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Journal Article•DOI•

Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

Stephen Sanders1, A. Gulhan Ercan-Sencicek, Vanessa Hus2, Rui Luo3, Michael T. Murtha, Daniel Moreno-De-Luca4, Su H. Chu5, Michael P. Moreau6, Abha R. Gupta1, Susanne Thomson7, Christopher E. Mason8, Kaya Bilguvar1, Patrícia B. S. Celestino-Soper9, Murim Choi1, Emily L. Crawford7, Lea K. Davis10, Nicole R. Davis Wright1, Rahul M. Dhodapkar1, Michael DiCola6, Nicholas M. DiLullo1, Thomas V. Fernandez1, Vikram Fielding-Singh11, Daniel O. Fishman7, Stephanie Frahm6, Rouben Garagaloyan, Gerald Goh1, Sindhuja Kammela1, Lambertus Klei12, Jennifer K. Lowe3, Sabata C. Lund2, Anna D. McGrew7, Kyle A. Meyer1, William J. Moffat1, John D. Murdoch1, Brian J. O'Roak13, Gordon T. Ober1, Rebecca S. Pottenger14, Melanie J. Raubeson1, Youeun Song1, Qi Wang6, Brian L. Yaspan7, Timothy W. Yu15, Ilana R. Yurkiewicz1, Arthur L. Beaudet9, Rita M. Cantor3, Martin Curland, Dorothy E. Grice16, Murat Gunel1, Richard P. Lifton1, Shrikant Mane1, Donna M. Martin2, Chad A. Shaw9, Michael Sheldon6, Jay A. Tischfield6, Christopher A. Walsh17, Eric M. Morrow18, David H. Ledbetter19, Eric Fombonne20, Catherine Lord2, Christa Lese Martin4, Andrew Brooks6, James S. Sutcliffe7, Edwin H. Cook10, Daniel H. Geschwind3, Kathryn Roeder5, Bernie Devlin12, Matthew W. State •
Yale University1, University of Michigan2, University of California, Los Angeles3, Emory University4, Carnegie Mellon University5, Rutgers University6, Vanderbilt University7, Cornell University8, Baylor College of Medicine9, University of Illinois at Chicago10, Stanford University11, University of Pittsburgh12, University of Washington13, Princeton University14, Boston Children's Hospital15, Columbia University16, Howard Hughes Medical Institute17, Brown University18, Geisinger Health System19, Montreal Children's Hospital20
09 Jun 2011-Neuron (Cell Press)-Vol. 70, Iss: 5, pp 863-885
TL;DR: A genome-wide analysis of rare copy-number variation in 1124 autism spectrum disorder families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling, finds significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome.
About: This article is published in Neuron.The article was published on 2011-06-09 and is currently open access. It has received 1198 citations till now. The article focuses on the topics: Epigenetics of autism & Heritability of autism.
Citations
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Journal Article•DOI•
The contribution of de novo coding mutations to autism spectrum disorder

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Ivan Iossifov1, Brian J. O'Roak2, Stephen Sanders3, Stephen Sanders4, Michael Ronemus1, Niklas Krumm2, Dan Levy1, Holly A.F. Stessman2, Kali Witherspoon2, Laura Vives2, Karynne E. Patterson2, Joshua D. Smith2, Bryan W. Paeper2, Deborah A. Nickerson2, Jeanselle Dea4, Shan Dong3, Shan Dong5, Luis E. Gonzalez3, Jeffrey D. Mandell4, Shrikant Mane3, Michael T. Murtha3, Catherine A.W. Sullivan3, Michael F. Walker4, Zainulabedin Waqar3, Liping Wei5, A. Jeremy Willsey3, A. Jeremy Willsey4, Boris Yamrom1, Yoon-ha Lee1, Ewa A. Grabowska1, Ertugrul Dalkic1, Ertugrul Dalkic6, Zihua Wang1, Steven Marks1, Peter Andrews1, Anthony Leotta1, Jude Kendall1, Inessa Hakker1, Julie Rosenbaum1, Beicong Ma1, Linda Rodgers1, Jennifer Troge1, Giuseppe Narzisi1, Seungtai Yoon1, Michael C. Schatz1, Kenny Ye7, W. Richard McCombie1, Jay Shendure2, Evan E. Eichler2, Evan E. Eichler8, Matthew W. State3, Matthew W. State4, Michael Wigler1 •
Cold Spring Harbor Laboratory1, University of Washington2, Yale University3, University of California, San Francisco4, Peking University5, Zonguldak Karaelmas University6, Yeshiva University7, Howard Hughes Medical Institute8
13 Nov 2014-Nature
TL;DR: It is estimated that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation.
Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

2,124 citations

Journal Article•DOI•
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

[...]

Brian J. O'Roak1, Laura Vives1, Santhosh Girirajan1, Emre Karakoc1, Niklas Krumm1, Bradley P. Coe1, Roie Levy1, Arthur Ko1, Choli Lee1, Joshua D. Smith1, Emily H. Turner1, Ian B. Stanaway1, Benjamin Vernot1, Maika Malig1, Carl Baker1, Beau Reilly1, Joshua M. Akey1, Elhanan Borenstein1, Elhanan Borenstein2, Mark J. Rieder1, Deborah A. Nickerson1, Raphael Bernier1, Jay Shendure1, Evan E. Eichler3, Evan E. Eichler1 •
University of Washington1, Santa Fe Institute2, Howard Hughes Medical Institute3
10 May 2012-Nature
TL;DR: It is shown that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD.
Abstract: It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

2,062 citations

Cites methods from "Multiple Recurrent De Novo CNVs, In..."

  • ...For each gene, we extracted (1) d = the number of differences between chimpanzee and human and (2) n = the number of bases aligned....

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Journal Article•DOI•
De novo mutations revealed by whole-exome sequencing are strongly associated with autism

[...]

Stephen Sanders1, Michael T. Murtha1, Abha R. Gupta1, John D. Murdoch1, Melanie J. Raubeson1, A. Jeremy Willsey1, A. Gulhan Ercan-Sencicek1, Nicholas M. DiLullo1, Neelroop N. Parikshak2, Jason L. Stein2, Michael F. Walker1, Gordon T. Ober1, Nicole A. Teran1, Youeun Song1, Paul El-Fishawy1, Ryan C. Murtha1, Murim Choi1, John D. Overton1, Robert D. Bjornson1, Nicholas Carriero1, Kyle A. Meyer1, Kaya Bilguvar1, Shrikant Mane1, Nenad Sestan1, Richard P. Lifton1, Murat Gunel1, Kathryn Roeder3, Daniel H. Geschwind2, Bernie Devlin4, Matthew W. State1 •
Yale University1, University of California, Los Angeles2, Carnegie Mellon University3, University of Pittsburgh4
10 May 2012-Nature
TL;DR: It is shown, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects.
Abstract: Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.

1,930 citations

Cites background from "Multiple Recurrent De Novo CNVs, In..."

  • ...The rate of de novo SNVs is shown in 15 probands with large multigenic CNVs (≥16 RefSeq genes) and 179 probands without such CNVs (demonstrated previously by genotype).(6) In the probands with large multigenic CNVs a trend toward less non-synonymous de novo SNVs are seen compared to probands without....

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Journal Article•DOI•
Patterns and rates of exonic de novo mutations in autism spectrum disorders

[...]

Benjamin M. Neale1, Yan Kou2, Li Liu3, Avi Ma'ayan2, Kaitlin E. Samocha1, Kaitlin E. Samocha4, Aniko Sabo5, Chiao-Feng Lin6, Christine Stevens4, Li-San Wang6, Vladimir Makarov2, Paz Polak4, Paz Polak7, Seungtai Yoon2, Jared Maguire4, Emily L. Crawford8, Nicholas G. Campbell8, Evan T. Geller6, Otto Valladares6, Chad M. Schafer3, Han Liu9, Tuo Zhao9, Guiqing Cai2, Jayon Lihm2, Ruth Dannenfelser2, Omar Jabado2, Zuleyma Peralta2, Uma Nagaswamy5, Donna M. Muzny5, Jeffrey G. Reid5, Irene Newsham5, Yuanqing Wu5, Lora Lewis5, Yi Han5, Benjamin F. Voight6, Benjamin F. Voight4, Elaine T. Lim4, Elaine T. Lim1, Elizabeth J. Rossin4, Elizabeth J. Rossin1, Andrew Kirby1, Andrew Kirby4, Jason Flannick4, Menachem Fromer1, Menachem Fromer4, Khalid Shakir4, Timothy Fennell4, Kiran V. Garimella4, Eric Banks4, Ryan Poplin4, Stacey Gabriel4, Mark A. DePristo4, Jack R. Wimbish, Braden E. Boone, Shawn Levy, Catalina Betancur10, Shamil R. Sunyaev4, Shamil R. Sunyaev7, Eric Boerwinkle11, Eric Boerwinkle5, Joseph D. Buxbaum, Edwin H. Cook12, Bernie Devlin13, Richard A. Gibbs5, Kathryn Roeder3, Gerard D. Schellenberg6, James S. Sutcliffe8, Mark J. Daly4, Mark J. Daly1 •
Harvard University1, Icahn School of Medicine at Mount Sinai2, Carnegie Mellon University3, Broad Institute4, Baylor College of Medicine5, University of Pennsylvania6, Brigham and Women's Hospital7, Vanderbilt University8, Johns Hopkins University9, French Institute of Health and Medical Research10, University of Texas Health Science Center at Houston11, University of Illinois at Chicago12, University of Pittsburgh13
04 Apr 2012-Nature
TL;DR: Results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors and support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold.
Abstract: Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.

1,700 citations

Journal Article•DOI•
De Novo Gene Disruptions in Children on the Autistic Spectrum

[...]

Ivan Iossifov1, Michael Ronemus1, Dan Levy1, Zihua Wang1, Inessa Hakker1, Julie Rosenbaum1, Boris Yamrom1, Yoon-ha Lee1, Giuseppe Narzisi1, Anthony Leotta1, Jude Kendall1, Ewa A. Grabowska1, Beicong Ma1, Steven Marks1, Linda Rodgers1, Asya Stepansky1, Jennifer Troge1, Peter Andrews1, Mitchell A. Bekritsky1, Kith Pradhan1, Elena Ghiban1, Melissa Kramer1, Jennifer Parla1, Ryan Demeter2, Lucinda Fulton2, Robert S. Fulton2, Vincent Magrini2, Kenny Ye3, Jennifer C. Darnell4, Robert B. Darnell4, Robert B. Darnell5, Elaine R. Mardis2, Richard K. Wilson2, Michael C. Schatz1, Richard W. McCombie1, Michael Wigler1 •
Cold Spring Harbor Laboratory1, Washington University in St. Louis2, Albert Einstein College of Medicine3, Rockefeller University4, Howard Hughes Medical Institute5
26 Apr 2012-Neuron
TL;DR: Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveals de novo small indels and point substitutions, which suggest FMRP-associated genes are especially dosage-sensitive targets of cognitive disorders.

1,354 citations

Cites background or result from "Multiple Recurrent De Novo CNVs, In..."

  • ...Adding the 6% differential for large-scale de novo copy number mutation previously observed (Levy et al., 2011; Sanders et al., 2011) to the 10% differential for LGDs, we reach a total differential of 16% between affected children and siblings....

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  • ...Analysis of the de novomutations has demonstrated a large number of potential autism target genes (Gilman et al., 2011; Levy et al., 2011; Marshall et al., 2008; Pinto et al., 2010; Sanders et al., 2011; Sebat et al., 2007)....

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  • ...The lack of signal is not attributable to the type of population we study, as we observe de novo copy number imbalance of the expected magnitude in this very same population (Levy et al., 2011; Sanders et al., 2011)....

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  • ...By contrast, a previous study indicated that for de novo copy number variation both parents contribute almost equally (Sanders et al., 2011)....

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References
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Journal Article•DOI•
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.

[...]

Da-Wei Huang1, Brad T. Sherman1, Richard A. Lempicki1•
Science Applications International Corporation1
01 Jan 2009-Nature Protocols
TL;DR: By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
Abstract: DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.

31,015 citations

"Multiple Recurrent De Novo CNVs, In..." refers methods in this paper

  • ...DAVID yielded consistent results with 59 pathways enriched in probands and 19 in siblings (p = 0.01, permutation analysis) (Figure 6)....

    [...]

  • ...and DAVID (Dennis et al., 2003; Huang et al., 2009), to analyze 1516 genes within CNVs exclusive to probands and 1357 genes exclusive to siblings....

    [...]

  • ...We used two gene ontology and pathway analysis tools, MetaCore from GeneGo, Inc. and DAVID (Dennis et al., 2003; Huang et al., 2009), to analyze 1516 genes within CNVs exclusive to probands and 1357 genes exclusive to siblings....

    [...]

  • ...This process was performed showed a difference R18 (the difference seen in [A], vertical dashed line), yieldin (C) Permutation analysis to calculate the significance value with DAVID (level 4 term seen in (A), vertical dashed line), giving a p value of 0.01....

    [...]

Journal Article•DOI•
PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses

[...]

Shaun Purcell1, Shaun Purcell2, Benjamin M. Neale2, Benjamin M. Neale3, Kathe Todd-Brown1, Lori Thomas1, Manuel A. R. Ferreira1, David Bender1, David Bender2, Julian Maller2, Julian Maller1, Pamela Sklar1, Pamela Sklar2, Paul I.W. de Bakker2, Paul I.W. de Bakker1, Mark J. Daly1, Mark J. Daly2, Pak C. Sham4 •
Harvard University1, Massachusetts Institute of Technology2, University of London3, University of Hong Kong4
01 Sep 2007-American Journal of Human Genetics
TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Abstract: Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.

26,280 citations

"Multiple Recurrent De Novo CNVs, In..." refers methods in this paper

  • ...Genotyped samples were analyzed using Plink (Purcell et al., 2007) to identify incorrect sex, Mendelian inconsistencies, and cryptic relatedness by assessing inheritance-by-descent (IBD); 11 families were removed as a result....

    [...]

  • ...Genotyped samples were analyzed by using PLINK (Purcell et al., 2007) to identify incorrect sex, Mendelian inconsistencies, and cryptic relatedness by assessing inheritance by descent; 11 families were removed as a result....

    [...]

Journal Article•DOI•
DAVID: Database for Annotation, Visualization, and Integrated Discovery

[...]

Glynn Dennis1, Brad T. Sherman1, Douglas A. Hosack1, Jun Jun Yang1, Wei Gao1, H. Clifford Lane2, Richard A. Lempicki1 •
Science Applications International Corporation1, National Institutes of Health2
14 Aug 2003-Genome Biology
TL;DR: DAMID is a web-accessible program that integrates functional genomic annotations with intuitive graphical summaries that assists in the interpretation of genome-scale datasets by facilitating the transition from data collection to biological meaning.
Abstract: The distributed nature of biological knowledge poses a major challenge to the interpretation of genome-scale datasets, including those derived from microarray and proteomic studies. This report describes DAVID, a web-accessible program that integrates functional genomic annotations with intuitive graphical summaries. Lists of gene or protein identifiers are rapidly annotated and summarized according to shared categorical data for Gene Ontology, protein domain, and biochemical pathway membership. DAVID assists in the interpretation of genome-scale datasets by facilitating the transition from data collection to biological meaning.

8,849 citations

"Multiple Recurrent De Novo CNVs, In..." refers methods in this paper

  • ...DAVID yielded consistent results with 59 pathways enriched in probands and 19 in siblings (p = 0.01, permutation analysis) (Figure 6)....

    [...]

  • ...and DAVID (Dennis et al., 2003; Huang et al., 2009), to analyze 1516 genes within CNVs exclusive to probands and 1357 genes exclusive to siblings....

    [...]

  • ...We used two gene ontology and pathway analysis tools, MetaCore from GeneGo, Inc. and DAVID (Dennis et al., 2003; Huang et al., 2009), to analyze 1516 genes within CNVs exclusive to probands and 1357 genes exclusive to siblings....

    [...]

  • ...This process was performed showed a difference R18 (the difference seen in [A], vertical dashed line), yieldin (C) Permutation analysis to calculate the significance value with DAVID (level 4 term seen in (A), vertical dashed line), giving a p value of 0.01....

    [...]

Journal Article•DOI•
NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins

[...]

Kim D. Pruitt1, Tatiana Tatusova1, Donna Maglott1•
National Institutes of Health1
17 Dec 2004-Nucleic Acids Research
TL;DR: The National Center for Biotechnology Information Reference Sequence (RefSeq) database provides a non-redundant collection of sequences representing genomic data, transcripts and proteins that pragmatically includes sequence data that are currently publicly available in the archival databases.
Abstract: The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database (http://www.ncbi.nlm.nih.gov/RefSeq/) provides a non-redundant collection of sequences representing genomic data, transcripts and proteins. Although the goal is to provide a comprehensive dataset representing the complete sequence information for any given species, the database pragmatically includes sequence data that are currently publicly available in the archival databases. The database incorporates data from over 2400 organisms and includes over one million proteins representing significant taxonomic diversity spanning prokaryotes, eukaryotes and viruses. Nucleotide and protein sequences are explicitly linked, and the sequences are linked to other resources including the NCBI Map Viewer and Gene. Sequences are annotated to include coding regions, conserved domains, variation, references, names, database cross-references, and other features using a combined approach of collaboration and other input from the scientific community, automated annotation, propagation from GenBank and curation by NCBI staff.

4,229 citations

"Multiple Recurrent De Novo CNVs, In..." refers background in this paper

  • ...(C) Number of RefSeq genes (Pruitt et al., 2007) overlapping rare de novo CNVs in probands versus siblings....

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Journal Article•DOI•
Detection of large-scale variation in the human genome.

[...]

A. John Iafrate1, Lars Feuk2, Miguel Rivera3, Miguel Rivera1, Marc L. Listewnik1, Patricia K. Donahoe3, Ying Qi2, Stephen W. Scherer2, Charles Lee3, Charles Lee1 •
Brigham and Women's Hospital1, University of Toronto2, Harvard University3
01 Sep 2004-Nature Genetics
TL;DR: This article identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals, and revealed that half of these regions overlap with genes, and many coincide with segmental duplications or gaps in human genome assembly.
Abstract: We identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals. Twenty-four variants are present in > 10% of the individuals that we examined. Half of these regions overlap with genes, and many coincide with segmental duplications or gaps in the human genome assembly. This previously unappreciated heterogeneity may underlie certain human phenotypic variation and susceptibility to disease and argues for a more dynamic human genome structure.

2,937 citations

"Multiple Recurrent De Novo CNVs, In..." refers background in this paper

  • ...Over the last several years, dramatic advances have emerged from studies of copy-number variation (CNV) characterizing 864 Neuron 70, 863–885, June 9, 2011 ª2011 Elsevier Inc. submicroscopic chromosomal deletions and duplications (Iafrate et al., 2004; Sebat et al., 2004)....

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  • ...submicroscopic chromosomal deletions and duplications (Iafrate et al., 2004; Sebat et al., 2004)....

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Related Papers (5)
Functional impact of global rare copy number variation in autism spectrum disorders

[...]

15 Jul 2010-Nature
Dalila Pinto, Alistair T. Pagnamenta, Lambertus Klei  +179 more
Strong Association of De Novo Copy Number Mutations with Autism

[...]

20 Apr 2007-Science
Jonathan Sebat, B. Lakshmi, Dheeraj Malhotra, Jennifer Troge, Christa Lese-Martin, Tom Walsh, Boris Yamrom, Seungtai Yoon, Alexander Krasnitz, Jude Kendall, Anthony Leotta, Deepa Pai, Ray Zhang, Yoon-ha Lee, James W. Hicks, Sarah J. Spence, Annette Lee, Kaija Puura, Terho Lehtimäki, David H. Ledbetter, Peter K. Gregersen, Joel D. Bregman, James S. Sutcliffe, Vaidehi Jobanputra, Wendy K. Chung, Dorothy Warburton, Mary Claire King, David Skuse, Daniel H. Geschwind, T. Conrad Gilliam, Kenny Ye, Michael Wigler 
De novo mutations revealed by whole-exome sequencing are strongly associated with autism

[...]

10 May 2012-Nature
Stephen Sanders, Michael T. Murtha, Abha R. Gupta, John D. Murdoch, Melanie J. Raubeson, A. Jeremy Willsey, A. Gulhan Ercan-Sencicek, Nicholas M. DiLullo, Neelroop N. Parikshak, Jason L. Stein, Michael F. Walker, Gordon T. Ober, Nicole A. Teran, Youeun Song, Paul El-Fishawy, Ryan C. Murtha, Murim Choi, John D. Overton, Robert D. Bjornson, Nicholas Carriero, Kyle A. Meyer, Kaya Bilguvar, Shrikant Mane, Nenad Sestan, Richard P. Lifton, Murat Gunel, Kathryn Roeder, Daniel H. Geschwind, Bernie Devlin, Matthew W. State 
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

[...]

10 May 2012-Nature
Brian J. O'Roak, Laura Vives, Santhosh Girirajan, Emre Karakoc, Niklas Krumm, Bradley P. Coe, Roie Levy, Arthur Ko, Choli Lee, Joshua D. Smith, Emily H. Turner, Ian B. Stanaway, Benjamin Vernot, Maika Malig, Carl Baker, Beau Reilly, Joshua M. Akey, Elhanan Borenstein, Elhanan Borenstein, Mark J. Rieder, Deborah A. Nickerson, Raphael Bernier, Jay Shendure, Evan E. Eichler, Evan E. Eichler 
Patterns and rates of exonic de novo mutations in autism spectrum disorders

[...]

04 Apr 2012-Nature
Benjamin M. Neale, Yan Kou, Li Liu, Avi Ma'ayan, Kaitlin E. Samocha, Kaitlin E. Samocha, Aniko Sabo, Chiao-Feng Lin, Christine Stevens, Li-San Wang, Vladimir Makarov, Paz Polak, Paz Polak, Seungtai Yoon, Jared Maguire, Emily L. Crawford, Nicholas G. Campbell, Evan T. Geller, Otto Valladares, Chad M. Schafer, Han Liu, Tuo Zhao, Guiqing Cai, Jayon Lihm, Ruth Dannenfelser, Omar Jabado, Zuleyma Peralta, Uma Nagaswamy, Donna M. Muzny, Jeffrey G. Reid, Irene Newsham, Yuanqing Wu, Lora Lewis, Yi Han, Benjamin F. Voight, Benjamin F. Voight, Elaine T. Lim, Elaine T. Lim, Elizabeth J. Rossin, Elizabeth J. Rossin, Andrew Kirby, Andrew Kirby, Jason Flannick, Menachem Fromer, Menachem Fromer, Khalid Shakir, Timothy Fennell, Kiran V. Garimella, Eric Banks, Ryan Poplin, Stacey Gabriel, Mark A. DePristo, Jack R. Wimbish, Braden E. Boone, Shawn Levy, Catalina Betancur, Shamil R. Sunyaev, Shamil R. Sunyaev, Eric Boerwinkle, Eric Boerwinkle, Joseph D. Buxbaum, Edwin H. Cook, Bernie Devlin, Richard A. Gibbs, Kathryn Roeder, Gerard D. Schellenberg, James S. Sutcliffe, Mark J. Daly, Mark J. Daly