Thursday, October 27, 2016

Nature Genetics Contents: November 2016 pp 1297 - 1448

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Nature Genetics

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November 2016 Volume 48, Issue 11

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Genome variation for non-geneticists   p1297
Single-nucleotide variation (SNPs or SNVs) in the human genome is now being used by the public and by researchers interested in the functional mechanisms of genetic perturbation for the 3D structure and function of the nucleus in various cells and tissues, and for understanding human-microbiota interactions. We have some requests for authors that may help prevent misunderstanding as familiar genetic markers acquire new users.

News and Views


p53 partners with RNA in the DNA damage response   pp1298 - 1299
Maite Huarte
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.

See also: Article by Schmitt et al.

Dangerous R loops form in the absence of H3K9 methylation   pp1299 - 1300
Anna Elisabetta Salcini
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.

See also: Article by Zeller et al.

The gut microbiome—an emerging complex trait   pp1301 - 1302
Andrew K Benson
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.

See also: Article by Wang et al. | Letter by Bonder et al. | Letter by Turpin et al.

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Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps   pp1303 - 1312
Valentina Iotchkova, Jie Huang, John A Morris, Deepti Jain, Caterina Barbieri et al.
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.

Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry   pp1313 - 1320
Olivia Corradin, Andrea J Cohen, Jennifer M Luppino, Ian M Bayles, Fredrick R Schumacher et al.
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.

Chromatin structure-based prediction of recurrent noncoding mutations in cancer   pp1321 - 1326
Kwoneel Kim, Kiwon Jang, Woojin Yang, Eun-Young Choi, Seong-Min Park et al.
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.

Brief Communication


Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy   pp1327 - 1329
Nadeem Riaz, Jonathan J Havel, Sviatoslav M Kendall, Vladimir Makarov, Logan A Walsh et al.
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.

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Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors   pp1330 - 1338
Candace D Middlebrooks, A Rouf Banday, Konichi Matsuda, Krizia-Ivana Udquim, Olusegun O Onabajo et al.
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.

The genomic landscape of schwannoma   pp1339 - 1348
Sameer Agnihotri, Shahrzad Jalali, Mark R Wilson, Arnavaz Danesh, Mira Li et al.
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.

Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia   pp1349 - 1358
Loic Broix, Hélène Jagline, Ekaterina L Ivanova, Stéphane Schmucker, Nathalie Drouot et al.
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.

TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons   pp1359 - 1369
Xavier Caubit, Paolo Gubellini, Joris Andrieux, Pierre L Roubertoux, Mehdi Metwaly et al.
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.

An inducible long noncoding RNA amplifies DNA damage signaling   pp1370 - 1376
Adam M Schmitt, Julia T Garcia, Tiffany Hung, Ryan A Flynn, Ying Shen et al.
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.

See also: News and Views by Huarte

The rate of meiotic gene conversion varies by sex and age   pp1377 - 1384
Bjarni V Halldorsson, Marteinn T Hardarson, Birte Kehr, Unnur Styrkarsdottir, Arnaldur Gylfason et al.
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.

Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability   pp1385 - 1395
Peter Zeller, Jan Padeken, Robin van Schendel, Veronique Kalck, Marcel Tijsterman et al.
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.

See also: News and Views by Salcini

Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota   pp1396 - 1406
Jun Wang, Louise B Thingholm, Jurgita Skiecevičienė, Philipp Rausch, Martin Kummen et al.
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.

See also: News and Views by Benson

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The effect of host genetics on the gut microbiome   pp1407 - 1412
Marc Jan Bonder, Alexander Kurilshikov, Ettje F Tigchelaar, Zlatan Mujagic, Floris Imhann et al.
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.

See also: News and Views by Benson

Association of host genome with intestinal microbial composition in a large healthy cohort   pp1413 - 1417
Williams Turpin, Osvaldo Espin-Garcia, Wei Xu, Mark S Silverberg, David Kevans et al.
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.

See also: News and Views by Benson

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants   pp1418 - 1424
Ying Jin, Genevieve Andersen, Daniel Yorgov, Tracey M Ferrara, Songtao Ben et al.
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.

Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency   pp1425 - 1429
Paola G Bronson, Diana Chang, Tushar Bhangale, Michael F Seldin, Ward Ortmann et al.
Paola Bronson, Lennart Hammarstrom 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.

Analysis of allelic expression patterns in clonal somatic cells by single-cell RNA-seq   pp1430 - 1435
Björn Reinius, Jeff E Mold, Daniel Ramskold, Qiaolin Deng, Per Johnsson et al.
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.

Coordinate redeployment of PRC1 proteins suppresses tumor formation during Drosophila development   pp1436 - 1442
Vincent Loubiere, Anna Delest, Aubin Thomas, Boyan Bonev, Bernd Schuettengruber et al.
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.

Technical Report


Reference-based phasing using the Haplotype Reference Consortium panel   pp1443 - 1448
Po-Ru Loh, Petr Danecek, Pier Francesco Palamara, Christian Fuchsberger, Yakir A Reshef et al.
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.

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