Volume 50 Issue 10, October 2018

Patient-derived cancer cell lines could address two major challenges in oncology: real-time drug response prediction and the creation of massive knowledge banks. A new study showcases the power of this approach for precision oncology.

Genome-wide analyses identify 42 risk loci for diverticular disease, 39 of which are new. Genes in associated regions are enriched for expression in connective tissue cell types and are coexpressed with genes involved in vascular and mesenchymal biology.

Fine-mapping and functional studies highlight potential causal risk variants for rheumatoid arthritis and type 1 diabetes, including missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28–CTLA4, and IL2RA.

Promoter capture Hi-C in colorectal cancer cells integrated with cancer genome and expression data identifies a noncoding, cis-regulatory element that is recurrently mutated in cancer, affecting ETV1 expression, cell viability and patient survival.

Large-scale loss-of-function screens and TP53 saturation mutagenesis screens in human cancer cell lines suggest that mutational processes combine with phenotypic selection to shape the landscape of somatic mutations at the TP53 locus.

The authors present an integrative framework for identifying structural variants (SVs) in cancer that applies optical mapping, Hi-C, and whole-genome sequencing. They find SVs affecting distal regulatory sequences, DNA replication, and three-dimensional chromatin structure.

Analysis of genomic and transcriptomic data from 462 patient-derived tumor cell (PDC) samples across 14 cancer types, along with pharmacological responses to 60 agents, indicates that PDC-derived drug sensitivities might be predictive of clinical response to targeted therapies.

Association analyses in over 1 million individuals identify 535 new loci influencing blood pressure traits. The results provide new insights into blood pressure regulation and highlight shared genetic architecture between blood pressure and lifestyle exposures.

Analyses of 3,514 whole-genome-sequenced individuals from Sardinia indicate that within-island substructure and sex-biased processes have impacted the genetic history of Sardinia, providing new insight into the demography of ancestral Sardinians.

The stay-green G gene, which controls seed dormancy, shows evidence of selection in soybean, rice and tomato. G interacts with NCED3 and PSY and modulates abscisic acid synthesis.

De novo mutations in MSL3 cause an X-linked syndrome affecting both males and females. MSL3 mutations reduce H4K16ac levels and lead to misregulation of cellular pathways involved in morphogenesis, cellular shape, and cell migration.

Analysis of bivalent promoters in embryonic stem cells (ESCs) shows that deletion of MLL2 in ESCs leads to increased Polycomb occupancy, reduced promoter accessibility, redistribution of long-range chromatin interactions, and failure to differentiate.

A Pitx1 enhancer shows activity in forelimbs and hindlimbs but only interacts with Pitx1 in hindlimbs because of its three-dimensional configuration. Structural variants that affect three-dimensional conformation induce Pitx1 expression in forelimbs and cause partial arm-to-leg transformation in mice and humans.

SEEKR is a method that deconstructs linear sequence relationships between lncRNAs and evaluates similarity on the basis of abundance of short motifs called k-mers. LncRNAs of related function often have similar k-mer profiles despite lacking linear homology.

Signed linkage disequilibrium profile regression is a new method for detecting directional effects of genomic annotations on disease risk. The results implicate new causal disease genes and can suggest mechanisms underlying the effects of causal genes on disease.