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Evan Eichler

Jayne Y Hehir-Kwa, Tobias Marschall, Wigard P Kloosterman, Laurent C Francioli, Jasmijn A Baaijens, Louis J Dijkstra, Abdel Abdellaoui, Vyacheslav Koval, Djie Tjwan Thung, René Wardenaar, Ivo Renkens, Bradley P Coe, Patrick Deelen, Joep de Ligt, Eric-Wubbo Lameijer, Freerk van Dijk, Fereydoun Hormozdiari, André G Uitterlinden, Cornelia M van Duijn, Evan E Eichler, Paul I W de Bakker, Morris A Swertz, Cisca Wijmenga, Gert-Jan B van Ommen, P Eline Slagboom, Dorret I Boomsma, Alexander Schönhuth, Kai Ye, Victor Guryev
Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs...
October 6, 2016: Nature Communications
Megan Y Dennis, Evan E Eichler
Duplications are the primary force by which new gene functions arise and provide a substrate for large-scale structural variation. Analysis of thousands of genomes shows that humans and great apes have more genetic differences in content and structure over recent segmental duplications than any other euchromatic region. Novel human-specific duplicated genes, ARHGAP11B and SRGAP2C, have recently been described with a potential role in neocortical expansion and increased neuronal spine density. Large segmental duplications and the structural variants they promote are also frequently stratified between human populations with a subset being subjected to positive selection...
August 29, 2016: Current Opinion in Genetics & Development
Keolu Fox, Jill M Johnsen, Bradley P Coe, Chris D Frazar, Alexander P Reiner, Evan E Eichler, Deborah A Nickerson
BACKGROUND: ABO is a blood group system of high clinical significance due to the prevalence of ABO variation that can cause major, potentially life-threatening, transfusion reactions. STUDY DESIGN AND METHODS: Using multiple large-scale next-generation sequence data sets, we demonstrate the application of read-depth approaches to discover previously unsuspected structural variation (SV) in the ABO gene in individuals of African ancestry. RESULTS: Our analysis of SV in the ABO gene across 6432 exomes reveals a partial deletion in the ABO gene in 32 individuals of African ancestry that predicts a novel O allele...
August 31, 2016: Transfusion
Xander Nuttle, Giuliana Giannuzzi, Michael H Duyzend, Joshua G Schraiber, Iñigo Narvaiza, Peter H Sudmant, Osnat Penn, Giorgia Chiatante, Maika Malig, John Huddleston, Chris Benner, Francesca Camponeschi, Simone Ciofi-Baffoni, Holly A F Stessman, Maria C N Marchetto, Laura Denman, Lana Harshman, Carl Baker, Archana Raja, Kelsi Penewit, Nicolette Janke, W Joyce Tang, Mario Ventura, Lucia Banci, Francesca Antonacci, Joshua M Akey, Chris T Amemiya, Fred H Gage, Alexandre Reymond, Evan E Eichler
Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution...
August 11, 2016: Nature
Lingling Shi, Yunfei Guo, Chengliang Dong, John Huddleston, Hui Yang, Xiaolu Han, Aisi Fu, Quan Li, Na Li, Siyi Gong, Katherine E Lintner, Qiong Ding, Zou Wang, Jiang Hu, Depeng Wang, Feng Wang, Lin Wang, Gholson J Lyon, Yongtao Guan, Yufeng Shen, Oleg V Evgrafov, James A Knowles, Francoise Thibaud-Nissen, Valerie Schneider, Chack-Yung Yu, Libing Zhou, Evan E Eichler, Kwok-Fai So, Kai Wang
Short-read sequencing has enabled the de novo assembly of several individual human genomes, but with inherent limitations in characterizing repeat elements. Here we sequence a Chinese individual HX1 by single-molecule real-time (SMRT) long-read sequencing, construct a physical map by NanoChannel arrays and generate a de novo assembly of 2.93 Gb (contig N50: 8.3 Mb, scaffold N50: 22.0 Mb, including 39.3 Mb N-bases), together with 206 Mb of alternative haplotypes. The assembly fully or partially fills 274 (28...
2016: Nature Communications
Ping C Mamiya, Todd L Richards, Bradley P Coe, Evan E Eichler, Patricia K Kuhl
Adult human brains retain the capacity to undergo tissue reorganization during second-language learning. Brain-imaging studies show a relationship between neuroanatomical properties and learning for adults exposed to a second language. However, the role of genetic factors in this relationship has not been investigated. The goal of the current study was twofold: (i) to characterize the relationship between brain white matter fiber-tract properties and second-language immersion using diffusion tensor imaging, and (ii) to determine whether polymorphisms in the catechol-O-methyltransferase (COMT) gene affect the relationship...
June 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
Nima Rafati, Lisa S Andersson, Sofia Mikko, Chungang Feng, Terje Raudsepp, Jessica Pettersson, Jan Janecka, Ove Wattle, Adam Ameur, Gunilla Thyreen, John Eberth, John Huddleston, Maika Malig, Ernest Bailey, Evan E Eichler, Göran Dalin, Bhanu Chowdary, Leif Andersson, Gabriella Lindgren, Carl-Johan Rubin
Skeletal atavism in Shetland ponies is a heritable disorder characterized by abnormal growth of the ulna and fibula that extend the carpal and tarsal joints, respectively. This causes abnormal skeletal structure and impaired movements, and affected foals are usually killed. In order to identify the causal mutation we subjected six confirmed Swedish cases and a DNA pool consisting of 21 control individuals to whole genome resequencing. We screened for polymorphisms where the cases and the control pool were fixed for opposite alleles and observed this signature for only 25 SNPs, most of which were scattered on genome assembly unassigned scaffolds...
2016: G3: Genes—Genomes—Genetics
John Huddleston, Evan E Eichler
Deciphering the genetic basis of human disease requires a comprehensive knowledge of genetic variants irrespective of their class or frequency. Although an impressive number of human genetic variants have been catalogued, a large fraction of the genetic difference that distinguishes two human genomes is still not understood at the base-pair level. This is because the emphasis has been on single-nucleotide variation as opposed to less tractable and more complex genetic variants, including indels and structural variants...
April 2016: Genetics
David Gordon, John Huddleston, Mark J P Chaisson, Christopher M Hill, Zev N Kronenberg, Katherine M Munson, Maika Malig, Archana Raja, Ian Fiddes, LaDeana W Hillier, Christopher Dunn, Carl Baker, Joel Armstrong, Mark Diekhans, Benedict Paten, Jay Shendure, Richard K Wilson, David Haussler, Chen-Shan Chin, Evan E Eichler
Accurate sequence and assembly of genomes is a critical first step for studies of genetic variation. We generated a high-quality assembly of the gorilla genome using single-molecule, real-time sequence technology and a string graph de novo assembly algorithm. The new assembly improves contiguity by two to three orders of magnitude with respect to previously released assemblies, recovering 87% of missing reference exons and incomplete gene models. Although regions of large, high-identity segmental duplications remain largely unresolved, this comprehensive assembly provides new biological insight into genetic diversity, structural variation, gene loss, and representation of repeat structures within the gorilla genome...
April 1, 2016: Science
Holly A F Stessman, Marjolein H Willemsen, Michaela Fenckova, Osnat Penn, Alexander Hoischen, Bo Xiong, Tianyun Wang, Kendra Hoekzema, Laura Vives, Ida Vogel, Han G Brunner, Ineke van der Burgt, Charlotte W Ockeloen, Janneke H Schuurs-Hoeijmakers, Jolien S Klein Wassink-Ruiter, Connie Stumpel, Servi J C Stevens, Hans S Vles, Carlo M Marcelis, Hans van Bokhoven, Vincent Cantagrel, Laurence Colleaux, Michael Nicouleau, Stanislas Lyonnet, Raphael A Bernier, Jennifer Gerdts, Bradley P Coe, Corrado Romano, Antonino Alberti, Lucia Grillo, Carmela Scuderi, Magnus Nordenskjöld, Malin Kvarnung, Hui Guo, Kun Xia, Amélie Piton, Bénédicte Gerard, David Genevieve, Bruno Delobel, Daphne Lehalle, Laurence Perrin, Fabienne Prieur, Julien Thevenon, Jozef Gecz, Marie Shaw, Rolph Pfundt, Boris Keren, Aurelia Jacquette, Annette Schenck, Evan E Eichler, Tjitske Kleefstra
Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID...
March 3, 2016: American Journal of Human Genetics
Holly A F Stessman, Tychele N Turner, Evan E Eichler
The next-generation sequencing revolution has substantially increased our understanding of the mutated genes that underlie complex neurodevelopmental disease. Exome sequencing has enabled us to estimate the number of genes involved in the etiology of neurodevelopmental disease, whereas targeted sequencing approaches have provided the means for quick and cost-effective sequencing of thousands of patient samples to assess the significance of individual genes. By leveraging such technologies and clinical exome sequencing, a genotype-first approach has emerged in which patients with a common genotype are first identified and then clinically reassessed as a group...
2016: Genome Medicine
Dorien Lugtenberg, Margot R F Reijnders, Michaela Fenckova, Emilia K Bijlsma, Raphael Bernier, Bregje W M van Bon, Eric Smeets, Anneke T Vulto-van Silfhout, Danielle Bosch, Evan E Eichler, Heather C Mefford, Gemma L Carvill, Ernie M H F Bongers, Janneke Hm Schuurs-Hoeijmakers, Claudia A Ruivenkamp, Gijs W E Santen, Arn M J M van den Maagdenberg, Cacha M P C D Peeters-Scholte, Sabine Kuenen, Patrik Verstreken, Rolph Pfundt, Helger G Yntema, Petra F de Vries, Joris A Veltman, Alexander Hoischen, Christian Gilissen, Bert B A de Vries, Annette Schenck, Tjitske Kleefstra, Lisenka E L M Vissers
Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID...
August 2016: European Journal of Human Genetics: EJHG
Tychele N Turner, Fereydoun Hormozdiari, Michael H Duyzend, Sarah A McClymont, Paul W Hook, Ivan Iossifov, Archana Raja, Carl Baker, Kendra Hoekzema, Holly A Stessman, Michael C Zody, Bradley J Nelson, John Huddleston, Richard Sandstrom, Joshua D Smith, David Hanna, James M Swanson, Elaine M Faustman, Michael J Bamshad, John Stamatoyannopoulos, Deborah A Nickerson, Andrew S McCallion, Robert Darnell, Evan E Eichler
We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0...
January 7, 2016: American Journal of Human Genetics
Michael H Duyzend, Xander Nuttle, Bradley P Coe, Carl Baker, Deborah A Nickerson, Raphael Bernier, Evan E Eichler
Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses, including intellectual disability, coordination disorder, and language disorder. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent of origin of the 16p11.2 copy-number variant (CNV) and the presence of additional CNVs in 126 families for which detailed phenotype data were available. Among de novo cases, we found a strong maternal bias for the origin of deletions (59/66, 89...
January 7, 2016: American Journal of Human Genetics
Wei Ba, Yan Yan, Margot R F Reijnders, Janneke H M Schuurs-Hoeijmakers, Ilse Feenstra, Ernie M H F Bongers, Daniëlle G M Bosch, Nicole De Leeuw, Rolph Pfundt, Christian Gilissen, Petra F De Vries, Joris A Veltman, Alexander Hoischen, Heather C Mefford, Evan E Eichler, Lisenka E L M Vissers, Nael Nadif Kasri, Bert B A De Vries
Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations...
March 1, 2016: Human Molecular Genetics
Junfeng Chen, John Huddleston, Reuben M Buckley, Maika Malig, Sara D Lawhon, Loren C Skow, Mi Ok Lee, Evan E Eichler, Leif Andersson, James E Womack
NK-lysin is an antimicrobial peptide and effector protein in the host innate immune system. It is coded by a single gene in humans and most other mammalian species. In this study, we provide evidence for the existence of four NK-lysin genes in a repetitive region on cattle chromosome 11. The NK2A, NK2B, and NK2C genes are tandemly arrayed as three copies in ∼30-35-kb segments, located 41.8 kb upstream of NK1. All four genes are functional, albeit with differential tissue expression. NK1, NK2A, and NK2B exhibited the highest expression in intestine Peyer's patch, whereas NK2C was expressed almost exclusively in lung...
December 29, 2015: Proceedings of the National Academy of Sciences of the United States of America
Dong-Hui Chen, Aurélie Méneret, Jennifer R Friedman, Olena Korvatska, Alona Gad, Emily S Bonkowski, Holly A Stessman, Diane Doummar, Cyril Mignot, Mathieu Anheim, Saunder Bernes, Marie Y Davis, Nathalie Damon-Perrière, Bertrand Degos, David Grabli, Domitille Gras, Fuki M Hisama, Katherine M Mackenzie, Phillip D Swanson, Christine Tranchant, Marie Vidailhet, Steven Winesett, Oriane Trouillard, Laura M Amendola, Michael O Dorschner, Michael Weiss, Evan E Eichler, Ali Torkamani, Emmanuel Roze, Thomas D Bird, Wendy H Raskind
OBJECTIVE: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship. METHODS: We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases. RESULTS: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations...
December 8, 2015: Neurology
Mark J P Chaisson, Richard K Wilson, Evan E Eichler
The discovery of genetic variation and the assembly of genome sequences are both inextricably linked to advances in DNA-sequencing technology. Short-read massively parallel sequencing has revolutionized our ability to discover genetic variation but is insufficient to generate high-quality genome assemblies or resolve most structural variation. Full resolution of variation is only guaranteed by complete de novo assembly of a genome. Here, we review approaches to genome assembly, the nature of gaps or missing sequences, and biases in the assembly process...
November 2015: Nature Reviews. Genetics
Peter H Sudmant, Tobias Rausch, Eugene J Gardner, Robert E Handsaker, Alexej Abyzov, John Huddleston, Yan Zhang, Kai Ye, Goo Jun, Markus Hsi-Yang Fritz, Miriam K Konkel, Ankit Malhotra, Adrian M Stütz, Xinghua Shi, Francesco Paolo Casale, Jieming Chen, Fereydoun Hormozdiari, Gargi Dayama, Ken Chen, Maika Malig, Mark J P Chaisson, Klaudia Walter, Sascha Meiers, Seva Kashin, Erik Garrison, Adam Auton, Hugo Y K Lam, Xinmeng Jasmine Mu, Can Alkan, Danny Antaki, Taejeong Bae, Eliza Cerveira, Peter Chines, Zechen Chong, Laura Clarke, Elif Dal, Li Ding, Sarah Emery, Xian Fan, Madhusudan Gujral, Fatma Kahveci, Jeffrey M Kidd, Yu Kong, Eric-Wubbo Lameijer, Shane McCarthy, Paul Flicek, Richard A Gibbs, Gabor Marth, Christopher E Mason, Androniki Menelaou, Donna M Muzny, Bradley J Nelson, Amina Noor, Nicholas F Parrish, Matthew Pendleton, Andrew Quitadamo, Benjamin Raeder, Eric E Schadt, Mallory Romanovitch, Andreas Schlattl, Robert Sebra, Andrey A Shabalin, Andreas Untergasser, Jerilyn A Walker, Min Wang, Fuli Yu, Chengsheng Zhang, Jing Zhang, Xiangqun Zheng-Bradley, Wanding Zhou, Thomas Zichner, Jonathan Sebat, Mark A Batzer, Steven A McCarroll, Ryan E Mills, Mark B Gerstein, Ali Bashir, Oliver Stegle, Scott E Devine, Charles Lee, Evan E Eichler, Jan O Korbel
Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes...
October 1, 2015: Nature
Elyse Mitchell, Andrew Douglas, Susanne Kjaegaard, Bert Callewaert, Arnaud Vanlander, Sandra Janssens, Amy Lawson Yuen, Cindy Skinner, Pinella Failla, Antonino Alberti, Emanuela Avola, Marco Fichera, Maria Kibaek, Maria C Digilio, Mark C Hannibal, Nicolette S den Hollander, Veronica Bizzarri, Alessandra Renieri, Maria Antonietta Mencarelli, Tomas Fitzgerald, Serena Piazzolla, Elke van Oudenhove, Corrado Romano, Charles Schwartz, Evan E Eichler, Anne Slavotinek, Luis Escobar, Diana Rajan, John Crolla, Nigel Carter, Jennelle C Hodge, Heather C Mefford
The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi-institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe...
December 2015: American Journal of Medical Genetics. Part A
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