Volume 48 Issue 11, November 2016

Stabilization of p53 protein is a key step in the cellular response to DNA damage. A new study describes a long noncoding RNA, DINO, transcribed from the CDKN1A promoter region that induces stabilization of p53 protein and promotes efficient activation of p53 target genes in response to DNA damage.

Methylation of histone H3 on lysine 9 (H3K9) is a hallmark of transcriptionally inactive heterochromatin that is deregulated in pathological conditions. A new study shows that complete loss of H3K9 methylation in Caenorhabditis elegans leads to derepression of repetitive elements and formation of DNA:RNA hybrids (R loops), resulting in increased rates of repeat-specific mutation.

As the first series of genetic analyses of gut microbiome composition in humans is now emerging, the results should be met with enthusiasm, but also with caution. Findings from the initial offerings demonstrate how population-scale approaches can provide deeper insights into host–microbiome interactions while at the same time illustrating that our understanding of the architecture of highly complex microbiome 'traits' is still rudimentary.

Nicole Soranzo, Alexander Reiner, Paul Auer and colleagues use whole-genome sequencing data to impute the genotypes of over 35,000 individuals and perform a genome-wide association study for 20 quantitative cardiometabolic and hematological traits. They find 17 new associations and apply fine-mapping analysis to resolve causal variants for a number of the loci.

Peter Scacheri and colleagues identify ‘outside’ SNPs that physically interact with GWAS risk SNPs as part of a target gene's regulatory circuitry. Their findings suggest a model whereby outside variants and GWAS SNPs that physically interact collude to influence target transcript levels as well as clinical risk.

Jung Kyoon Choi and colleagues identify sets of regulatory mutations in breast and lung cancer samples that converge on the same gene target across individual samples. They use features of these mutation sets to develop a method for predicting functionally recurrent regulatory mutations that may function as drivers in cancer.

Timothy Chan and colleagues find that somatic mutations in SERPINB3 or SERPINB4 are associated with longer survival in patients with melanoma who received anti-CTLA4 immunotherapy. These findings may have implications for precision medicine efforts in cancer.

Ludmila Prokunina-Olsson and colleagues report a fine-mapping and association analysis of germline variants in the APOBEC3 region associated with cancer risk. They identify two variants with differential effects in bladder and breast cancer, and their in vitro results suggest that environmental exposures may induce tissue-specific APOBEC mutagenesis and contribute to oncogenesis in carriers of APOBEC3 risk variants.

Gelareh Zadeh, Kenneth Aldape and colleagues present an integrative genomic analysis of schwannomas. In addition to finding recurrent mutations in ARID1A, ARID1B and DDR1, they identify a recurrent SH3PXD2A-HTRA1 fusion that confers increased proliferation, invasion and in vivo transformation, and is associated with sensitivity to MEK inhibition.

Jamel Chelly and colleagues identify mutations in the E3 ubiquitin ligase gene NEDD4L that cause a syndrome of periventricular nodular heterotopia associated with neurodevelopmental disorders, cleft palate and toe syndactyly. The authors show that the mutations affect the mTORC1 and AKT pathways and cause defects in mouse brain development.

Laurent Fasano and colleagues identify TSHZ3 deletions in patients with autism spectrum disorder. Tshz3-mutant mice show functional changes at synapses established by cortical projection neurons and exhibit autism-like behavioral patterns.

Howard Chang and colleagues identify a long noncoding RNA, DINO, that is transcribed upstream of CDKN1A and induced by p53 in response to DNA damage. They show that DINO binds to p53 protein and promotes its stabilization, producing a feedback loop that amplifies DNA damage signaling.

Bjarni Halldorsson, Kari Stefansson and colleagues use SNP array and whole-genome sequencing data to estimate the meiotic gene conversion rate (G) in humans. They find that G for SNPs is 7.0 conversions/Mb per generation, is 2.17 greater in mothers than in fathers, and increases with maternal age.

Susan Gasser and colleagues find that methylation at histone H3 lysine 9 (H3K9me) is required for repression of simple repeats and transposons in Caenorhabditis elegans. Loss of H3K9me in worms leads to extensive accumulation of insertions and deletions at repeat elements, which correlate with R-loop formation and increased sensitivity to replication stress.

Andre Franke and colleagues perform a genome-wide association study for the gut microbiome, examining the influence of host genetics on overall microbial variation and individual taxa. They find significant associations at the VDR (vitamin D receptor) locus and observe correlations between microbiota and metabolites of VDR, including bile acids.

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.

Richard Spritz and colleagues present a genome-wide association study of autoimmune vitiligo in 4,680 cases and 39,586 controls and report 23 new risk loci. Their results highlight specific pathways, including immune response, apoptosis and melanocyte function, that may be important in the pathobiology of autoimmune vitiligo.

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.

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.

Po-Ru Loh, Alkes Price and colleagues present Eagle2, a reference-based phasing algorithm that allows for highly accurate and efficient phasing of genotypes across a broad range of cohort sizes. They demonstrate an approximately 10% improvement in accuracy and 20% improvement in speed compared to a competing method, SHAPEIT2.