Nature Genetics Contents: December 2016 pp 1449 - 1591

If you are unable to see the message below, click here to view.

Advertisement Fast PGx SNP assays Our Novallele™ genotyping assays detect genetic variations, single-nucleotide polymorphisms (SNPs) and both small and large indels, of the human genome using any thermocycler capable of high-resolution melting (HRM). The assays cover several research areas, including pharmacogenetics, and provide scientists a simple method to detect mutations of consequence. Learn more at www.canon-biomedical.com. TABLE OF CONTENTS December 2016 Volume 48, Issue 12 Editorial News and Views Analysis Articles Letters Technical Reports Corrigenda Advertisement   WE SEQUENCE, YOU DISCOVER We offer complete NGS services to support your Genomic Research programs or Clinical Trial projects, executed in our CAP and ISO accredited laboratories around the world. For small projects, or for large-scale population studies, we are at your service with fast, high quality and affordable results.  Learn More About BGI Preferred Sequencing Services. Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement DIRECTOR Center of Human Genomics and Precision Medicine leadership_recruitments@med.wisc.edu To apply click here    Advertisement In January 2017 Cell Press will take over publishing the Molecular Therapy family of journals. To keep receiving e-alerts for these titles, please visit http://www.cell.com/molecular-therapy-family/home   Editorial Top Combined harvest of knowledge   p1449 doi:10.1038/ng.3739 Investment in national infrastructure should include a scalable open informatics solution for agricultural genomics, germplasm and crop traits. This is a priority measure for economic stimulus and food security. As building this knowledge harvester should be simpler than the infrastructure required for precision medicine, it will also pave the way to that goal. News and Views Top Understanding unspecific complaints through genetics   pp1450 - 1451 Eli Sprecher doi:10.1038/ng.3730 Unspecific and unexplained medical complaints can be frustrating to both patients and clinicians. A cause for these complex symptoms and signs may now have been identified. See also: Letter by Lyons et al. A DNA element that remembers winter   pp1451 - 1452 Chenlong Li and Yuhai Cui doi:10.1038/ng.3727 Polycomb-mediated silencing of the floral repressor gene FLC in response to long-term cold is a central event during vernalization in Arabidopsis thaliana, but how it is initiated is unclear. Two new studies identify a DNA element that mediates FLC silencing by attracting a pair of transcriptional repressors, VAL1 and VAL2, which in turn trigger epigenetic silencing by the Polycomb complex PHD-PRC2. See also: Article by Yuan et al. Human host range of Mycobacterium tuberculosis   pp1453 - 1454 Ruth Hershberg doi:10.1038/ng.3724 A new study demonstrates that the most widespread lineage of the causative agent of tuberculosis consists of both globally distributed and geographically restricted sublineages. The geographically restricted sublineages are likely able to infect only specific human populations, whereas the globally distributed ones likely have a broader human host range. See also: Article by Stucki et al. Genetics JOBS of the week Postdoctoral Fellows: Cancer Genetics, Epigenetics and Biomarkers BAYLOR SCOTT & WHITE HEALTH Tenure Track Position in Developmental Biology & Molecular Genetics University of Calgary Postdoctoral Scientist in Molecular genetics of human T cell development Ghent University Tenure-track Faculty in Genomics and Human Genetics Duke University Tenure-Track Faculty Position in Developmental Biology Department of Genetics, (Assistant / Associate / Full Professor) Yale University School of Medicine More Science jobs from Genetics EVENT Population Variation Genetics 22nd May - 26th May 2017 Norwich, UK More science events from Analysis Top Genome-wide significance testing of variation from single case exomes   pp1455 - 1461 Amy B Wilfert, Katherine R Chao, Madhurima Kaushal, Sanjay Jain, Sebastian Zollner et al. doi:10.1038/ng.3697 Donald Conrad and colleagues present a method, PSAP, for prioritizing potential Mendelian disease-causing variants in single human exomes using pathogenicity scores and observed allele frequencies in the unaffected population. They apply PSAP to cohorts of undiagnosed disease exomes and identify candidate disease variants for future study. Advertisement Focus on Psychiatric Disorders Compared to other areas, psychiatric research faces unique biological, technological, clinical, regulatory and ethical challenges. In this focus Nature Neuroscience and Nature Medicine present a collection of Commentaries, Perspectives, and Reviews that address these challenges. Access the Focus online Produced with support of a grant from:  Avanir Pharmaceuticals, Inc.     Articles Top Genome-wide analysis identifies 12 loci influencing human reproductive behavior   pp1462 - 1472 Nicola Barban, Rick Jansen, Ronald de Vlaming, Ahmad Vaez, Jornt J Mandemakers et al. doi:10.1038/ng.3698 Melinda Mills, Nicola Barban, Harold Snieder, Marcel den Hoed and colleagues perform a meta-analysis of data from over 300,000 individuals for age at first birth and number of children ever born. They identify 12 significant loci that associate with these traits, providing insights into the genetic basis of human reproductive behavior. Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction   pp1473 - 1480 Mary A M Cleaton, Claire L Dent, Mark Howard, Jennifer A Corish, Isabelle Gutteridge et al. doi:10.1038/ng.3699 Marika Charalambous and colleagues show that, in mice, the fetus is the source of maternal circulating DLK1, which regulates the mother's metabolism during pregnancy. They also find that maternal circulating DLK1 levels predict embryonic weight in mice and associate with fetal growth restriction in a human cohort. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia   pp1481 - 1489 Jinghui Zhang, Kelly McCastlain, Hiroki Yoshihara, Beisi Xu, Yunchao Chang et al. doi:10.1038/ng.3691 Charles Mullighan, Jinghui Zhang and colleagues characterize a subtype of B-progenitor acute lymphoblastic leukemia with deregulated DUX4 and ERG. They find that aberrant DUX4 activation results in loss of ERG function, either through deletion or by the induction a novel transforming ERG isoform, ERGalt, that inhibits wild-type ERG activity. Clonal evolution of chemotherapy-resistant urothelial carcinoma   pp1490 - 1499 Bishoy M Faltas, Davide Prandi, Scott T Tagawa, Ana M Molina, David M Nanus et al. doi:10.1038/ng.3692 Mark Rubin, Francesca Demichelis and colleagues study the evolution of urothelial carcinomas by performing whole-exome sequencing of tumors collected from patients before and after chemotherapy. They find marked within-patient tumor heterogeneity and increased mutations involved in integrin signaling pathways and APOBEC-induced mutation signatures after treatment. Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma   pp1500 - 1507 Jia-Jie Hao, De-Chen Lin, Huy Q Dinh, Anand Mayakonda, Yan-Yi Jiang et al. doi:10.1038/ng.3683 Ming-Rong Wang, Benjamin Berman and colleagues perform whole-exome sequencing and global methylation profiling on different tumor regions of esophageal squamous cell carcinoma. They find evidence for intratumoral heterogeneity and identify late driver mutations targeting oncogenes and early driver mutations occurring in tumor-suppressor genes. General rules for functional microRNA targeting   pp1517 - 1526 Doyeon Kim, You Me Sung, Jinman Park, Sukjun Kim, Jongkyu Kim et al. doi:10.1038/ng.3694 Daehyun Baek and colleagues present a systematic analysis of more than 2 billion potential miRNA-gene target interactions using publicly available human microarray data. The authors find evidence for four canonical and seven non-canonical site types that show detectable downregulation of target genes, and they present functional validation for the new site types. A cis cold memory element and a trans epigenome reader mediate Polycomb silencing of FLC by vernalization in Arabidopsis   pp1527 - 1534 Wenya Yuan, Xiao Luo, Zicong Li, Wannian Yang, Yizhong Wang et al. doi:10.1038/ng.3712 Yuehui He and colleagues show that VAL1 and VAL2 bind to a cis-regulatory element at the FLC locus and are required for its epigenetic silencing during vernalization in Arabidopsis. They further report that VAL proteins recognize the repressive histone mark H3K27me3 and are necessary for genomic binding of the Polycomb silencing partner LHP1. See also: News and Views by Li & Cui Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages   pp1535 - 1543 David Stucki, Daniela Brites, Leila Jeljeli, Mireia Coscolla, Qingyun Liu et al. doi:10.1038/ng.3704 Sebastien Gagneux and colleagues analyze a global collection of Mycobacterium tuberculosis clinical isolates to classify sublineages by phylogeography. They find globally distributed 'generalist' and geographically restricted 'specialist' sublineages of lineage 4, indicating that different evolutionary strategies were adopted to succeed in various ecological niches. See also: News and Views by Hershberg Advertisement Nature Index 2016 Rising Stars:  The Nature Index 2016: Rising Stars supplement identifies the people and organizations that have the potential to ascend within the world of science. The rising stars are identified by harnessing the power of the Nature Index, which tracks high-quality research of over 8,000 global institutions.  Access the free supplement in full today!     Letters Top Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer   pp1544 - 1550 Corina Lesseur, Brenda Diergaarde, Andrew F Olshan, Victor Wünsch-Filho, Andrew R Ness et al. doi:10.1038/ng.3685 Paul Brennan and colleagues perform genome-wide association analysis for oral cavity and pharyngeal cancer in trans-ancestry populations. They find seven new loci across different cancer subtypes, including a protective association in the HLA region that has a stronger effect in patients with human papillomavirus-positive cancers. The genomic landscape of core-binding factor acute myeloid leukemias   pp1551 - 1556 Zachary J Faber, Xiang Chen, Amanda Larson Gedman, Kristy Boggs, Jinjun Cheng et al. doi:10.1038/ng.3709 Lars Bullinger, Jinghui Zhang, Jeffery Klco, James Downing and colleagues report a detailed genomic analysis of pediatric and adult core-binding factor acute myeloid leukemias (CBF-AMLs). They identify recurrent mutations in CCND2, MGA, DHX15 and ZBTB7A and highlight dramatic differences in the landscape of cooperating mutations between different CBF-AML subtypes. Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality   pp1557 - 1563 Ruben N Eppinga, Yanick Hagemeijer, Stephen Burgess, David A Hinds, Kari Stefansson et al. doi:10.1038/ng.3708 Pim van der Harst and colleagues report a genome-wide association study for resting heart rate in individuals of European ancestry and identify 64 associated loci, 46 of which have not been previously reported. A genetic risk score constructed using the associated variants is significantly associated with increased mortality risk. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number   pp1564 - 1569 Jonathan J Lyons, Xiaomin Yu, Jason D Hughes, Quang T Le, Ali Jamil et al. doi:10.1038/ng.3696 Joshua Milner and colleagues show that increased TPSAB1 copy number causes a multisystem disorder marked by elevated basal serum tryptase levels. Shared symptoms in affected individuals include irritable bowel syndrome, cutaneous flushing and pruritus, connective tissue abnormalities and dysautonomia. See also: News and Views by Sprecher Prospective functional classification of all possible missense variants in PPARG   pp1570 - 1575 Amit R Majithia, Ben Tsuda, Maura Agostini, Keerthana Gnanapradeepan, Robert Rice et al. doi:10.1038/ng.3700 Amit Majithia and colleagues employ a pooled assay in human macrophages to assess the functional effects of all possible missense variants in PPARG. Their study shows the value of saturation mutagenesis and prospective experimental characterization to support diagnostic interpretation of newly discovered missense variants in disease-related genes. Wheat Fhb1 encodes a chimeric lectin with agglutinin domains and a pore-forming toxin-like domain conferring resistance to Fusarium head blight   pp1576 - 1580 Nidhi Rawat, Michael O Pumphrey, Sixin Liu, Xiaofei Zhang, Vijay K Tiwari et al. doi:10.1038/ng.3706 Bikram Gill and colleagues report map-based cloning of Fhb1, which confers resistance to Fusarium head blight in wheat. They show that the PFT gene at Fhb1 confers resistance and encodes a chimeric lectin with agglutinin domains and a pore-forming toxin domain, identifying a new type of durable plant-resistance gene. Technical Reports Top M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity   pp1581 - 1586 Karthik A Jagadeesh, Aaron M Wenger, Mark J Berger, Harendra Guturu, Peter D Stenson et al. doi:10.1038/ng.3703 Gill Bejerano and colleagues present M-CAP, a classifier that estimates variant pathogenicity in clinical exome data sets. They show that M-CAP outperforms other existing methods at all thresholds and correctly dismisses 60% of rare missense variants of uncertain significance at 95% sensitivity. Scaling probabilistic models of genetic variation to millions of humans   pp1587 - 1590 Prem Gopalan, Wei Hao, David M Blei and John D Storey doi:10.1038/ng.3710 John Storey, David Blei and colleagues present a method, TeraStructure, for estimating population structure from human genomic data sets on a scale not possible with current methods. TeraStructure is able to analyze data from the Human Genome Diversity Panel and the 1000 Genomes Project in less than three hours. Corrigenda Top Corrigendum: Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults   p1591 Takahiko Yasuda, Shinobu Tsuzuki, Masahito Kawazu, Fumihiko Hayakawa, Shinya Kojima et al. doi:10.1038/ng1216-1587a Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses   p1591 Aysu Okbay, Bart M L Baselmans, Jan-Emmanuel De Neve, Patrick Turley, Michel G Nivard et al. doi:10.1038/ng1216-1587b Top Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. The contents of the Natureevents Directory are now live. The digital version is available here. Find the latest scientific conferences, courses, meetings and symposia on natureevents.com. For event advertising opportunities across the Nature Publishing Group portfolio please contact natureevents@nature.com More Nature Events

You have been sent this Table of Contents Alert because you have opted in to receive it. You can change or discontinue your e-mail alerts at any time, by modifying your preferences on your nature.com account at: www.nature.com/myaccount (You will need to log in to be recognised as a nature.com registrant) For further technical assistance, please contact our registration department For print subscription enquiries, please contact our subscription department For other enquiries, please contact our customer feedback department Nature Publishing Group | One New York Plaza, Suite 4500 | New York | NY 10004-1562 | USA Nature Publishing Group's worldwide offices: London - Paris - Munich - New Delhi - Tokyo - Melbourne San Diego - San Francisco - Washington - New York - Boston Macmillan Publishers Limited is a company incorporated in England and Wales under company number 785998 and whose registered office is located at The Campus, 4 Crinan Street, London, N1 9XW. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.