Ancestry-inspired genomic health Nat. Genet. (IF 27.959) Pub Date : 2017-08-30
A solution to screening for recessive heritable disorders and identifying genetic influences on common diseases is to be found in the history of one of the world's most populous regions. Large South Asian populations are a mosaic of smaller populations, many of which have founder effects as extreme as those in the European isolates that first inspired genetic medicine.
Expanding the effects of ERG on chromatin landscapes and dysregulated transcription in prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 Deepak Babu, Melissa J Fullwood
ERG overexpression in prostate cancers promotes the development of widespread changes in gene expression and chromatin landscapes, leading to redistribution of key transcription factors in prostate cancers positive for the TMPRSS2-ERG fusion gene. The overexpression of ERG is further assisted by the development of a super-enhancer in the ERG locus.
Genetic insights into mammalian heart regeneration Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 Ana Vujic, Vinícius Bassaneze, Richard T Lee
Genetic and functional analyses of 120 mouse strains have identified a heart regeneration candidate gene that modulates the contractile sarcomeric apparatus. This gene, Tnni3k, controls the frequency of the mononuclear, diploid cardiomyocyte population, which affects cardiomyocyte proliferative potential after injury.
Concepts, estimation and interpretation of SNP-based heritability Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 Jian Yang, Jian Zeng, Michael E Goddard, Naomi R Wray, Peter M Visscher
Jian Yang and colleagues explore the uses and abuses of heritability estimates derived from pedigrees and from GWAS SNPs and make recommendations for best practice in future applications of SNP-based heritability.
Genomic prediction unifies animal and plant breeding programs to form platforms for biological discovery Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 John M Hickey, Tinashe Chiurugwi, Ian Mackay, Wayne Powell
Wayne Powell and colleagues compare the different tools and approaches used by the plant breeding community versus the animal breeding community for crop and livestock improvement. They argue that the two disciplines can be united via adoption of genomic selection along with the exchange of resources and techniques between the two areas.
Reaching for the next branch on the biobank tree of knowledge Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 Nancy J Cox
An innovative study analyzing genetic association across tree-structured routine healthcare data in the UK Biobank represents a new branch on a tree that is poised to grow rapidly and offer new kinds of insights on how genome variation relates to human health and disease. Indeed, this tree is likely to offer new kinds of insights into the very nature of human disease.
Classification of common human diseases derived from shared genetic and environmental determinants Nat. Genet. (IF 27.959) Pub Date : 2017-08-07 Kanix Wang, Hallie Gaitsch, Hoifung Poon, Nancy J Cox, Andrey Rzhetsky
Andrey Rzhetsky and colleagues analyze electronic medical records from over one-third of the US population to estimate disease heritability and to determine the genetic and environmental contributions to disease variance. They obtain 84 new heritability estimates and find that the genetic correlation values for disease pairs differ from their environmental correlation values.
Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank Nat. Genet. (IF 27.959) Pub Date : 2017-07-31 Adrian Cortes, Calliope A Dendrou, Allan Motyer, Luke Jostins, Damjan Vukcevic, Alexander Dilthey, Peter Donnelly, Stephen Leslie, Lars Fugger, Gil McVean
Gil McVean and colleagues present a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Their method displays increased power to detect genetic effects over other approaches and identifies novel associations between classical HLA alleles and common immune-mediated diseases.
A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF Nat. Genet. (IF 27.959) Pub Date : 2017-07-31 Jiyeon Choi, Mai Xu, Matthew M Makowski, Tongwu Zhang, Matthew H Law, Michael A Kovacs, Anton Granzhan, Wendy J Kim, Hemang Parikh, Michael Gartside, Jeffrey M Trent, Marie-Paule Teulade-Fichou, Mark M Iles, Julia A Newton-Bishop, D Timothy Bishop, Stuart MacGregor, Nicholas K Hayward, Michiel Vermeulen, Kevin M Brown
Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a ~100-kb region spanning the PARP1 gene. Expression quantitative trait locus (eQTL) analysis in multiple cell types of the melanocytic lineage consistently demonstrated that the 1q42.1 melanoma risk allele (rs3219090[G]) is correlated with higher PARP1 levels. In silico fine-mapping and functional validation identified a common intronic indel, rs144361550 (−/GGGCCC; r2 = 0.947 with rs3219090), as displaying allele-specific transcriptional activity. A proteomic screen identified RECQL as binding to rs144361550 in an allele-preferential manner. In human primary melanocytes, PARP1 promoted cell proliferation and rescued BRAFV600E-induced senescence phenotypes in a PARylation-independent manner. PARP1 also transformed TERT-immortalized melanocytes expressing BRAFV600E. PARP1-mediated senescence rescue was accompanied by transcriptional activation of the melanocyte-lineage survival oncogene MITF, highlighting a new role for PARP1 in melanomagenesis.
TMPRSS2–ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2017-08-07 Ken J Kron, Alexander Murison, Stanley Zhou, Vincent Huang, Takafumi N Yamaguchi, Yu-Jia Shiah, Michael Fraser, Theodorus van der Kwast, Paul C Boutros, Robert G Bristow, Mathieu Lupien
TMPRSS2–ERG (T2E) structural rearrangements typify ~50% of prostate tumors and result in overexpression of the ERG transcription factor. Using chromatin, genomic and expression data, we show distinct cis-regulatory landscapes between T2E-positive and non-T2E primary prostate tumors, which include clusters of regulatory elements (COREs). This difference is mediated by ERG co-option of HOXB13 and FOXA1, implementing a T2E-specific transcriptional profile. We also report a T2E-specific CORE on the structurally rearranged ERG locus arising from spreading of the TMPRSS2 locus pre-existing CORE, assisting in its overexpression. Finally, we show that the T2E-specific cis-regulatory landscape underlies a vulnerability against the NOTCH pathway. Indeed, NOTCH pathway inhibition antagonizes the growth and invasion of T2E-positive prostate cancer cells. Taken together, our work shows that overexpressed ERG co-opts master transcription factors to deploy a unique cis-regulatory landscape, inducing a druggable dependency on NOTCH signaling in T2E-positive prostate tumors.
Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration Nat. Genet. (IF 27.959) Pub Date : 2017-08-07 Michaela Patterson, Lindsey Barske, Ben Van Handel, Christoph D Rau, Peiheng Gan, Avneesh Sharma, Shan Parikh, Matt Denholtz, Ying Huang, Yukiko Yamaguchi, Hua Shen, Hooman Allayee, J Gage Crump, Thomas I Force, Ching-Ling Lien, Takako Makita, Aldons J Lusis, S Ram Kumar, Henry M Sucov
Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.
PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK–ERK signaling Nat. Genet. (IF 27.959) Pub Date : 2017-07-24 Slim Mzoughi, Jingxian Zhang, Delphine Hequet, Shun Xie Teo, Haitong Fang, Qiao Rui Xing, Marco Bezzi, Michelle Kay Yi Seah, Sheena L M Ong, Eun Myoung Shin, Heike Wollmann, Esther S M Wong, Muthafar Al-Haddawi, Colin L Stewart, Vinay Tergaonkar, Yuin-Han Loh, N Ray Dunn, Daniel M Messerschmidt, Ernesto Guccione
The transcriptional network acting downstream of LIF, WNT and MAPK–ERK to stabilize mouse embryonic stem cells (ESCs) in their naive state has been extensively characterized. However, the upstream factors regulating these three signaling pathways remain largely uncharted. PR-domain-containing proteins (PRDMs) are zinc-finger sequence-specific chromatin factors that have essential roles in embryonic development and cell fate decisions. Here we characterize the transcriptional regulator PRDM15, which acts independently of PRDM14 to regulate the naive state of mouse ESCs. Mechanistically, PRDM15 modulates WNT and MAPK–ERK signaling by directly promoting the expression of Rspo1 (R-spondin1) and Spry1 (Sprouty1). Consistent with these findings, CRISPR–Cas9-mediated disruption of PRDM15-binding sites in the Rspo1 and Spry1 promoters recapitulates PRDM15 depletion, both in terms of local chromatin organization and the transcriptional modulation of these genes. Collectively, our findings uncover an essential role for PRDM15 as a chromatin factor that modulates the transcription of upstream regulators of WNT and MAPK–ERK signaling to safeguard naive pluripotency.
A gene encoding maize caffeoyl-CoA O-methyltransferase confers quantitative resistance to multiple pathogens Nat. Genet. (IF 27.959) Pub Date : 2017-07-24 Qin Yang, Yijian He, Mercy Kabahuma, Timothy Chaya, Amy Kelly, Eli Borrego, Yang Bian, Farid El Kasmi, Li Yang, Paulo Teixeira, Judith Kolkman, Rebecca Nelson, Michael Kolomiets, Jeffery L Dangl, Randall Wisser, Jeffrey Caplan, Xu Li, Nick Lauter, Peter Balint-Kurti
Alleles that confer multiple disease resistance (MDR) are valuable in crop improvement, although the molecular mechanisms underlying their functions remain largely unknown. A quantitative trait locus, qMdr9.02, associated with resistance to three important foliar maize diseases—southern leaf blight, gray leaf spot and northern leaf blight—has been identified on maize chromosome 9. Through fine-mapping, association analysis, expression analysis, insertional mutagenesis and transgenic validation, we demonstrate that ZmCCoAOMT2, which encodes a caffeoyl-CoA O-methyltransferase associated with the phenylpropanoid pathway and lignin production, is the gene within qMdr9.02 conferring quantitative resistance to both southern leaf blight and gray leaf spot. We suggest that resistance might be caused by allelic variation at the level of both gene expression and amino acid sequence, thus resulting in differences in levels of lignin and other metabolites of the phenylpropanoid pathway and regulation of programmed cell death.
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease Nat. Genet. (IF 27.959) Pub Date : 2017-07-17 Rebecca Sims, Sven J van der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert Olaso, Per Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen, Charles C White, Kara L Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung-Hoan Choi, Gary W Beecham, Cécile Dulary, Stefan Herms, Albert V Smith, Cory C Funk, Céline Derbois, Andreas J Forstner, Shahzad Ahmad, Hongdong Li, Delphine Bacq, Denise Harold, Claudia L Satizabal, Otto Valladares, Alessio Squassina, Rhodri Thomas, Jennifer A Brody, Liming Qu, Pascual Sánchez-Juan, Taniesha Morgan, Frank J Wolters, Yi Zhao, Florentino Sanchez Garcia, Nicola Denning, Myriam Fornage, John Malamon, Maria Candida Deniz Naranjo, Elisa Majounie, Thomas H Mosl..
Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.
Association analyses based on false discovery rate implicate new loci for coronary artery disease Nat. Genet. (IF 27.959) Pub Date : 2017-07-17 Christopher P Nelson, Anuj Goel, Adam S Butterworth, Stavroula Kanoni, Tom R Webb, Eirini Marouli, Lingyao Zeng, Ioanna Ntalla, Florence Y Lai, Jemma C Hopewell, Olga Giannakopoulou, Tao Jiang, Stephen E Hamby, Emanuele Di Angelantonio, Themistocles L Assimes, Erwin P Bottinger, John C Chambers, Robert Clarke, Colin N A Palmer, Richard M Cubbon, Patrick Ellinor, Raili Ermel, Evangelos Evangelou, Paul W Franks, Christopher Grace, Dongfeng Gu, Aroon D Hingorani, Joanna M M Howson, Erik Ingelsson, Adnan Kastrati, Thorsten Kessler, Theodosios Kyriakou, Terho Lehtimäki, Xiangfeng Lu, Yingchang Lu, Winfried März, Ruth McPherson, Andres Metspalu, Mar Pujades-Rodriguez, Arno Ruusalepp, Eric E Schadt, Amand F Schmidt, Michael J Sweeting, Pierre A Zalloua, Kamal AlGhalayini, Bernard D Keavney, Jaspal S Kooner, Ruth J F Loos, Riyaz S Patel, Martin K Rutter, Maciej Tomaszewski, Ioanna Tzoulaki, Eleftheria Zeggini, Jeanette Erdmann, George Dedoussis, Johan L M Björkegren, Heribert Schunke..
Hugh Watkins and colleagues meta-analyze data from the UK Biobank along with recent genome-wide association studies for coronary artery disease. They identify 13 new loci that were genome-wide significant and 243 loci at a 5% false discovery rate.
Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease Nat. Genet. (IF 27.959) Pub Date : 2017-07-17 Derek Klarin, Qiuyu Martin Zhu, Connor A Emdin, Mark Chaffin, Steven Horner, Brian J McMillan, Alison Leed, Michael E Weale, Chris C A Spencer, François Aguet, Ayellet V Segrè, Kristin G Ardlie, Amit V Khera, Virendar K Kaushik, Pradeep Natarajan, Sekar Kathiresan
Sekar Kathiresan and colleagues perform a genome-wide association test for coronary artery disease (CAD) using data from the UK Biobank. They identify 15 new loci and perform phenome-wide association scanning, implicating insulin resistance pathways and transendothelial migration of leukocytes in CAD.
Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability Nat. Genet. (IF 27.959) Pub Date : 2017-08-07 Erna V Ivarsdottir, Valgerdur Steinthorsdottir, Maryam S Daneshpour, Gudmar Thorleifsson, Patrick Sulem, Hilma Holm, Snaevar Sigurdsson, Astradur B Hreidarsson, Gunnar Sigurdsson, Ragnar Bjarnason, Arni V Thorsson, Rafn Benediktsson, Gudmundur Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Sirous Zeinali, Fereidoun Azizi, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Kari Stefansson
Daniel Gudbjartsson, Kari Stefansson and colleagues assess the effect of variants associated with mean fasting glucose levels on the variance in fasting glucose levels. They find that variants that increase both the levels and variance of fasting glucose increase type 2 diabetes risk, whereas those that increase the levels but reduce the variance do not.
The promise of discovering population-specific disease-associated genes in South Asia Nat. Genet. (IF 27.959) Pub Date : 2017-07-17 Nathan Nakatsuka, Priya Moorjani, Niraj Rai, Biswanath Sarkar, Arti Tandon, Nick Patterson, Gandham SriLakshmi Bhavani, Katta Mohan Girisha, Mohammed S Mustak, Sudha Srinivasan, Amit Kaushik, Saadi Abdul Vahab, Sujatha M Jagadeesh, Kapaettu Satyamoorthy, Lalji Singh, David Reich, Kumarasamy Thangaraj
Kumarasamy Thangaraj, David Reich and colleagues identify 81 South Asian groups descended from extreme founder events, including 14 with a census size of over 1 million people, thus providing an opportunity to test for and decrease the burden of recessive genetic diseases in these populations.
Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries Nat. Genet. (IF 27.959) Pub Date : 2017-07-24 Valentina Boeva, Caroline Louis-Brennetot, Agathe Peltier, Simon Durand, Cécile Pierre-Eugène, Virginie Raynal, Heather C Etchevers, Sophie Thomas, Alban Lermine, Estelle Daudigeos-Dubus, Birgit Geoerger, Martin F Orth, Thomas G P Grünewald, Elise Diaz, Bertrand Ducos, Didier Surdez, Angel M Carcaboso, Irina Medvedeva, Thomas Deller, Valérie Combaret, Eve Lapouble, Gaelle Pierron, Sandrine Grossetête-Lalami, Sylvain Baulande, Gudrun Schleiermacher, Emmanuel Barillot, Hermann Rohrer, Olivier Delattre, Isabelle Janoueix-Lerosey
Isabelle Janoueix-Lerosey, Valentina Boeva and colleagues analyze the super-enhancer landscape of 25 neuroblastoma cell lines to define core regulatory circuits controlling gene expression programs. They find and functionally characterize two types of cell identity that contribute to the tumor heterogeneity of neuroblastoma.
Necessary complexity Nat. Genet. (IF 27.959) Pub Date : 2017-07-27
This month's research articles span the range of scales of gene-regulatory mechanisms, from a deceptively simple gene therapy vector, via synthetic gene expression circuits, to extremely intricate epigenetic switches. We encourage investigation of synthetic circuits exploring the functions of the 3D genome.
Monogenic immune disorders and severe atopic disease Nat. Genet. (IF 27.959) Pub Date : 2017-07-27 Catherine M Biggs, Henry Y Lu, Stuart E Turvey
Severe allergic disease is common, and few monogenic causes of atopy have been described. A new study that convincingly links severe atopic dermatitis to heterozygous CARD11 mutations with dominant-interfering activity serves as a timely reminder that clinicians should consider the possibility of an underlying monogenic immune disorder when caring for patients suffering from severe allergic disease.
Hacking DNA copy number for circuit engineering Nat. Genet. (IF 27.959) Pub Date : 2017-07-27 Feilun Wu, Lingchong You
DNA copy number represents an essential parameter in the dynamics of synthetic gene circuits but typically is not explicitly considered. A new study demonstrates how dynamic control of DNA copy number can serve as an effective strategy to program robust oscillations in gene expression circuits.
The osteoarthritis and height GDF5 locus yields its secrets Nat. Genet. (IF 27.959) Pub Date : 2017-07-27 Guillaume Lettre
A new study reports molecular characterization of the GDF5 locus, which is associated with osteoarthritis risk and adult height in humans. This study provides evidence of positive selection for short stature at GDF5 in modern humans, as well as in archaic Neandertals and Denisovans.
The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability Nat. Genet. (IF 27.959) Pub Date : 2017-06-26 Tarjinder Singh, James T R Walters, Mandy Johnstone, David Curtis, Jaana Suvisaari, Minna Torniainen, Elliott Rees, Conrad Iyegbe, Douglas Blackwood, Andrew M McIntosh, Georg Kirov, Daniel Geschwind, Robin M Murray, Marta Di Forti, Elvira Bramon, Michael Gandal, Christina M Hultman, Pamela Sklar, INTERVAL Study, UK10K Consortium, Aarno Palotie, Patrick F Sullivan, Michael C O'Donovan, Michael J Owen, Jeffrey C Barrett
Jeffrey Barrett, Tarjinder Singh and colleagues present a meta-analysis of rare coding variants and copy number variants in a large collection of schizophrenia cases and controls, combined with de novo mutation data from family trios. They find that rare, damaging variants contribute to risk of schizophrenia both with and without intellectual disability and that there is overlap between genetic risk for schizophrenia and other neurodevelopmental disorders.
Genotype–covariate interaction effects and the heritability of adult body mass index Nat. Genet. (IF 27.959) Pub Date : 2017-07-10 Matthew R Robinson, Geoffrey English, Gerhard Moser, Luke R Lloyd-Jones, Marcus A Triplett, Zhihong Zhu, Ilja M Nolte, Jana V van Vliet-Ostaptchouk, Harold Snieder, The LifeLines Cohort Study, Tonu Esko, Lili Milani, Reedik Mägi, Andres Metspalu, Patrik K E Magnusson, Nancy L Pedersen, Erik Ingelsson, Magnus Johannesson, Jian Yang, David Cesarini, Peter M Visscher
Matthew Robinson, Peter Visscher and colleagues use phenotypic data on 172,000 sibling pairs and phenotypic and SNP data on 150,832 unrelated individuals to estimate the heritability of body mass index across a range of experimental designs. They conclude that substantially larger sample sizes across ages and lifestyle factors will be required to understand the full genetic architecture of this trait.
Identification of sequence variants influencing immunoglobulin levels Nat. Genet. (IF 27.959) Pub Date : 2017-06-19 Stefan Jonsson, Gardar Sveinbjornsson, Aitzkoa Lopez de Lapuente Portilla, Bhairavi Swaminathan, Rosina Plomp, Gillian Dekkers, Ram Ajore, Mina Ali, Arthur E H Bentlage, Evelina Elmér, Gudmundur I Eyjolfsson, Sigurjon A Gudjonsson, Urban Gullberg, Arnaldur Gylfason, Bjarni V Halldorsson, Markus Hansson, Hilma Holm, Åsa Johansson, Ellinor Johnsson, Aslaug Jonasdottir, Bjorn R Ludviksson, Asmundur Oddsson, Isleifur Olafsson, Sigurgeir Olafsson, Olof Sigurdardottir, Asgeir Sigurdsson, Lilja Stefansdottir, Gisli Masson, Patrick Sulem, Manfred Wuhrer, Anna-Karin Wihlborg, Gudmar Thorleifsson, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Gestur Vidarsson, Ingileif Jonsdottir, Björn Nilsson, Kari Stefansson
Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10−55, β = −0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10−8, β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
Germline hypomorphic CARD11 mutations in severe atopic disease Nat. Genet. (IF 27.959) Pub Date : 2017-06-19 Chi A Ma, Jeffrey R Stinson, Yuan Zhang, Jordan K Abbott, Michael A Weinreich, Pia J Hauk, Paul R Reynolds, Jonathan J Lyons, Celeste G Nelson, Elisa Ruffo, Batsukh Dorjbal, Salomé Glauzy, Natsuko Yamakawa, Swadhinya Arjunaraja, Kelsey Voss, Jennifer Stoddard, Julie Niemela, Yu Zhang, Sergio D Rosenzweig, Joshua J McElwee, Thomas DiMaggio, Helen F Matthews, Nina Jones, Kelly D Stone, Alejandro Palma, Matías Oleastro, Emma Prieto, Andrea R Bernasconi, Geronimo Dubra, Silvia Danielian, Jonathan Zaiat, Marcelo A Marti, Brian Kim, Megan A Cooper, Neil Romberg, Eric Meffre, Erwin W Gelfand, Andrew L Snow, Joshua D Milner
Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor–induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.
Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk Nat. Genet. (IF 27.959) Pub Date : 2017-07-03 Terence D Capellini, Hao Chen, Jiaxue Cao, Andrew C Doxey, Ata M Kiapour, Michael Schoor, David M Kingsley
Variants in GDF5 are associated with human arthritis and decreased height, but the causal mutations are still unknown. We surveyed the Gdf5 locus for regulatory regions in transgenic mice and fine-mapped separate enhancers controlling expression in joints versus growing ends of long bones. A large downstream regulatory region contains a novel growth enhancer (GROW1), which is required for normal Gdf5 expression at ends of developing bones and for normal bone lengths in vivo. Human GROW1 contains a common base-pair change that decreases enhancer activity and colocalizes with peaks of positive selection in humans. The derived allele is rare in Africa but common in Eurasia and is found in Neandertals and Denisovans. Our results suggest that an ancient regulatory variant in GROW1 has been repeatedly selected in northern environments and that past selection on growth phenotypes explains the high frequency of a GDF5 haplotype that also increases arthritis susceptibility in many human populations.
The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia Nat. Genet. (IF 27.959) Pub Date : 2017-07-03 Yu Liu, John Easton, Ying Shao, Jamie Maciaszek, Zhaoming Wang, Mark R Wilkinson, Kelly McCastlain, Michael Edmonson, Stanley B Pounds, Lei Shi, Xin Zhou, Xiaotu Ma, Edgar Sioson, Yongjin Li, Michael Rusch, Pankaj Gupta, Deqing Pei, Cheng Cheng, Malcolm A Smith, Jaime Guidry Auvil, Daniela S Gerhard, Mary V Relling, Naomi J Winick, Andrew J Carroll, Nyla A Heerema, Elizabeth Raetz, Meenakshi Devidas, Cheryl L Willman, Richard C Harvey, William L Carroll, Kimberly P Dunsmore, Stuart S Winter, Brent L Wood, Brian P Sorrentino, James R Downing, Mignon L Loh, Stephen P Hunger, Jinghui Zhang, Charles G Mullighan
Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.
Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma Nat. Genet. (IF 27.959) Pub Date : 2017-06-26 Sjors M Kas, Julian R de Ruiter, Koen Schipper, Stefano Annunziato, Eva Schut, Sjoerd Klarenbeek, Anne Paulien Drenth, Eline van der Burg, Christiaan Klijn, Jelle J ten Hoeve, David J Adams, Marco J Koudijs, Jelle Wesseling, Micha Nethe, Lodewyk F A Wessels, Jos Jonkers
Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8–14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1. These mice developed multiple independent mammary tumors of which the majority resembled human ILC in terms of morphology and gene expression. Recurrent and mutually exclusive transposon insertions were identified in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, whose products have been implicated in the regulation of the actin cytoskeleton. Notably, MYH9, PPP1R12B and TP53BP2 were also frequently aberrated in human ILC, highlighting these genes as drivers of a novel oncogenic pathway underlying ILC development.
Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium Nat. Genet. (IF 27.959) Pub Date : 2017-06-26 Terrence F Meehan, Nathalie Conte, David B West, Julius O Jacobsen, Jeremy Mason, Jonathan Warren, Chao-Kung Chen, Ilinca Tudose, Mike Relac, Peter Matthews, Natasha Karp, Luis Santos, Tanja Fiegel, Natalie Ring, Henrik Westerberg, Simon Greenaway, Duncan Sneddon, Hugh Morgan, Gemma F Codner, Michelle E Stewart, James Brown, Neil Horner, The International Mouse Phenotyping Consortium, Melissa Haendel, Nicole Washington, Christopher J Mungall, Corey L Reynolds, Juan Gallegos, Valerie Gailus-Durner, Tania Sorg, Guillaume Pavlovic, Lynette R Bower, Mark Moore, Iva Morse, Xiang Gao, Glauco P Tocchini-Valentini, Yuichi Obata, Soo Young Cho, Je Kyung Seong, John Seavitt, Arthur L Beaudet, Mary E Dickinson, Yann Herault, Wolfgang Wurst, Martin Hrabe de Angelis, K C Kent Lloyd, Ann M Flenniken, Lauryl M J Nutter, Susan Newbigging, Colin McKerlie, Monica J Justice, Stephen A Murray, Karen L Svenson, Robert E Braun, Jacqueline K White, Allan Bradley, Paul Flicek, Sara Wells, William C ..
Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard–Soulier, Bardet–Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.
The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain Nat. Genet. (IF 27.959) Pub Date : 2017-07-03 Yan Jiang, Yong-Hwee Eddie Loh, Prashanth Rajarajan, Teruyoshi Hirayama, Will Liao, Bibi S Kassim, Behnam Javidfar, Brigham J Hartley, Lisa Kleofas, Royce B Park, Benoit Labonte, Seok-Man Ho, Sandhya Chandrasekaran, Catherine Do, Brianna R Ramirez, Cyril J Peter, Julia T C W, Brian M Safaie, Hirofumi Morishita, Panos Roussos, Eric J Nestler, Anne Schaefer, Benjamin Tycko, Kristen J Brennand, Takeshi Yagi, Li Shen, Schahram Akbarian
We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Setdb1 (also known as Kmt1e; encodes a histone H3 lysine 9 methyltransferase), including a large topologically associated 1.2-Mb domain conserved in humans and mice that encompasses >70 genes at the clustered protocadherin locus (hereafter referred to as cPcdh). The cPcdh topologically associated domain (TADcPcdh) in neurons from mutant mice showed abnormal accumulation of the transcriptional regulator and three-dimensional (3D) genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression. Genes encoding stochastically expressed protocadherins were transcribed by increased numbers of cortical neurons, indicating relaxation of single-cell constraint. SETDB1-dependent loop formations bypassed 0.2–1 Mb of linear genome and radiated from the TADcPcdh fringes toward cis-regulatory sequences within the cPcdh locus, counterbalanced shorter-range facilitative promoter–enhancer contacts and carried loop-bound polymorphisms that were associated with genetic risk for schizophrenia. We show that the SETDB1 repressor complex, which involves multiple KRAB zinc finger proteins, shields neuronal genomes from excess CTCF binding and is critically required for structural maintenance of TADcPcdh.
Truncating mutations in RBM12 are associated with psychosis Nat. Genet. (IF 27.959) Pub Date : 2017-06-19 Stacy Steinberg, Steinunn Gudmundsdottir, Gardar Sveinbjornsson, Jaana Suvisaari, Tiina Paunio, Minna Torniainen-Holm, Michael L Frigge, Gudrun A Jonsdottir, Johanna Huttenlocher, Sunna Arnarsdottir, Oddur Ingimarsson, Magnus Haraldsson, Thorarinn Tyrfingsson, Thorgeir E Thorgeirsson, Augustine Kong, Gudmundur L Norddahl, Daniel F Gudbjartsson, Engilbert Sigurdsson, Hreinn Stefansson, Kari Stefansson
Kari Stefansson and colleagues identify a nonsense mutation in RBM12 segregating with psychosis in an extended Icelandic pedigree and an independent frameshift mutation in RBM12 segregating with psychosis in a Finnish family. They further show that carriers of the Icelandic mutation who are unaffected by psychosis exhibit a psychiatric disorder and cognitive test battery profile resembling that of patients with schizophrenia.
Variants in the fetal genome near FLT1 are associated with risk of preeclampsia Nat. Genet. (IF 27.959) Pub Date : 2017-06-19 Ralph McGinnis, Valgerdur Steinthorsdottir, Nicholas O Williams, Gudmar Thorleifsson, Scott Shooter, Sigrun Hjartardottir, Suzannah Bumpstead, Lilja Stefansdottir, Lucy Hildyard, Jon K Sigurdsson, John P Kemp, Gabriela B Silva, Liv Cecilie V Thomsen, Tiina Jääskeläinen, Eero Kajantie, Sally Chappell, Noor Kalsheker, Ashley Moffett, Susan Hiby, Wai Kwong Lee, Sandosh Padmanabhan, Nigel A B Simpson, Vivien A Dolby, Eleonora Staines-Urias, Stephanie M Engel, Anita Haugan, Lill Trogstad, Gulnara Svyatova, Nodira Zakhidova, Dilbar Najmutdinova, The FINNPEC Consortium, The GOPEC Consortium, Anna F Dominiczak, Håkon K Gjessing, Juan P Casas, Frank Dudbridge, James J Walker, Fiona Broughton Pipkin, Unnur Thorsteinsdottir, Reynir T Geirsson, Debbie A Lawlor, Ann-Charlotte Iversen, Per Magnus, Hannele Laivuori, Kari Stefansson, Linda Morgan
Ralph McGinnis, Valgerdur Steinthorsdottir, Linda Morgan and colleagues perform a genome-wide association study in the offspring of preeclampsia pregnancies and identify variants in the fetal genome near FLT1 that are associated with risk of preeclampsia. FLT1 is known to encode an isoform of placental origin implicated in the pathology of preeclampsia, providing biological support for the association of this locus with preeclampsia risk.
Neuroblastoma is composed of two super-enhancer-associated differentiation states Nat. Genet. (IF 27.959) Pub Date : 2017-06-26 Tim van Groningen, Jan Koster, Linda J Valentijn, Danny A Zwijnenburg, Nurdan Akogul, Nancy E Hasselt, Marloes Broekmans, Franciska Haneveld, Natalia E Nowakowska, Johannes Bras, Carel J M van Noesel, Aldo Jongejan, Antoine H van Kampen, Linda Koster, Frank Baas, Lianne van Dijk-Kerkhoven, Margriet Huizer-Smit, Maria C Lecca, Alvin Chan, Arjan Lakeman, Piet Molenaar, Richard Volckmann, Ellen M Westerhout, Mohamed Hamdi, Peter G van Sluis, Marli E Ebus, Jan J Molenaar, Godelieve A Tytgat, Bart A Westerman, Johan van Nes, Rogier Versteeg
Rogier Versteeg, Johan van Nes and colleagues report that neuroblastomas comprise two cell types, mesenchymal and adrenergic, that have different responses to chemotherapeutic agents in vitro. Using ChIP–seq and expression profiling of pairs of phenotypically divergent isogenic cell lines, they identify candidate transcription factors for regulation of the two cell states.
Identification of liver-specific enhancer–promoter activity in the 3′ untranslated region of the wild-type AAV2 genome Nat. Genet. (IF 27.959) Pub Date : 2017-06-19 Grant J Logan, Allison P Dane, Claus V Hallwirth, Christine M Smyth, Emilie E Wilkie, Anais K Amaya, Erhua Zhu, Neeta Khandekar, Samantha L Ginn, Sophia H Y Liao, Sharon C Cunningham, Natsuki Sasaki, Martí Cabanes-Creus, Patrick P L Tam, David W Russell, Leszek Lisowski, Ian E Alexander
Ian Alexander and colleagues characterize a liver-specific enhancer–promoter element that is found in the genome of wild-type adeno-associated virus type 2 (AAV2), from which gene transfer vectors have been derived. They suggest that these sequences could provide a possible link between AAV integration events in the liver and gene dysregulation and pathogenesis.
Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia Nat. Genet. (IF 27.959) Pub Date : 2017-07-03 Masafumi Seki, Shunsuke Kimura, Tomoya Isobe, Kenichi Yoshida, Hiroo Ueno, Yaeko Nakajima-Takagi, Changshan Wang, Lin Lin, Ayana Kon, Hiromichi Suzuki, Yusuke Shiozawa, Keisuke Kataoka, Yoichi Fujii, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Teppei Shimamura, Kyoko Masuda, Hiroshi Kawamoto, Kentaro Ohki, Motohiro Kato, Yuki Arakawa, Katsuyoshi Koh, Ryoji Hanada, Hiroshi Moritake, Masaharu Akiyama, Ryoji Kobayashi, Takao Deguchi, Yoshiko Hashii, Toshihiko Imamura, Atsushi Sato, Nobutaka Kiyokawa, Akira Oka, Yasuhide Hayashi, Masatoshi Takagi, Atsushi Manabe, Akira Ohara, Keizo Horibe, Masashi Sanada, Atsushi Iwama, Hiroyuki Mano, Satoru Miyano, Seishi Ogawa, Junko Takita
Junko Takita, Seishi Ogawa and colleagues profile 121 cases of pediatric T cell acute lymphoblasic leukemia (T-ALL) and identify recurrent SPI1 (PU.1) gene fusions. They find that these SPI1 fusions correlated with poor survival, retained transcriptional activity and, in a mouse stem cell model, enhanced cell proliferation.
Synchronized DNA cycling across a bacterial population Nat. Genet. (IF 27.959) Pub Date : 2017-07-10 Leo Baumgart, William Mather, Jeff Hasty
Jeff Hasty and colleagues use an endonuclease from S. cerevisiae along with quorum sensing from A. fischeri to produce sustained cycling of DNA plasmid concentration across a colony of E. coli cells. This copy number modulation system enables dynamic regulation of gene circuit elements without the need for specially engineered promoters.
Genome-wide characterization of mammalian promoters with distal enhancer functions Nat. Genet. (IF 27.959) Pub Date : 2017-06-05 Lan T M Dao, Ariel O Galindo-Albarrán, Jaime A Castro-Mondragon, Charlotte Andrieu-Soler, Alejandra Medina-Rivera, Charbel Souaid, Guillaume Charbonnier, Aurélien Griffon, Laurent Vanhille, Tharshana Stephen, Jaafar Alomairi, David Martin, Magali Torres, Nicolas Fernandez, Eric Soler, Jacques van Helden, Denis Puthier, Salvatore Spicuglia
Gene expression in mammals is precisely regulated by the combination of promoters and gene-distal regulatory regions, known as enhancers. Several studies have suggested that some promoters might have enhancer functions. However, the extent of this type of promoters and whether they actually function to regulate the expression of distal genes have remained elusive. Here, by exploiting a high-throughput enhancer reporter assay, we unravel a set of mammalian promoters displaying enhancer activity. These promoters have distinct genomic and epigenomic features and frequently interact with other gene promoters. Extensive CRISPR–Cas9 genomic manipulation demonstrated the involvement of these promoters in the cis regulation of expression of distal genes in their natural loci. Our results have important implications for the understanding of complex gene regulation in normal development and disease.
Lineage-specific functions of TET1 in the postimplantation mouse embryo Nat. Genet. (IF 27.959) Pub Date : 2017-05-15 Rita Khoueiry, Abhishek Sohni, Bernard Thienpont, Xinlong Luo, Joris Vande Velde, Michela Bartoccetti, Bram Boeckx, An Zwijsen, Anjana Rao, Diether Lambrechts, Kian Peng Koh
The mammalian TET enzymes catalyze DNA demethylation. While they have been intensely studied as major epigenetic regulators, little is known about their physiological roles and the extent of functional redundancy following embryo implantation. Here we define non-redundant roles for TET1 at an early postimplantation stage of the mouse embryo, when its paralogs Tet2 and Tet3 are not detectably expressed. TET1 regulates numerous genes defining differentiation programs in the epiblast and extraembryonic ectoderm. In epiblast cells, TET1 demethylates gene promoters via hydroxymethylation and maintains telomere stability. Surprisingly, TET1 represses a majority of epiblast target genes independently of methylation changes, in part through regulation of the gene encoding the transcriptional repressor JMJD8. Dysregulated gene expression in the absence of TET1 causes embryonic defects, which are partially penetrant in an inbred strain but fully lethal in non-inbred mice. Collectively, our study highlights an interplay between the catalytic and non-catalytic activities of TET1 that is essential for normal development.
DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats Nat. Genet. (IF 27.959) Pub Date : 2017-06-12 David Brocks, Christopher R Schmidt, Michael Daskalakis, Hyo Sik Jang, Nakul M Shah, Daofeng Li, Jing Li, Bo Zhang, Yiran Hou, Sara Laudato, Daniel B Lipka, Johanna Schott, Holger Bierhoff, Yassen Assenov, Monika Helf, Alzbeta Ressnerova, Md Saiful Islam, Anders M Lindroth, Simon Haas, Marieke Essers, Charles D Imbusch, Benedikt Brors, Ina Oehme, Olaf Witt, Michael Lübbert, Jan-Philipp Mallm, Karsten Rippe, Rainer Will, Dieter Weichenhan, Georg Stoecklin, Clarissa Gerhäuser, Christopher C Oakes, Ting Wang, Christoph Plass
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.
Paused RNA polymerase II inhibits new transcriptional initiation Nat. Genet. (IF 27.959) Pub Date : 2017-05-15 Wanqing Shao, Julia Zeitlinger
RNA polymerase II (Pol II) pauses downstream of the transcription initiation site before beginning productive elongation. This pause is a key component of metazoan gene expression regulation. Some promoters have a strong disposition for Pol II pausing and often mediate faster, more synchronous changes in expression. This requires multiple rounds of transcription and thus cannot rely solely on pause release. However, it is unclear how pausing affects the initiation of new transcripts during consecutive rounds of transcription. Using our recently developed ChIP-nexus method, we find that Pol II pausing inhibits new initiation. We propose that paused Pol II helps prevent new initiation between transcription bursts, which may reduce noise.
Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2 Nat. Genet. (IF 27.959) Pub Date : 2017-06-05 Iva A Tchasovnikarova, Richard T Timms, Christopher H Douse, Rhys C Roberts, Gordon Dougan, Robert E Kingston, Yorgo Modis, Paul J Lehner
Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot–Marie–Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR–Cas9-mediated forward genetic screen, we identified MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploited a new method, differential viral accessibility (DIVA), to show that loss of MORC2 results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The ATPase activity of MORC2 is critical for HUSH-mediated silencing, and the most common alteration affecting the ATPase domain in CMT patients (p.Arg252Trp) hyperactivates HUSH-mediated repression in neuronal cells. These data define a critical role for MORC2 in epigenetic silencing by the HUSH complex and provide a mechanistic basis underpinning the role of MORC2 mutations in CMT disease.
Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease Nat. Genet. (IF 27.959) Pub Date : 2017-05-22 Hao Lu, Maria C Rondón Galeano, Elisabeth Ott, Geraldine Kaeslin, P Jaya Kausalya, Carina Kramer, Nadina Ortiz-Brüchle, Nadescha Hilger, Vicki Metzis, Milan Hiersche, Shang Yew Tay, Robert Tunningley, Shubha Vij, Andrew D Courtney, Belinda Whittle, Elke Wühl, Udo Vester, Björn Hartleben, Steffen Neuber, Valeska Frank, Melissa H Little, Daniel Epting, Peter Papathanasiou, Andrew C Perkins, Graham D Wright, Walter Hunziker, Heon Yung Gee, Edgar A Otto, Klaus Zerres, Friedhelm Hildebrandt, Sudipto Roy, Carol Wicking, Carsten Bergmann
Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.
Between-region genetic divergence reflects the mode and tempo of tumor evolution Nat. Genet. (IF 27.959) Pub Date : 2017-06-05 Ruping Sun, Zheng Hu, Andrea Sottoriva, Trevor A Graham, Arbel Harpak, Zhicheng Ma, Jared M Fischer, Darryl Shibata, Christina Curtis
Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. By simulating spatial tumor growth under different evolutionary modes and examining patterns of between-region subclonal genetic divergence from multiregion sequencing (MRS) data, we demonstrate that it is feasible to distinguish tumors driven by strong positive subclonal selection from those evolving neutrally or under weak selection, as the latter fail to dramatically alter subclonal composition. We developed a classifier based on measures of between-region subclonal genetic divergence and projected patient data into model space, finding different modes of evolution both within and between solid tumor types. Our findings have broad implications for how human tumors progress, how they accumulate intratumoral heterogeneity, and ultimately how they may be more effectively treated.
PGBD5 promotes site-specific oncogenic mutations in human tumors Nat. Genet. (IF 27.959) Pub Date : 2017-05-15 Anton G Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C MacArthur, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N Blackford, Christopher E Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D Socci, Elizabeth Perlman, Cristina R Antonescu, Charles W M Roberts, Hanno Steen, Elizabeth Mullen, Stephen P Jackson, David Torrents, Zhiping Weng, Scott A Armstrong, Alex Kentsis
Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.
Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci Nat. Genet. (IF 27.959) Pub Date : 2017-05-29 Tin Aung, Mineo Ozaki, Mei Chin Lee, Ursula Schlötzer-Schrehardt, Gudmar Thorleifsson, Takanori Mizoguchi, Robert P Igo, Aravind Haripriya, Susan E Williams, Yury S Astakhov, Andrew C Orr, Kathryn P Burdon, Satoko Nakano, Kazuhiko Mori, Khaled Abu-Amero, Michael Hauser, Zheng Li, Gopalakrishnan Prakadeeswari, Jessica N Cooke Bailey, Alina Popa Cherecheanu, Jae H Kang, Sarah Nelson, Ken Hayashi, Shin-ichi Manabe, Shigeyasu Kazama, Tomasz Zarnowski, Kenji Inoue, Murat Irkec, Miguel Coca-Prados, Kazuhisa Sugiyama, Irma Järvelä, Patricio Schlottmann, S Fabian Lerner, Hasnaa Lamari, Yildirim Nilgün, Mukharram Bikbov, Ki Ho Park, Soon Cheol Cha, Kenji Yamashiro, Juan C Zenteno, Jost B Jonas, Rajesh S Kumar, Shamira A Perera, Anita S Y Chan, Nino Kobakhidze, Ronnie George, Lingam Vijaya, Tan Do, Deepak P Edward, Lourdes de Juan Marcos, Mohammad Pakravan, Sasan Moghimi, Ryuichi Ideta, Daniella Bach-Holm, Per Kappelgaard, Barbara Wirostko, Samuel Thomas, Daniel Gaston, Karen Bedard, W..
Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10−14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
Reevaluation of SNP heritability in complex human traits Nat. Genet. (IF 27.959) Pub Date : 2017-05-22 Doug Speed, Na Cai, Michael R Johnson, Sergey Nejentsev, David J Balding
SNP heritability, the proportion of phenotypic variance explained by SNPs, has been reported for many hundreds of traits. Its estimation requires strong prior assumptions about the distribution of heritability across the genome, but current assumptions have not been thoroughly tested. By analyzing imputed data for a large number of human traits, we empirically derive a model that more accurately describes how heritability varies with minor allele frequency (MAF), linkage disequilibrium (LD) and genotype certainty. Across 19 traits, our improved model leads to estimates of common SNP heritability on average 43% (s.d. 3%) higher than those obtained from the widely used software GCTA and 25% (s.d. 2%) higher than those from the recently proposed extension GCTA-LDMS. Previously, DNase I hypersensitivity sites were reported to explain 79% of SNP heritability; using our improved heritability model, their estimated contribution is only 24%.
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders Nat. Genet. (IF 27.959) Pub Date : 2017-05-15 Daniel J Weiner, Emilie M Wigdor, Stephan Ripke, Raymond K Walters, Jack A Kosmicki, Jakob Grove, Kaitlin E Samocha, Jacqueline I Goldstein, Aysu Okbay, Jonas Bybjerg-Grauholm, Thomas Werge, David M Hougaard, Jacob Taylor, David Skuse, Bernie Devlin, Richard Anney, Stephan J Sanders, Somer Bishop, Preben Bo Mortensen, Anders D Børglum, George Davey Smith, Mark J Daly, Elise B Robinson
Elise Robinson and colleagues present the polygenic transmission disequilibrium test (pTDT) for evaluating transmission of polygenic risk in family-based study designs. The authors apply pTDT to a cohort of autism spectrum disorder (ASD) families and find that common polygenic variation acts additively with de novo variants to contribute to ASD risk.
Transposase-driven rearrangements in human tumors Nat. Genet. (IF 27.959) Pub Date : 2017-06-28 Stephen C Mack, Hiromichi Suzuki, Michael D Taylor
A new study shows that aberrant DNA transposase activity promotes structural alterations that are clonally selected to drive tumor development. This discovery uncovers novel mechanisms of tumor-suppressor gene inactivation and highlights a new approach to cancer gene identification.
Epigenetic modifier drugs trigger widespread transcription of endogenous retroviruses Nat. Genet. (IF 27.959) Pub Date : 2017-06-28 Dixie L Mager, Matthew C Lorincz
A study in this issue demonstrates that epigenome-modifying drugs used in cancer chemotherapy induce transcription from thousands of previously unannotated transcription start sites, most of which are derived from ancient endogenous retroviruses (ERVs). This work, coupled with previous related findings, suggests that induction of ERVs, rather than direct effects on specific genes, may have a central role in the cellular responses to such agents and, in turn, their therapeutic efficacy.
Promoting transcription over long distances Nat. Genet. (IF 27.959) Pub Date : 2017-06-28 Rui R Catarino, Christoph Neumayr, Alexander Stark
Promoters and enhancers have long been regarded as distinct elements, a notion that has been challenged more recently. Two new studies now identify promoters that function as long-range enhancers in vivo to regulate the transcription of distal genes.
Data models to GO-FAIR Nat. Genet. (IF 27.959) Pub Date : 2017-06-28
This journal and Scientific Data are calling for submissions containing linked open data models that embody and extend the FAIR principles: that data should be findable, accessible, interoperable and reusable by both humans and machines. These principles are achievable with existing resources, languages and vocabularies to enable computers to combine and reanalyze data sets automatically and lead humans to new discoveries.
The complex genetics of hypoplastic left heart syndrome Nat. Genet. (IF 27.959) Pub Date : 2017-05-22 Xiaoqin Liu, Hisato Yagi, Shazina Saeed, Abha S Bais, George C Gabriel, Zhaohan Chen, Kevin A Peterson, You Li, Molly C Schwartz, William T Reynolds, Manush Saydmohammed, Brian Gibbs, Yijen Wu, William Devine, Bishwanath Chatterjee, Nikolai T Klena, Dennis Kostka, Karen L de Mesy Bentley, Madhavi K Ganapathiraju, Phillip Dexheimer, Linda Leatherbury, Omar Khalifa, Anchit Bhagat, Maliha Zahid, William Pu, Simon Watkins, Paul Grossfeld, Stephen A Murray, George A Porter, Michael Tsang, Lisa J Martin, D Woodrow Benson, Bruce J Aronow, Cecilia W Lo
Cecilia Lo and colleagues report the recovery of mice with hypoplastic left heart syndrome (HLHS) from a large mutagenesis screen. They find genetic heterogeneity among HLHS mice and functionally validate mutations in two genes, Sap130 and Pcdha, as contributing to HLHS in a combinatorial manner.
Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation Nat. Genet. (IF 27.959) Pub Date : 2017-05-29 Shawn Yost, Bas de Wolf, Sandra Hanks, Anna Zachariou, Chiara Marcozzi, Matthew Clarke, Richarda M de Voer, Banafsheh Etemad, Esther Uijttewaal, Emma Ramsay, Harriet Wylie, Anna Elliott, Susan Picton, Audrey Smith, Sarah Smithson, Sheila Seal, Elise Ruark, Gunnar Houge, Jonathon Pines, Geert J P L Kops, Nazneen Rahman
Nazneen Rahman, Geert Kops and colleagues report the identification of biallelic loss-of-function mutations in TRIP13 in six individuals with Wilms tumor who presented with features of mosaic variegated aneuploidy. They show that TRIP13-mutant cells show spindle assembly checkpoint defects and suggest that mechanisms leading to aneuploidy may contribute directly to increased cancer risk.
Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor Nat. Genet. (IF 27.959) Pub Date : 2017-06-12 Zhaoming Wang, Katherine A McGlynn, Ewa Rajpert-De Meyts, D Timothy Bishop, Charles C Chung, Marlene D Dalgaard, Mark H Greene, Ramneek Gupta, Tom Grotmol, Trine B Haugen, Robert Karlsson, Kevin Litchfield, Nandita Mitra, Kasper Nielsen, Louise C Pyle, Stephen M Schwartz, Vésteinn Thorsson, Saran Vardhanabhuti, Fredrik Wiklund, Clare Turnbull, Stephen J Chanock, Peter A Kanetsky, Katherine L Nathanson
Katherine Nathanson, Peter Kanetsky and colleagues present a meta-analysis of five genome-wide association studies of testicular germ cell tumor (TGCT). They identify eight new susceptibility loci and new independent signals at two previously reported loci, providing further clues to the etiology of TGCT.
Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor Nat. Genet. (IF 27.959) Pub Date : 2017-06-12 Kevin Litchfield, Max Levy, Giulia Orlando, Chey Loveday, Philip J Law, Gabriele Migliorini, Amy Holroyd, Peter Broderick, Robert Karlsson, Trine B Haugen, Wenche Kristiansen, Jérémie Nsengimana, Kerry Fenwick, Ioannis Assiotis, ZSofia Kote-Jarai, Alison M Dunning, Kenneth Muir, Julian Peto, Rosalind Eeles, Douglas F Easton, Darshna Dudakia, Nick Orr, Nora Pashayan, D Timothy Bishop, Alison Reid, Robert A Huddart, Janet Shipley, Tom Grotmol, Fredrik Wiklund, Richard S Houlston, Clare Turnbull
Clare Turnbull and colleagues report discovery of 19 new susceptibility loci for testicular germ cell tumor (TGCT) and provide evidence for a network of physical interactions between TGCT risk variants and candidate causal genes. Their findings implicate widespread disruption of developmental transcriptional regulators in TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis.
Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes Nat. Genet. (IF 27.959) Pub Date : 2017-06-12 James D McKay, Rayjean J Hung, Younghun Han, Xuchen Zong, Robert Carreras-Torres, David C Christiani, Neil E Caporaso, Mattias Johansson, Xiangjun Xiao, Yafang Li, Jinyoung Byun, Alison Dunning, Karen A Pooley, David C Qian, Xuemei Ji, Geoffrey Liu, Maria N Timofeeva, Stig E Bojesen, Xifeng Wu, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C Aldrich, William S Bush, Adonina Tardon, Gad Rennert, M Dawn Teare, John K Field, Lambertus A Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B Schabath, Angeline S Andrew, Hongbing Shen, Yun-Chul Hong, Jian-Min Yuan, Pier Alberto Bertazzi, Angela C Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S Johansen, Anders Mellemgaard, Walid Saliba, Christopher A Haiman, Lynne R Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Henricus F M van der Heijden, Jin Hee Kim, Juncheng Dai, Zhibin Hu, Michael P A Davies, Michael W Marcus, Hans Brunnström, Jonas Manjer..
Christopher Amos and colleagues perform genome-wide association analysis for lung cancer using cohorts genotyped on the OncoArray and combing these with existing data. They identify 18 loci, 10 of which are new, finding heterogeneity across the different lung cancer subtypes, and explore candidate genes through eQTL analysis in lung tissue.
Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis Nat. Genet. (IF 27.959) Pub Date : 2017-05-29 Kazuyoshi Ishigaki, Yuta Kochi, Akari Suzuki, Yumi Tsuchida, Haruka Tsuchiya, Shuji Sumitomo, Kensuke Yamaguchi, Yasuo Nagafuchi, Shinichiro Nakachi, Rika Kato, Keiichi Sakurai, Hirofumi Shoda, Katsunori Ikari, Atsuo Taniguchi, Hisashi Yamanaka, Fuyuki Miya, Tatsuhiko Tsunoda, Yukinori Okada, Yukihide Momozawa, Yoichiro Kamatani, Ryo Yamada, Michiaki Kubo, Keishi Fujio, Kazuhiko Yamamoto
Yuta Kochi and colleagues perform expression quantitative trait loci (eQTL) analysis on five subsets of immune cells individually sorted from blood from 105 individuals. They develop an integrated analysis pipeline of expression and epigenomic data along with gene association to identify cell-specific candidate causal genes and apply this to rheumatoid arthritis.
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms Nat. Genet. (IF 27.959) Pub Date : 2017-05-22 Joanna M M Howson, Wei Zhao, Daniel R Barnes, Weang-Kee Ho, Robin Young, Dirk S Paul, Lindsay L Waite, Daniel F Freitag, Eric B Fauman, Elias L Salfati, Benjamin B Sun, John D Eicher, Andrew D Johnson, Wayne H H Sheu, Sune F Nielsen, Wei-Yu Lin, Praveen Surendran, Anders Malarstig, Jemma B Wilk, Anne Tybjærg-Hansen, Katrine L Rasmussen, Pia R Kamstrup, Panos Deloukas, Jeanette Erdmann, Sekar Kathiresan, Nilesh J Samani, Heribert Schunkert, Hugh Watkins, Ron Do, Daniel J Rader, Julie A Johnson, Stanley L Hazen, Arshed A Quyyumi, John A Spertus, Carl J Pepine, Nora Franceschini, Anne Justice, Alex P Reiner, Steven Buyske, Lucia A Hindorff, Cara L Carty, Kari E North, Charles Kooperberg, Eric Boerwinkle, Kristin Young, Mariaelisa Graff, Ulrike Peters, Devin Absher, Chao A Hsiung, Wen-Jane Lee, Kent D Taylor, Ying-Hsiang Chen, I-Te Lee, Xiuqing Guo, Ren-Hua Chung, Yi-Jen Hung, Jerome I Rotter, Jyh-Ming J Juang, Thomas Quertermous, Tzung-Dau Wang, Asif Rasheed, Philippe Frossard, ..
Joanna Howson and colleagues perform a genome-wide association study and meta-analysis for coronary artery disease in large, trans-ancestry cohorts. They identify 15 new loci and correlate these regions with cell-type-specific gene expression and plasma protein levels to find novel pathways and potential mechanisms of disease.
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