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Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

November 24, 2012 by 2012pharmaceutical

Reporter: Aviva Lev-Ari, PhD, RN

What is the Human Variome Project?

Abstract

The successor to the Human Genome Project intends to establish, by international cooperation, an encyclopedic catalog of sequence variants indexed to the human genome sequence.

Introduction

Genomics is not just for rich countries any more. Anyone can contribute to the Human Variome Project (HVP; see Commentary,page 433). Indeed, the project might just be ambitious enough that everyone really will need to contribute. By stating that all human genetics and genomics contributes to a single aim, the HVP essentially reduces duplication of effort while increasing credit for participation.

However, it will have to find ways to coordinate the disparate activities of clinicians, researchers, database curators and bioinformaticians by providing the means and incentives to lodge the variants they have found in public databases. Variome aims to get all to use compatible nomenclature and phenotype reporting systems and to index variant and phenotype data to gene models in the coordinate system generated by the Human Genome Project. Automation and expert curation, and open comment and expert review, will all have a place in this endeavor. How will we do this without creating more than a necessary minimum of new databases, procedures and bureaucracy?

A very important point, but a tough one to get across, is that much of the necessary work is currently happening across the globe—but is just insufficiently coordinated. The individuals already hard at work aren’t getting the credit they deserve. In a sense, the rest of the world’s geneticists deserve the kind of service that US researchers receive from the excellent coordinating work of the National Human Genome Research Institute and the repositories of the National Center for Biotechnology Information (NCBI), together with the kind of attention afforded by international journals. If only these kinds of coordination, recording and attention could be brought to bear, however briefly, on publication units as small as single instances of a variant gene! Thus, Variome aims to add value to databases such as OMIM, GenBank, dbSNP, dbGAP and the HapMap and organizations including NCBI and the European Bioinformatics Institute (EBI) by working with them all. It will start gene by gene, evaluating variants already found and curated for mendelian diseases, and will add rare and common variants in common diseases as they are reported. As it does so, HVP participants will develop mechanisms to expedite and automate reporting of variants and their occurrence.

In the consensus-building exercise of the first Human Variome meeting (page 433), delegates constructed a wish list of recommendations that numerically exceeded the number of participants at the meeting. We think that two points emerge as particularly important to the success of the project: publication and credit.

To be successful in persuading clinical and diagnostic laboratories to contribute variations and persuading researchers to evaluate the pathogenic potential of each variant, the HVP will need to introduce publishing innovations at both ends of the citation spectrum. It will need to track the citation of each variant’s accession code in papers, database entries and across the web. This closing of the online publication loop might be termed microattribution. Perhaps existing journals could be persuaded to take responsibility for monitoring and highlighting the citation of database entries in their papers, so that the HVP can readily aggregate this information. A journal devoted to the human variome could commission peer-reviewed, gene-based synopses of mendelian mutations based on information in locus-specific databases (see pages 425 and 427), meta-analyses of association studies and resequencing data such as those reported by Jonathan Cohen and colleagues in this issue (page 513, with News and Views on page 439). Phenotypic and diagnostic information might be linked to these synopses from existing databases such as the dysmorphology databases, PharmGKB (page 426) and GeneTests (http://www.genetests.org). Genome browsers including Ensembl and UCSC might then be persuaded to display a Variome track. We envisage such synopses to be a gene-based extension of the disease-based annual synopses for association studies we proposed last year (Nat. Genet. 38, 1; 2006). The first of these, on Alzheimer disease, was published by Lars Bertram and colleagues (Nat. Genet. 39, 17–23; 2007) using their newly created AlzGene database.

Which genes should the HVP annotate first to demonstrate the utility and impact of its coordinating activities? Perhaps we can learn from one of the most impressive recent exercises in evidence-based medicine: namely, the American College of Medical Genetics‘ systematic prioritization of genes for newborn screening (http://mchb.hrsa.gov/screening/). Variome synopses would take into account the prevalence, seriousness and treatability of the clinical condition(s), the value added by combining all three types of genetic study listed above and the availability of all three kinds of evidence in existing laboratories, databases and publications.

There are, inevitably, limits to what can be achieved by a gene-based view of human variation. Gene models are revised and re-annotated, and structural genomic variation plays havoc with reference genome builds and the context within which point variants and haplotypes are found. Physicians and the general public will want a disease-based view—and the associated diagnostic genetic tests, rather than genome annotation. Delaying the appearance of such alternative views, there is often a many-to-many correspondence between genes and disease phenotypes. On the brighter side, this complexity should provide good business for database designers and review journals.

As the participants of the Variome meeting note in their Commentary, the effort to index and evaluate all of human variation will provide many new opportunities in genomics for researchers whose home countries did not participate in the initial human genome sequencing project. They are right that this is both the project and the time to achieve the globalization of genomics.

SOURCE:

Nature Genetics 39, 423 (2007)
doi:10.1038/ng0407-423

Our Vision for the Future

Imagine you are sick. For many, this is not a difficult task. Now imagine you are sick and none of your doctors know why. Your symptoms suggest that you have a rare genetic disease, and you’ve been tested for a mutation in the gene responsible, but the results are inconclusive. The laboratory found a change in your genetic sequence, but is unable to definitively state that it’s what’s causing your symptoms. And with no definitive result from the test, your doctor—and your insurance company—are unwilling to prescribe the expensive course of drugs needed to control your symptoms.While many people might be willing to dismiss the chances of this happening to them, when you start to look at the facts, things start to get a little frightening. There are over 6,000 diseases that can be caused by a mutation in a single gene and it is estimated that 1 child in every 200 born will suffer from one of these diseases. Add to that the number of cancers that have an inherited genetic component and the chances of you, or someone you know being in this position is quite high.

Now imagine that the information the laboratory and your doctor needed to make an accurate diagnosis was out there, but it wasn’t accessible to them: it was hidden away in an obscure academic paper, or in some researcher’s forgotten notes.

Unfortunately, this is the situation that is currently facing thousands of people across the globe who are suffering the devastating effects of genetic illnesses.

The role that our genes play in our health and well-being is well known. The genetic makeup of an individual can cause a host of genetic disorders that can manifest from early childhood (cystic fibrosis, Prader-Willi Syndrome, Fragile X Syndrome) to adulthood (Alzheimer’s disease, polycystic kidney disease, Huntington’s disease) as well as significantly increase the risk of contracting more common diseases such as schizophrenia, diabetes, depression and cancer.

The world is rapidly moving towards an era where it is both economically and scientifically feasible to sequence the genome of every patient presenting with a chronic condition; already in the past decade the cost of a whole-genome sequence has dropped from several billion dollars to a few thousand.

But being able to sequence the genome of a patient cheaply and easily will be useless if we are unable to determine if the variations present in a sequence have an effect on human health. We are suffering from a critical lack of information about the consequences of the vast majority of the mutations possible within the human genome. And, even more concerning, is the fact that even when that information exists, it is not being shared and captured by the global medical research community in a manner that guarantees widespread dissemination and long-term preservation.

The Human Variome Project is trying to change this. We strongly believe in the free and open sharing of information on genetic variation and its consequences and are dedicated to developing and maintaining the standards, systems and infrastructure that will embed information sharing into routine clinical practice. We envision a world where the availability of, and access to, genetic variation information is not an impediment to diagnosis and treatment; where the burden of genetic disease on the human population is significantly decreased; where never again will a doctor have to look at a genetic sequence and ask, “What does this change mean for my patient?”

The Human Variome Project is motivated by the knowledge that by working together, we will be able to significantly reduce the needless physical, psychological, emotional and economic suffering of millions of people.

SOURCE:

http://www.humanvariomeproject.org/index.php/about/our-vision-for-the-future

Human Variome Project International Limited is a not-for-profit Australian public company limited by guarantee that was founded in 2010 to provide central coordination efforts to the global Human Variome Project effort and run the International Coordinating Office. The company has no shareholders and is endorsed by the Australian Tax Office as a deductible gift recipient as a Health Project Charity.

Human Variome Project International Limited, as a company limited by guarantee, is a public unlisted company. It must file accounts annually with the Australian Securities and Investment Commission, it must be audited and, as a public company, the directors and officers of the company must comply with all the duties and responsibilities set out in the Australian Corporations Act. UNESCO also stipulates strict conditions for compliance with its functions and operation as a non-government and non-profit making organisation.

Human Variome Project International’s objects and powers include:

to promote the prevention or the control of diseases in human beings
to develop and provide educational programs, training and courses in public administration, public sector management, public policy, public affairs and any other related fields
to alleviate human suffering by collecting, organising and sharing data on genetic variation;
to further the Human Variome Project
to act as the co-ordinating office for the Human Variome Project
to attract and employ academics, researchers, practitioners and other staff as required to provide and support the services to further the objects of the Company
to provide facilities for research, study and education related to the Human Variome Project
to carry out and conduct the business of provider of administrative and consulting services;
to seek, encourage and accept gifts, grants, donations or endorsements
to affiliate with and enter into co-operative agreements with research educational institutions, government, local governments, practitioner bodies, non-government organisations, commercial, cultural and any other institutions or bodies

Company Members

Mr David Abraham
Professor Richard Cotton
Sir John Burn
Dr David Rimoin
Dr Eric Haan
Professor Jean-Jacques Cassiman
(representative of) National Institute of Gene Science and Technology Development (China)

SOURCE:
http://www.humanvariomeproject.org/index.php?option=com_content&view=article&id=164&Itemid=152

Scientific Advisory Committee

The Board of Directors is advised by the Scientific Advisory Committee in matters of strategic scientific direction for current and future projects. The Scientific Advisory Committee has a variety of {ln:roles and responsibilities}, as wells as the delegated authority of the Board of Directors on the publication of all HVP Standards and Guidelines, and the arbitration of any dispute resolution processes in the generation of HVP Standards and Guidelines.The Scientific Advisory Committee consists of twelve members including one Chair. The Scientific Advisory Committee members are elected by the two Advisory Councils every two years, with half the positions on the Committee becoming vacant every two years. The Chair of the Scientific Advisory Committee is appointed by the Coordinating Office from among the members of the Scientific Advisory Committee. Membership of the Committee, in an ex-officio capacity, is also extended to:

the Scientific Director of the Human Variome Project Coordinating Office;
the President of the Human Genome Variation Society;
the President of the International Federation of Human Genetics Societies; and
a representative from the central genetic databases, chosen from amongst themselves.

Any Individual Member of the Human Variome Project Consortium is eligible to stand for election to the Scientific Advisory Committee. Candidates must be nominated and seconded by a member of either of the Advisory Councils.

The Scientific Advisory Committee meets on a face–to–face basis once per year, usually in conjunction with the HVP Fora series. The Scientific Advisory Committee also regularly meets via telephone/video–conference.

Current Committee

Arleen Auerbach	The Rockefeller University	USA
Mireille Claustres	IURC, Institut Universitaire Clinical Research	France
Richard Cotton	Human Variome Project	Australia
Garry Cutting	Johns Hopkins School of Medicine	USA
Johan T. den Dunnen	Leiden University Medical Center	The Netherlands
Mona El Ruby	National Research Centre	Egypt
Aida Falcón de Vargas	Venezuelan Central University	Venezuela
Marc Greenblatt	University of Vermont	USA
Stephen Lam	Hong Kong Department of Health	Hong Kong
Finlay Macrae	The Royal Melbourne Hospital	Australia
Yoichi Matsubara	Tohoku University School of Medicine	Japan
Gert-Jan B. van Ommen	Leiden University Medical Center	The Netherlands
Mauno Vihinen	Lund University	Sweden
Non-Voting Members
Professor Sir John Burn	National Institute of Health Research	UK
Ming Qi	Zhejiang University Medical School and James Watson Institute of Genome Sciences	China
Richard Gibbs	Baylor College of Medicine	USA

Document Repository

Documents (minutes, etc.) relating to the International Scientific Adviosry Committee can be found here.

SOURCE:

http://www.humanvariomeproject.org/index.php/about/scientific-advisory-committee

Nature Genetics Journal

November 2012, Volume 44 No11 pp1171-1285

Credit for clinical trial data –p1171

doi:10.1038/ng.2464

Full Text- Credit for clinical trial data | PDF (85 KB)- Credit for clinical trial data

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News and Views

Tracking the evolution of cancer methylomes –pp1173 – 1174

Arnaud R Krebs & Dirk Schübeler

doi:10.1038/ng.2451

Cellular transformation in cancer has long been associated with aberrant DNA methylation, most notably, hypermethylation of promoter sequences. A new study uses a clever approach of selective high-resolution profiling to follow DNA methylation over a time course of cellular transformation and challenges the notion that hypermethylation in cancer arises in an orchestrated fashion.

Full Text- Tracking the evolution of cancer methylomes | PDF (2,267 KB)- Tracking the evolution of cancer methylomes

Older males beget more mutations –pp1174 – 1176

Matthew Hurles

doi:10.1038/ng.2448

Three papers characterizing human germline mutation rates bolster evidence for a relatively low rate of base substitution in modern humans and highlight a central role for paternal age in determining rates of mutation. These studies represent the advent of a transformation in our understanding of mutation rates and processes, which may ultimately have public health implications.

Full Text- Older males beget more mutations | PDF (2,319 KB)- Older males beget more mutations

FOXA1 and breast cancer risk –pp1176 – 1177

Kerstin B Meyer & Jason S Carroll

doi:10.1038/ng.2449

Many SNPs associated with human disease are located in non-coding regions of the genome. A new study shows that SNPs associated with breast cancer risk are located in enhancer regions and alter binding affinity for the pioneer factor FOXA1.

Full Text- FOXA1 and breast cancer risk | PDF (254 KB)- FOXA1 and breast cancer risk

Brief Communications

Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis –pp1179 – 1181

Lambert Busque, Jay P Patel, Maria E Figueroa, Aparna Vasanthakumar, Sylvie Provost, Zineb Hamilou, Luigina Mollica, Juan Li, Agnes Viale, Adriana Heguy, Maryam Hassimi, Nicholas Socci, Parva K Bhatt, Mithat Gonen, Christopher E Mason, Ari Melnick, Lucy A Godley, Cameron W Brennan, Omar Abdel-Wahab & Ross L Levine

doi:10.1038/ng.2413

Ross Levine, Lambert Busque and colleagues report the identification of recurrent somatic mutations in TET2 in elderly female individuals with clonal hematopoiesis. The mutations were identified in individuals without clinically apparent hematological malignancies.

Abstract- Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis | Full Text- Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis | PDF (324 KB)- Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis | Supplementary information

Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk –pp1182 – 1184

Nick Orr, Alina Lemnrau, Rosie Cooke, Olivia Fletcher, Katarzyna Tomczyk, Michael Jones, Nichola Johnson, Christopher J Lord, Costas Mitsopoulos, Marketa Zvelebil, Simon S McDade, Gemma Buck, Christine Blancher, KConFab Consortium, Alison H Trainer, Paul A James, Stig E Bojesen, Susanne Bokmand, Heli Nevanlinna, Johanna Mattson, Eitan Friedman, Yael Laitman, Domenico Palli, Giovanna Masala, Ines Zanna, Laura Ottini, Giuseppe Giannini, Antoinette Hollestelle, Ans M W van den Ouweland, Srdjan Novaković, Mateja Krajc, Manuela Gago-Dominguez, Jose Esteban Castelao, Håkan Olsson, Ingrid Hedenfalk, Douglas F Easton, Paul D P Pharoah, Alison M Dunning, D Timothy Bishop, Susan L Neuhausen, Linda Steele, Richard S Houlston, Montserrat Garcia-Closas, Alan Ashworth & Anthony J Swerdlow

doi:10.1038/ng.2417

Nick Orr and colleagues report a genome-wide association study for male breast cancer. They identify a new susceptibility locus atRAD51B and examine association evidence for known female breast cancer loci in these cohorts.

Abstract- Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk | Full Text- Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk | PDF (301 KB)- Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk | Supplementary information

A common single-nucleotide variant in T is strongly associated with chordoma –pp1185 – 1187

Nischalan Pillay, Vincent Plagnol, Patrick S Tarpey, Samira B Lobo, Nadège Presneau, Karoly Szuhai, Dina Halai, Fitim Berisha, Stephen R Cannon, Simon Mead, Dalia Kasperaviciute, Jutta Palmen, Philippa J Talmud, Lars-Gunnar Kindblom, M Fernanda Amary, Roberto Tirabosco & Adrienne M Flanagan

doi:10.1038/ng.2419

Adrienne Flanagan and colleagues identify a common variant in the T gene associated with strong risk of chordoma, a rare malignant bone tumor. The risk variant alters an amino acid in the DNA-binding domain of the T transcription factor and is associated with differential expression of T and its downstream targets.

Abstract- A common single-nucleotide variant in T is strongly associated with chordoma | Full Text- A common single-nucleotide variant in T is strongly associated with chordoma | PDF (317 KB)- A common single-nucleotide variant in T is strongly associated with chordoma | Supplementary information

Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy –pp1188 – 1190

Sarah E Heron, Katherine R Smith, Melanie Bahlo, Lino Nobili, Esther Kahana, Laura Licchetta, Karen L Oliver, Aziz Mazarib, Zaid Afawi, Amos Korczyn, Giuseppe Plazzi, Steven Petrou, Samuel F Berkovic, Ingrid E Scheffer & Leanne M Dibbens

doi:10.1038/ng.2440

Samuel Berkovic and colleagues report the identification of missense mutations in KCNT1, which encodes a sodium-gated potassium channel, that cause severe autosomal dominant nocturnal frontal lobe epilepsy.

Abstract- Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy | Full Text- Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy | PDF (294 KB)- Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy | Supplementary information

Articles

Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression –pp1191 – 1198

Richard Cowper-Sal·lari, Xiaoyang Zhang, Jason B Wright, Swneke D Bailey, Michael D Cole, Jerome Eeckhoute, Jason H Moore & Mathieu Lupien

doi:10.1038/ng.2416

Mathieu Lupien, Jason Moore and colleagues show that breast cancer risk–associated SNPs commonly disrupt the binding of FOXA1 to chromatin, thereby directly affecting gene expression.

Abstract- Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression | Full Text- Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression | PDF (1,353 KB)- Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression | Supplementary information

LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression –pp1199 – 1206

Jan J Molenaar, Raquel Domingo-Fernández, Marli E Ebus, Sven Lindner, Jan Koster, Ksenija Drabek, Pieter Mestdagh, Peter van Sluis, Linda J Valentijn, Johan van Nes, Marloes Broekmans, Franciska Haneveld, Richard Volckmann, Isabella Bray, Lukas Heukamp, Annika Sprüssel, Theresa Thor, Kristina Kieckbusch, Ludger Klein-Hitpass, Matthias Fischer, Jo Vandesompele, Alexander Schramm, Max M van Noesel, Luigi Varesio, Frank Speleman, Angelika Eggert, Raymond L Stallings, Huib N Caron, Rogier Versteeg & Johannes H Schulte

doi:10.1038/ng.2436

Jan Molenaar and colleagues show that LIN28B is overexpressed and amplified in human neuroblastomas and that LIN28B regulates let-7 family miRNAs and MYCN. They create a transgenic mouse model of LIN28B overexpression and show that these mice develop neuroblastoma tumors.

Abstract- LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression | Full Text- LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression | PDF (1,453 KB)- LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression | Supplementary information

Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues –pp1207 – 1214

Gilad Landan, Netta Mendelson Cohen, Zohar Mukamel, Amir Bar, Alina Molchadsky, Ran Brosh, Shirley Horn-Saban, Daniela Amann Zalcenstein, Naomi Goldfinger, Adi Zundelevich, Einav Nili Gal-Yam, Varda Rotter & Amos Tanay

doi:10.1038/ng.2442

Amos Tanay and colleagues characterize DNA methylation polymorphism within cell populations and track immortalized fibroblasts in culture for over 300 generations to show that formation of differentially methylated regions occurs through a stochastic process and nearly deterministic epigenetic remodeling.

Abstract- Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues | Full Text- Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues | PDF (1,518 KB)- Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues | Supplementary information

Intracontinental spread of human invasive SalmonellaTyphimurium pathovariants in sub-Saharan Africa-pp1215 – 1221

Chinyere K Okoro, Robert A Kingsley, Thomas R Connor, Simon R Harris, Christopher M Parry, Manar N Al-Mashhadani, Samuel Kariuki, Chisomo L Msefula, Melita A Gordon, Elizabeth de Pinna, John Wain, Robert S Heyderman, Stephen Obaro, Pedro L Alonso, Inacio Mandomando, Calman A MacLennan, Milagritos D Tapia, Myron M Levine, Sharon M Tennant, Julian Parkhill & Gordon Dougan

doi:10.1038/ng.2423

Gordon Dougan and colleagues report whole-genome sequencing of a global collection of 179 Salmonella Typhimurium isolates, including 129 diverse sub-Saharan African isolates associated with invasive disease. They determine the phylogenetic structure of invasive Salmonella Typhimurium in sub-Saharan Africa and find that the majority are from two closely related highly conserved lineages, which emerged in the last 60 years in close temporal association with the current HIV epidemic.

Abstract- Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa | Full Text- Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa | PDF (1,126 KB)- Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa | Supplementary information

Letters

Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population –pp1222 – 1226

Tomomitsu Hirota, Atsushi Takahashi, Michiaki Kubo, Tatsuhiko Tsunoda, Kaori Tomita, Masafumi Sakashita, Takechiyo Yamada, Shigeharu Fujieda, Shota Tanaka, Satoru Doi, Akihiko Miyatake, Tadao Enomoto, Chiharu Nishiyama, Nobuhiro Nakano, Keiko Maeda, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, Emiko Noguchi, Tohru Sakamoto, Nobuyuki Hizawa, Koji Ebe, Hidehisa Saeki, Takashi Sasaki, Tamotsu Ebihara, Masayuki Amagai, Satoshi Takeuchi, Masutaka Furue, Yusuke Nakamura & Mayumi Tamari

doi:10.1038/ng.2438

Mayumi Tamari and colleagues report a genome-wide association study for atopic dermatitis, a chronic inflammatory skin disease, in a Japanese population. They identify eight new susceptibility loci for atopic dermatitis and compare their results to those of previous studies in European and Chinese populations.

First Paragraph- Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population | Full Text- Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population | PDF (999 KB)- Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population | Supplementary information

CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation –pp1227 – 1230

Nataly Manjarrez-Orduño, Emiliano Marasco, Sharon A Chung, Matthew S Katz, Jenna F Kiridly, Kim R Simpfendorfer, Jan Freudenberg, David H Ballard, Emil Nashi, Thomas J Hopkins, Deborah S Cunninghame Graham, Annette T Lee, Marieke J H Coenen, Barbara Franke, Dorine W Swinkels, Robert R Graham, Robert P Kimberly, Patrick M Gaffney, Timothy J Vyse, Timothy W Behrens, Lindsey A Criswell, Betty Diamond & Peter K Gregersen

doi:10.1038/ng.2439

Peter Gregersen and colleagues identify a regulatory variant inCSK, coding for an intracellular kinase that physically interacts with Lyp (PTPN22), associated with systemic lupus erythematosus (SLE). Their work suggests that the Lyp-Csk complex influences susceptibility to SLE through regulation of B-cell signaling, maturation and activation.

First Paragraph- CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation | Full Text- CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation | PDF (747 KB)- CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation | Supplementary information

Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 –pp1231 – 1235

Jianfeng Xu, Zengnan Mo, Dingwei Ye, Meilin Wang, Fang Liu, Guangfu Jin, Chuanliang Xu, Xiang Wang, Qiang Shao, Zhiwen Chen, Zhihua Tao, Jun Qi, Fangjian Zhou, Zhong Wang, Yaowen Fu, Dalin He, Qiang Wei, Jianming Guo, Denglong Wu, Xin Gao, Jianlin Yuan, Gongxian Wang, Yong Xu, Guozeng Wang, Haijun Yao, Pei Dong, Yang Jiao, Mo Shen, Jin Yang, Jun Ou-Yang, Haowen Jiang, Yao Zhu, Shancheng Ren, Zhengdong Zhang, Changjun Yin, Xu Gao, Bo Dai, Zhibin Hu, Yajun Yang, Qijun Wu, Hongyan Chen, Peng Peng, Ying Zheng, Xiaodong Zheng, Yongbing Xiang, Jirong Long, Jian Gong, Rong Na, Xiaoling Lin, Hongjie Yu, Zhong Wang, Sha Tao, Junjie Feng, Jishan Sun, Wennuan Liu, Ann Hsing, Jianyu Rao, Qiang Ding, Fredirik Wiklund, Henrik Gronberg, Xiao-Ou Shu, Wei Zheng, Hongbing Shen, Li Jin, Rong Shi, Daru Lu, Xuejun Zhang, Jielin Sun, S Lilly Zheng & Yinghao Sun

doi:10.1038/ng.2424

Yinghao Sun and colleagues report a genome-wide association study for prostate cancer in Han Chinese men. They identify two new risk-associated loci at chromosomes 9q31 and 19q13.

First Paragraph- Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 | Full Text- Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 | PDF (686 KB)- Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 | Supplementary information

Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia-pp1236 – 1242

Marta Kulis, Simon Heath, Marina Bibikova, Ana C Queirós, Alba Navarro, Guillem Clot, Alejandra Martínez-Trillos, Giancarlo Castellano, Isabelle Brun-Heath, Magda Pinyol, Sergio Barberán-Soler, Panagiotis Papasaikas, Pedro Jares, Sílvia Beà, Daniel Rico, Simone Ecker, Miriam Rubio, Romina Royo, Vincent Ho, Brandy Klotzle, Lluis Hernández, Laura Conde, Mónica López-Guerra, Dolors Colomer, Neus Villamor, Marta Aymerich, María Rozman, Mónica Bayes, Marta Gut, Josep L Gelpí, Modesto Orozco, Jian-Bing Fan, Víctor Quesada, Xose S Puente, David G Pisano, Alfonso Valencia, Armando López-Guillermo, Ivo Gut, Carlos López-Otín, Elías Campo & José I Martín-Subero

doi:10.1038/ng.2443

José Martin-Subero and colleagues report whole-genome bisulfite sequencing and methylome analysis of two CLLs and three B-cell subpopulations using high-density microarrays on 139 CLLs. They identify widespread hypomethylation in the gene body that is largely associated with intragenic enhancer elements.

First Paragraph- Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia | Full Text- Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia | PDF (2,067 KB)- Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia | Supplementary information

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature –pp1243 – 1248

Gillian I Rice, Paul R Kasher, Gabriella M A Forte, Niamh M Mannion, Sam M Greenwood, Marcin Szynkiewicz, Jonathan E Dickerson, Sanjeev S Bhaskar, Massimiliano Zampini, Tracy A Briggs, Emma M Jenkinson, Carlos A Bacino, Roberta Battini, Enrico Bertini, Paul A Brogan, Louise A Brueton, Marialuisa Carpanelli, Corinne De Laet, Pascale de Lonlay, Mireia del Toro, Isabelle Desguerre, Elisa Fazzi, Àngels Garcia-Cazorla, Arvid Heiberg, Masakazu Kawaguchi, Ram Kumar, Jean-Pierre S-M Lin, Charles M Lourenco, Alison M Male, Wilson Marques Jr, Cyril Mignot, Ivana Olivieri, Simona Orcesi, Prab Prabhakar, Magnhild Rasmussen, Robert A Robinson, Flore Rozenberg, Johanna L Schmidt, Katharina Steindl, Tiong Y Tan, William G van der Merwe, Adeline Vanderver, Grace Vassallo, Emma L Wakeling, Evangeline Wassmer, Elizabeth Whittaker, John H Livingston, Pierre Lebon, Tamio Suzuki, Paul J McLaughlin, Liam P Keegan, Mary A O’Connell, Simon C Lovell & Yanick J Crow

doi:10.1038/ng.2414

Yanick Crow and colleagues show that mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutières syndrome, accompanied by upregulation of interferon-stimulated genes.ADAR1 encodes an enzyme that catalyzes the deamination of adeonosine to inosine in double-stranded RNA, and the findings suggest a possible role for RNA editing in limiting the accumulation of repeat-derived RNA species.

First Paragraph- Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature | Full Text- Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature | PDF (844 KB)- Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature | Supplementary information

Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm-pp1249 – 1254

Alexander J Doyle, Jefferson J Doyle, Seneca L Bessling, Samantha Maragh, Mark E Lindsay, Dorien Schepers, Elisabeth Gillis, Geert Mortier, Tessa Homfray, Kimberly Sauls, Russell A Norris, Nicholas D Huso, Dan Leahy, David W Mohr, Mark J Caulfield, Alan F Scott, Anne Destrée, Raoul C Hennekam, Pamela H Arn, Cynthia J Curry, Lut Van Laer, Andrew S McCallion, Bart L Loeys & Harry C Dietz

doi:10.1038/ng.2421

Harry Dietz and colleagues report the identification of mutations in SKI in Shprintzen-Goldberg syndrome, which shares features with Marfan syndrome and Loeys-Dietz syndrome. SKI encodes a known repressor of TGF-β activity, and this work provides evidence for paradoxical increased TGF-β signaling as the mechanism underlying these related syndromes.

First Paragraph- Mutations in the TGF-[beta] repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm | Full Text- Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm | PDF (1,158 KB)- Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm | Supplementary information

De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy-pp1255 – 1259

Giulia Barcia, Matthew R Fleming, Aline Deligniere, Valeswara-Rao Gazula, Maile R Brown, Maeva Langouet, Haijun Chen, Jack Kronengold, Avinash Abhyankar, Roberta Cilio, Patrick Nitschke, Anna Kaminska, Nathalie Boddaert, Jean-Laurent Casanova, Isabelle Desguerre, Arnold Munnich, Olivier Dulac, Leonard K Kaczmarek, Laurence Colleaux & Rima Nabbout

doi:10.1038/ng.2441

Rima Nabbout and colleagues report the identification of de novomutations in the KCNT1 potassium channel gene in individuals with malignant migrating partial seizures of infancy, a rare epileptic encephalopathy with pharmacoresistant seizures and developmental delay. The authors show that the mutations have a gain-of-function effect on KCNT1 channel activity.

First Paragraph- De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy | Full Text- De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy | PDF (745 KB)- De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy | Supplementary information

CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development –pp1260 – 1264

Ganeshwaran H Mochida, Vijay S Ganesh, Maria I de Michelena, Hugo Dias, Kutay D Atabay, Katie L Kathrein, Hsuan-Ting Huang, R Sean Hill, Jillian M Felie, Daniel Rakiec, Danielle Gleason, Anthony D Hill, Athar N Malik, Brenda J Barry, Jennifer N Partlow, Wen-Hann Tan, Laurie J Glader, A James Barkovich, William B Dobyns, Leonard I Zon & Christopher A Walsh

doi:10.1038/ng.2425

Christopher Walsh and colleagues identify mutations in CHMP1Ain human cerebellar hypoplasia and microcephaly. Cells lackingCHMP1A show decreased cell proliferation and decreased expression of BMI1, a negative regulator of stem cell proliferation.

First Paragraph- CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development | Full Text- CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development | PDF (1,449 KB)- CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development | Supplementary information

Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48 –pp1265 – 1271

Saima Riazuddin, Inna A Belyantseva, Arnaud P J Giese, Kwanghyuk Lee, Artur A Indzhykulian, Sri Pratima Nandamuri, Rizwan Yousaf, Ghanshyam P Sinha, Sue Lee, David Terrell, Rashmi S Hegde, Rana A Ali, Saima Anwar, Paula B Andrade-Elizondo, Asli Sirmaci, Leslie V Parise, Sulman Basit, Abdul Wali, Muhammad Ayub, Muhammad Ansar, Wasim Ahmad, Shaheen N Khan, Javed Akram, Mustafa Tekin, Sheikh Riazuddin, Tiffany Cook, Elke K Buschbeck, Gregory I Frolenkov, Suzanne M Leal, Thomas B Friedman & Zubair M Ahmed

doi:10.1038/ng.2426

Zubair Ahmed and colleagues identify homozygous mutations inCIB2, a gene that encodes a calcium- and integrin-binding protein, that cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. CIB2 is required for hair cell development and retinal photoreceptor cells in zebrafish and Drosophila melanogaster.

First Paragraph- Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48 | Full Text- Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48 | PDF (1,380 KB)- Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48 | Supplementary information

Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma –pp1272 – 1276

Elizabeth Pohler, Ons Mamai, Jennifer Hirst, Mozheh Zamiri, Helen Horn, Toshifumi Nomura, Alan D Irvine, Benvon Moran, Neil J Wilson, Frances J D Smith, Christabelle S M Goh, Aileen Sandilands, Christian Cole, Geoffrey J Barton, Alan T Evans, Hiroshi Shimizu, Masashi Akiyama, Mitsuhiro Suehiro, Izumi Konohana, Mohammad Shboul, Sebastien Teissier, Lobna Boussofara, Mohamed Denguezli, Ali Saad, Moez Gribaa, Patricia J Dopping-Hepenstal, John A McGrath, Sara J Brown, David R Goudie, Bruno Reversade, Colin S Munro & W H Irwin McLean

doi:10.1038/ng.2444

Irwin McLean and colleagues report that heterozygous loss-of-function mutations in AAGAB, which encodes a cytosolic protein implicated in vesicular trafficking, cause punctate palmoplantar keratoderma. They further show that knockdown of AAGAB in keratinocytes leads to increased cell proliferation accompanied by highly elevated levels of epidermal growth factor receptor.

First Paragraph- Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma | Full Text- Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma | PDF (848 KB)- Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma | Supplementary information

Estimating the human mutation rate using autozygosity in a founder population –pp1277 – 1281

Catarina D Campbell, Jessica X Chong, Maika Malig, Arthur Ko, Beth L Dumont, Lide Han, Laura Vives, Brian J O’Roak, Peter H Sudmant, Jay Shendure, Mark Abney, Carole Ober & Evan E Eichler

doi:10.1038/ng.2418

Evan Eichler and colleagues report an estimate of the mutation rate in humans that is based on the whole-genome sequences of five parent-offspring trios from a Hutterite population and genotyping data from an extended pedigree. They use a new approach for estimating the mutation rate over multiple generations that takes into account the extensive autozygosity in this founder population.

First Paragraph- Estimating the human mutation rate using autozygosity in a founder population | Full Text- Estimating the human mutation rate using autozygosity in a founder population | PDF (620 KB)- Estimating the human mutation rate using autozygosity in a founder population | Supplementary information

Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission –pp1282 – 1285

Christoph Freyer, Lynsey M Cree, Arnaud Mourier, James B Stewart, Camilla Koolmeister, Dusanka Milenkovic, Timothy Wai, Vasileios I Floros, Erik Hagström, Emmanouella E Chatzidaki, Rudolf J Wiesner, David C Samuels, Nils-Göran Larsson & Patrick F Chinnery

doi:10.1038/ng.2427

Patrick Chinnery, Nils-Goran Larsson and colleagues show that mitochondrial heteroplasmy levels are principally determined prenatally within the developing female germline in mice transmitting a heteroplasmic single base-pair deletion in the mitochondrial tRNA^Met gene.

First Paragraph- Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission | Full Text- Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission | PDF (523 KB)- Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission | Supplementary information