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Bioinformatics Tool Review: Genome Variant Analysis Tools

Posted in Big Data, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Cancer Informatics, Clinical Genomics, Computational Biology/Systems and Bioinformatics, Genome Biology, Personalized and Precision Medicine & Genomic Research, Uncategorized, tagged , , , , , , , , , , , , , on October 23, 2018| Leave a Comment »

Bioinformatics Tool Review: Genome Variant Analysis Tools, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Bioinformatics Tool Review: Genome Variant Analysis Tools

Curator: Stephen J. Williams, Ph.D.

Updated 02/07/2021

Updated 11/15/2018

The following post will be an ongoing curation of reviews of gene variant bioinformatic software.

The Ensembl Variant Effect Predictor.

McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F.

Genome Biol. 2016 Jun 6;17(1):122. doi: 10.1186/s13059-016-0974-4.

Author information

1

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK. wm2@ebi.ac.uk.

2

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.

3

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK. fiona@ebi.ac.uk.

Abstract

The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.

Rare diseases can be difficult to diagnose due to low incidence and incomplete penetrance of implicated alleles however variant analysis of whole genome sequencing can identify underlying genetic events responsible for the disease (Nature, 2015).  However, a large cohort is required for many WGS association studies in order to produce enough statistical power for interpretation (see post and here).  To this effect major sequencing projects have been initiated worldwide including:

A more thorough curation of sequencing projects can be seen in the following post:

Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

And although sequencing costs have dramatically been reduced over the years, the costs to determine the functional consequences of such variants remains high, as thorough basic research studies must be conducted to validate the interpretation of variant data with respect to the underlying disease, as only a small fraction of variants from a genome sequencing project will encode for a functional protein.  Correct annotation of sequences and variants, identification of correct corresponding reference genes or transcripts in GENCODE or RefSeq respectively offer compelling challenges to the proper identification of sequenced variants as potential functional variants.

To this effect, the authors developed the Ensembl Variant Effect Predictor (VEP), which is a software suite that performs annotations and analysis of most types of genomic variation in coding and non-coding regions of the genome.

Summary of Features

  • Annotation: VEP can annotate two broad categories of genomic variants
    • Sequence variants with specific and defined changes: indels, base substitutions, SNVs, tandem repeats
    • Larger structural variants > 50 nucleotides
  • Species and assembly/genomic database support: VEP can analyze data from any species with assembled genome sequence and annotated gene set. VEP supports chromosome assemblies such as the latest GRCh38, FASTA, as well as transcripts from RefSeq as well as user-derived sequences
  • Transcript Annotation: VEP includes a wide variety of gene and transcript related information including NCBI Gene ID, Gene Symbol, Transcript ID, NCBI RefSeq ID, exon/intron information, and cross reference to other databases such as UniProt
  • Protein Annotation: Protein-related fields include Protein ID, RefSeq ID, SwissProt, UniParc ID, reference codons and amino acids, SIFT pathogenicity score, protein domains
  • Noncoding Annotation: VEP reports variants in noncoding regions including genomic regulatory regions, intronic regions, transcription binding motifs. Data from ENCODE, BLUEPRINT, and NIH Epigenetics RoadMap are used for primary annotation.  Plugins to the Perl coding are also available to link other databases which annotate noncoding sequence features.
  • Frequency, phenotype, and citation annotation: VEP searches Ensembl databases containing a large amount of germline variant information and checks variants against the dbSNP single nucleotide polymorphism database. VEP integrates with mutational databases such as COSMIC, the Human Gene Mutation Database, and structural and copy number variants from Database of Genomic Variants.  Allele Frequencies are reported from 1000 Genomes and NHLBI and integrates with PubMed for literature annotation.  Phenotype information is from OMIM, Orphanet, GWAS and clinical information of variants from ClinVar.
  • Flexible Input and Output Formats: VEP supports input data format called “variant call format” or VCP, a standard in next-gen sequencing. VEP has the ability to process variant identifiers from other database formats.  Output formats are tab deliminated and give the user choices in presentation of results (HTML or text based)
  • Choice of user interface
    • Online tool (VEP Web): simple point and click; incorporates Instant VEP Functionality and copy and paste features. Results can be stored online in cloud storage on Ensembl.
    • VEP script: VEP is available as a downloadable PERL script (see below for link) and can process large amounts of data rapidly. This interface is powerfully flexible with the ability to integrate multiple plugins available from Ensembl and GitHub.  The ability to alter the PERL code and add plugins and code functions allows the flexibility to modify any feature of VEP.
    • VEP REST API: provides robust computational access to any programming language and returns basic variant annotation. Can make use of external plugins.

 

Watch Video on VES Instructional Webinar: https://youtu.be/7Fs7MHfXjWk

Watch Video on VES Web Version training on How to Analyze Your Sequence in VEP

Availability of data and materials

The dataset supporting the conclusions of this article is available from Illumina’s Platinum Genomes [93] and using the Ensembl release 75 gene set. Pre-built data sets are available for all Ensembl and Ensembl Genomes species [94]. They can also be downloaded automatically during set up whilst installing the VEP.

References

Large-scale discovery of novel genetic causes of developmental disorders.

Deciphering Developmental Disorders Study.

Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. PMID:25533962

Updated 11/15/2018

Research Points to Caution in Use of Variant Effect Prediction Bioinformatic Tools

Although we have the ability to use high throughput sequencing to identify allelic variants occurring in rare disease, correlation of these variants with the underlying disease is often difficult due to a few concerns:

  • For rare sporadic diseases, classical gene/variant association studies have proven difficult to perform (Meyts et al. 2016)
  • As Whole Exome Sequencing (WES) returns a considerable number of variants, how to differentiate the normal allelic variation found in the human population from disease-causing pathogenic alleles
  • For rare diseases, pathogenic allele frequencies are generally low

Therefore, for these rare pathogenic alleles, the use of bioinformatics tools in order to predict the resulting changes in gene function may provide insight into disease etiology when validation of these allelic changes might be experimentally difficult.

In a 2017 Genes & Immunity paper, Line Lykke Andersen and Rune Hartmann tested the reliability of various bioinformatic software to predict the functional consequence of variants of six different genes involved in interferon induction and sixteen allelic variants of the IFNLR1 gene.  These variants were found in cohorts of patients presenting with herpes simplex encephalitis (HSE). Most of the adult population is seropositive for Herpes Simplex Virus (HSV) however a minor fraction (1 in 250,000 individuals per year) of HSV infected individuals will develop HSE (Hjalmarsson et al., 2007).  It has been suggested that HSE occurs in individuals with rare primary immunodeficiencies caused by gene defects affecting innate immunity through reduced production of interferons (IFN) (Zhang et al., Lim et al.).

References

Meyts I, Bosch B, Bolze A, Boisson B, Itan Y, Belkadi A, et al. Exome and genome sequencing for inborn errors of immunity. J Allergy Clin Immunol. 2016;138:957–69.

Hjalmarsson A, Blomqvist P, Skoldenberg B. Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality. Clin Infect Dis. 2007;45:875–80.

Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522–7.

Lim HK, Seppanen M, Hautala T, Ciancanelli MJ, Itan Y, Lafaille FG, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83:1888–97.

Genes Immun. 2017 Dec 4. doi: 10.1038/s41435-017-0002-z.

Frequently used bioinformatics tools overestimate the damaging effect of allelic variants.

Andersen LL1, Terczyńska-Dyla E1, Mørk N2, Scavenius C1, Enghild JJ1, Höning K3, Hornung V3,4, Christiansen M5,6, Mogensen TH2,6, Hartmann R7.

Abstract

We selected two sets of naturally occurring human missense allelic variants within innate immune genes. The first set represented eleven non-synonymous variants in six different genes involved in interferon (IFN) induction, present in a cohort of patients suffering from herpes simplex encephalitis (HSE) and the second set represented sixteen allelic variants of the IFNLR1 gene. We recreated the variants in vitro and tested their effect on protein function in a HEK293T cell based assay. We then used an array of 14 available bioinformatics tools to predict the effect of these variants upon protein function. To our surprise two of the most commonly used tools, CADD and SIFT, produced a high rate of false positives, whereas SNPs&GO exhibited the lowest rate of false positives in our test. As the problem in our test in general was false positive variants, inclusion of mutation significance cutoff (MSC) did not improve accuracy.

Methodology

  1. Identification of rare variants
  2. Genomes of nineteen Dutch patients with a history of HSE sequenced by WES and identification of novel HSE causing variants determined by filtering the single nucleotide polymorphisms (SNPs) that had a frequency below 1% in the NHBLI Exome Sequencing Project Exome Variant Server and the 1000 Genomes Project and were present within 204 genes involved in the immune response to HSV.
  3. Identified variants (204) manually evaluated for involvement of IFN induction based on IDBase and KEGG pathway database analysis.
  4. In-silico predictions: Variants classified by the in silico variant pathogenicity prediction programs: SIFT, Mutation Assessor, FATHMM, PROVEAN, SNAP2, PolyPhen2, PhD-SNP, SNP&GO, FATHMM-MKL, MutationTaster2, PredictSNP, Condel, MetaSNP, and CADD. Each program returned prediction scores measuring likelihood of a variant either being ‘deleterious’ or ‘neutral’. Prediction accuracy measured as

ACC = (true positive+true negative)/(true positive+true negative+false positive+false negative)

  1. Validation of prediction software/tools

In order to validate the predictive value of the software, HEK293T cells, deficient in IRF3, MAVS, and IKKe/TBK1, were cotransfected with the nine variants of the aforementioned genes and a luciferase reporter under control of the IFN-b promoter and luciferase activity measured as an indicator of IFN signaling function.  Western blot was performed to confirm the expression of the constructs.

Results

Table 2 Summary of the
bioinformatic predictions		 HSE variants IFNLR1 variants Overall ACC
TN TP FN FP Total ACC TN TP FN FP Total ACC
Uniform cutoff
SIFT 4 1 0 4 9 0.56 8 1 0 7 16 0.56 0.56
Mutation assessor 6 1 0 2 9 0.78 9 1 0 6 16 0.63 0.68
FATHMM 7 1 0 1 9 0.89 0.89
PROVEAN 8 1 0 0 9 1.00 11 1 0 4 16 0.75 0.84
SNAP2 5 1 0 3 9 0.67 8 0 1 7 16 0.50 0.56
PolyPhen2 6 1 0 2 9 0.78 12 1 0 3 16 0.81 0.80
PhD-SNP 7 1 0 1 9 0.89 11 1 0 4 16 0.75 0.80
SNPs&GO 8 1 0 0 9 1.00 14 1 0 1 16 0.94 0.96
FATHMM MKL 4 1 0 4 9 0.56 13 0 1 2 16 0.81 0.72
MutationTaster2 4 0 1 4 9 0.44 14 0 1 1 16 0.88 0.72
PredictSNP 6 1 0 2 9 0.78 11 1 0 4 16 0.75 0.76
Condel 6 1 0 2 9 0.78 0.78
Meta-SNP 8 1 0 0 9 1.00 11 1 0 4 16 0.75 0.84
CADD 2 1 0 6 9 0.33 8 0 1 7 16 0.50 0.44
MSC 95% cutoff
SIFT 5 1 0 3 9 0.67 8 1 0 8 16 0.50 0.56
PolyPhen2 6 1 0 2 9 0.78 13 1 0 3 16 0.81 0.80
CADD 4 1 0 4 9 0.56 7 0 1 9 16 0.44 0.48

Note: TN: true negative, TP: true positive, FN: false negative, FP: false positive, ACC: accuracy

Functional testing (data obtained from reporter construct experiments) were considered as the correct outcome.

Three prediction tools (PROVEAN, SNP&GO, and MetaSNP correctly predicted the effect of all nine variants tested.

Updated 02/07/2021

InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution
Jun-Ichi Takeda , Kentaro Nanatsue , Ryosuke Yamagishi , Mikako Ito , Nobuhiko Haga 2, Hiromi Hirata , Tomoo Ogi , Kinji Ohno in NAR Genomics and  Bioinformatics. 2020 May 26;2(2):lqaa038.doi: 10.1093/nargab/lqaa038. eCollection 2020 Jun.

Abstract

In predicting the pathogenicity of a nonsynonymous single-nucleotide variant (nsSNV), a radical change in amino acid properties is prone to be classified as being pathogenic. However, not all such nsSNVs are associated with human diseases. We generated random forest (RF) models individually for each amino acid substitution to differentiate pathogenic nsSNVs in the Human Gene Mutation Database and common nsSNVs in dbSNP. We named a set of our models ‘Individual Meta RF’ (InMeRF). Ten-fold cross-validation of InMeRF showed that the areas under the curves (AUCs) of receiver operating characteristic (ROC) and precision-recall curves were on average 0.941 and 0.957, respectively. To compare InMeRF with seven other tools, the eight tools were generated using the same training dataset, and were compared using the same three testing datasets. ROC-AUCs of InMeRF were ranked first in the eight tools. We applied InMeRF to 155 pathogenic and 125 common nsSNVs in seven major genes causing congenital myasthenic syndromes, as well as in VANGL1 causing spina bifida, and found that the sensitivity and specificity of InMeRF were 0.942 and 0.848, respectively. We made the InMeRF web service, and also made genome-wide InMeRF scores available online (https://www.med.nagoya-u.ac.jp/neurogenetics/InMeRF/).

Source: https://pubmed.ncbi.nlm.nih.gov/33543123/

ADDRESS: A database of disease-associated human variants incorporating protein structure and folding stabilities
Jaie Woodard , Chengxin Zhang , Yang Zhang in J Mol Biol. 2021 Feb 1;166840. doi: 10.1016/j.jmb.2021.166840.

Abstract

Numerous human diseases are caused by mutations in genomic sequences. Since amino acid changes affect protein function through mechanisms often predictable from protein structure, the integration of structural and sequence data enables us to estimate with greater accuracy whether and how a given mutation will lead to disease. Publicly available annotated databases enable hypothesis assessment and benchmarking of prediction tools. However, the results are often presented as summary statistics or black box predictors, without providing full descriptive information. We developed a new semi-manually curated human variant database presenting information on the protein contact-map, sequence-to-structure mapping, amino acid identity change, and stability prediction for the popular UniProt database. We found that the profiles of pathogenic and benign missense polymorphisms can be effectively deduced using decision trees and comparative analyses based on the presented dataset. The database is made publicly available through https://zhanglab.ccmb.med.umich.edu/ADDRESS.

Source: https://pubmed.ncbi.nlm.nih.gov/33539887/

PopDel identifies medium-size deletions simultaneously in tens of thousands of genomes
Sebastian Niehus , Hákon Jónsson , Janina Schönberger  , Eythór Björnsson, Doruk Beyter , Hannes P Eggertsson , Patrick Sulem  Kári Stefánsson , Bjarni V Halldórsson Birte Kehr 
in Nature Communications. 2021 Feb 1;12(1):730.doi: 10.1038/s41467-020-20850-5.

Abstract

Thousands of genomic structural variants (SVs) segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is a major computational challenge. Most current approaches identify SVs in single genomes and afterwards merge the identified variants into a joint call set across many genomes. We describe the approach PopDel, which directly identifies deletions of about 500 to at least 10,000 bp in length in data of many genomes jointly, eliminating the need for subsequent variant merging. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDel’s running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies.

Source: https://pubmed.ncbi.nlm.nih.gov/33526789/

Other articles related to Genomics and Bioinformatics on this online Open Access Journal Include:

Finding the Genetic Links in Common Disease: Caveats of Whole Genome Sequencing Studies

Large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes

US Personalized Cancer Genome Sequencing Market Outlook 2018 –

Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

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

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Interviews with Scientific Leaders, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , on November 24, 2012| 5 Comments »

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

E-mail
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 E-mail
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

Table of contents

November 2012, Volume 44 No11 pp1171-1285

  • Credit for clinical trial data –p1171
topof page

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

See also: Article by Landan et al.

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

See also: Letter by Campbell et al.

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

See also: Article by Cowper-Sal·lari et al.

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

See also: News and Views by Meyer & Carroll

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

See also: News and Views by Krebs & Schübeler

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

See also: News and Views by Hurles

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 tRNAMet 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

SOURCE:

http://www.nature.com/ng/journal/v44/n11/index.html 

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