarsdottir and colleagues identify rare genotypes in COMP and CHADL associated with high risk of total hip replacement due to osteoarthritis. The high odds ratios associated with these rare risk genotypes suggest that they may represent Mendelian forms of osteoarthritis.

Christian Schaaf, Yaping Yang and colleagues report that germline mutations in ABL1, which is best known as part of the fusion gene BCR-ABL1 on the Philadelphia chromosome, cause an autosomal dominant disorder characterized by heart disease, skeletal abnormalities and failure to thrive. They find that these mutations increase the kinase activity of ABL1, establishing another example of mutations in a proto-oncogene leading to developmental defects.

Raul Rabadan, Woong-Yang Park, Do-Hyun Nam and colleagues examine the genomic and transcriptomic profiles of tumors from 52 patients with glioblastoma using both bulk and single-cell analyses. They find that tumors that are isolated from distinct locations or at different times are seeded from different clones, suggesting the need for multisector biopsies.

Bjarni Halldorsson, Kari Stefansson and colleagues analyze genomic data from 15,219 Icelanders to identify non-repetitive sequences that are missing from the reference genome. They describe 3,791 breakpoint-resolved sequence variants and find overlap with GWAS markers as well as the presence of a proportion of these variants in the chimpanzee genome.

Timothy Yu and colleagues report that biallelic mutations in DCC cause a developmental syndrome characterized by widespread disruption of midline-bridging neuronal commissures, including agenesis of the corpus callosum, absence of hippocampal and anterior commissures, and ventral midline brainstem malformations. Clinical manifestations include horizontal gaze palsy, mirror movements, scoliosis and intellectual disability.

Shamil Sunyaev, Chris Cotsapas and colleagues present a joint likelihood framework for determining the statistical evidence of shared genetic effects of overlapping disease-associated loci and expression quantitative trait loci (eQTLs). They find evidence for shared genetic effects at 25% of eQTL–autoimmune disease locus pairs.

Stanislav Shvartsman and colleagues quantify signaling changes caused by disease-associated mutations in MAP2K1 (encoding MEK) in fruit fly and zebrafish embryos. They find that intrinsically active MEK variants can both increase and reduce the levels of pathway activation depending on cellular context.

Edward Buckler, Sarah Hearne and colleagues integrate two approaches to characterize the genetic diversity of a large number of geographically distributed maize landraces. They examine flowering time and adaptation to altitude and find that the majority of the associated SNPs overlap both traits.

Daniel Kastner, Elaine Remmers and colleagues perform an association study of Behçet's disease based on dense genotyping of immune-related loci. They identify new association signals near genes involved in host response to microbial exposure and extend evidence for shared susceptibility loci with Crohn's disease and leprosy.

Michael Cho and colleagues report a genome-wide association study of risk for chronic obstructive pulmonary disease (COPD) in a large, multi-ancestry cohort. They identify 22 genome-wide significant loci, including 13 not previously associated with COPD and 4 not previously associated with any lung function trait.

Betty Tsao, Jian Zhao, Nan Shen and colleagues show that a common missense variant in NCF1 confers susceptibility to multiple autoimmune diseases. This variant, which leads to reduced production of reactive oxygen species, accounts for the strong association signal previously identified in the GTF2IRD1–GTF2I region at 7q11.23.