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Evan Eichler

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https://www.readbyqxmd.com/read/28191889/targeted-sequencing-identifies-91-neurodevelopmental-disorder-risk-genes-with-autism-and-developmental-disability-biases
#1
Holly A F Stessman, Bo Xiong, Bradley P Coe, Tianyun Wang, Kendra Hoekzema, Michaela Fenckova, Malin Kvarnung, Jennifer Gerdts, Sandy Trinh, Nele Cosemans, Laura Vives, Janice Lin, Tychele N Turner, Gijs Santen, Claudia Ruivenkamp, Marjolein Kriek, Arie van Haeringen, Emmelien Aten, Kathryn Friend, Jan Liebelt, Christopher Barnett, Eric Haan, Marie Shaw, Jozef Gecz, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand, Charles Schwartz, R Frank Kooy, Geert Vandeweyer, Celine Helsmoortel, Corrado Romano, Antonino Alberti, Mirella Vinci, Emanuela Avola, Stefania Giusto, Eric Courchesne, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, David G Amaral, Ingrid E Scheffer, Martin B Delatycki, Paul J Lockhart, Fereydoun Hormozdiari, Benjamin Harich, Anna Castells-Nobau, Kun Xia, Hilde Peeters, Magnus Nordenskjöld, Annette Schenck, Raphael A Bernier, Evan E Eichler
Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100)...
February 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28155877/epigenetic-origin-of-evolutionary-novel-centromeres
#2
Doron Tolomeo, Oronzo Capozzi, Roscoe R Stanyon, Nicoletta Archidiacono, Pietro D'Addabbo, Claudia R Catacchio, Stefania Purgato, Giovanni Perini, Werner Schempp, John Huddleston, Maika Malig, Evan E Eichler, Mariano Rocchi
Most evolutionary new centromeres (ENC) are composed of large arrays of satellite DNA and surrounded by segmental duplications. However, the hypothesis is that ENCs are seeded in an anonymous sequence and only over time have acquired the complexity of "normal" centromeres. Up to now evidence to test this hypothesis was lacking. We recently discovered that the well-known polymorphism of orangutan chromosome 12 was due to the presence of an ENC. We sequenced the genome of an orangutan homozygous for the ENC, and we focused our analysis on the comparison of the ENC domain with respect to its wild type counterpart...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28132691/de-novo-disruption-of-the-proteasome-regulatory-subunit-psmd12-causes-a-syndromic-neurodevelopmental-disorder
#3
Sébastien Küry, Thomas Besnard, Frédéric Ebstein, Tahir N Khan, Tomasz Gambin, Jessica Douglas, Carlos A Bacino, Stephan J Sanders, Andrea Lehmann, Xénia Latypova, Kamal Khan, Mathilde Pacault, Stephanie Sacharow, Kimberly Glaser, Eric Bieth, Laurence Perrin-Sabourin, Marie-Line Jacquemont, Megan T Cho, Elizabeth Roeder, Anne-Sophie Denommé-Pichon, Kristin G Monaghan, Bo Yuan, Fan Xia, Sylvain Simon, Dominique Bonneau, Philippe Parent, Brigitte Gilbert-Dussardier, Sylvie Odent, Annick Toutain, Laurent Pasquier, Deborah Barbouth, Chad A Shaw, Ankita Patel, Janice L Smith, Weimin Bi, Sébastien Schmitt, Wallid Deb, Mathilde Nizon, Sandra Mercier, Marie Vincent, Caroline Rooryck, Valérie Malan, Ignacio Briceño, Alberto Gómez, Kimberly M Nugent, James B Gibson, Benjamin Cogné, James R Lupski, Holly A F Stessman, Evan E Eichler, Kyle Retterer, Yaping Yang, Richard Redon, Nicholas Katsanis, Jill A Rosenfeld, Peter-Michael Kloetzel, Christelle Golzio, Stéphane Bézieau, Paweł Stankiewicz, Bertrand Isidor
Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features...
February 2, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28073353/discovery-of-large-genomic-inversions-using-long-range-information
#4
Marzieh Eslami Rasekh, Giorgia Chiatante, Mattia Miroballo, Joyce Tang, Mario Ventura, Chris T Amemiya, Evan E Eichler, Francesca Antonacci, Can Alkan
BACKGROUND: Although many algorithms are now available that aim to characterize different classes of structural variation, discovery of balanced rearrangements such as inversions remains an open problem. This is mainly due to the fact that breakpoints of such events typically lie within segmental duplications or common repeats, which reduces the mappability of short reads. The algorithms developed within the 1000 Genomes Project to identify inversions are limited to relatively short inversions, and there are currently no available algorithms to discover large inversions using high throughput sequencing technologies...
January 10, 2017: BMC Genomics
https://www.readbyqxmd.com/read/27907889/denovo-db-a-compendium-of-human-de-novo-variants
#5
Tychele N Turner, Qian Yi, Niklas Krumm, John Huddleston, Kendra Hoekzema, Holly A F Stessman, Anna-Lisa Doebley, Raphael A Bernier, Deborah A Nickerson, Evan E Eichler
Whole-exome and whole-genome sequencing have facilitated the large-scale discovery of de novo variants in human disease. To date, most de novo discovery through next-generation sequencing focused on congenital heart disease and neurodevelopmental disorders (NDDs). Currently, de novo variants are one of the most significant risk factors for NDDs with a substantial overlap of genes involved in more than one NDD. To facilitate better usage of published data, provide standardization of annotation, and improve accessibility, we created denovo-db (http://denovo-db...
January 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27895111/discovery-and-genotyping-of-structural-variation-from-long-read-haploid-genome-sequence-data
#6
John Huddleston, Mark Jp Chaisson, Karyn Meltz Steinberg, Wes Warren, Kendra Hoekzema, David S Gordon, Tina A Graves-Lindsay, Katherine M Munson, Zev N Kronenberg, Laura Vives, Paul Peluso, Matthew Boitano, Chen-Shin Chin, Jonas Korlach, Richard K Wilson, Evan E Eichler
In an effort to more fully understand the full spectrum of human genetic variation, we generated deep single-molecule, real-time (SMRT) sequencing data from two haploid human genomes. Using an assembly-based approach (SMRT-SV), we systematically assessed each genome independently for structural variants (SVs) and indels resolving the sequence structure of 461,553 genetic variants from 2 bp to 28 kbp in length. We find that >89% of these variants have been missed as part of analysis of the 1000 Genomes Project even after adjusting for more common variants (MAF >1%)...
November 28, 2016: Genome Research
https://www.readbyqxmd.com/read/27824329/de-novo-genic-mutations-among-a-chinese-autism-spectrum-disorder-cohort
#7
Tianyun Wang, Hui Guo, Bo Xiong, Holly A F Stessman, Huidan Wu, Bradley P Coe, Tychele N Turner, Yanling Liu, Wenjing Zhao, Kendra Hoekzema, Laura Vives, Lu Xia, Meina Tang, Jianjun Ou, Biyuan Chen, Yidong Shen, Guanglei Xun, Min Long, Janice Lin, Zev N Kronenberg, Yu Peng, Ting Bai, Honghui Li, Xiaoyan Ke, Zhengmao Hu, Jingping Zhao, Xiaobing Zou, Kun Xia, Evan E Eichler
Recurrent de novo (DN) and likely gene-disruptive (LGD) mutations contribute significantly to autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, we sequence 189 risk genes in 1,543 Chinese ASD probands (1,045 from trios). We report an 11-fold increase in the odds of DN LGD mutations compared with expectation under an exome-wide neutral model of mutation. In aggregate, ∼4% of ASD patients carry a DN mutation in one of just 29 autism risk genes. The most prevalent gene for recurrent DN mutations is SCN2A (1...
November 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27822858/targeted-capture-and-high-throughput-sequencing-using-molecular-inversion-probes-mips
#8
Stuart Cantsilieris, Holly A Stessman, Jay Shendure, Evan E Eichler
Molecular inversion probes (MIPs) in combination with massively parallel DNA sequencing represent a versatile, yet economical tool for targeted sequencing of genomic DNA. Several thousand genomic targets can be selectively captured using long oligonucleotides containing unique targeting arms and universal linkers. The ability to append sequencing adaptors and sample-specific barcodes allows large-scale pooling and subsequent high-throughput sequencing at relatively low cost per sample. Here, we describe a "wet bench" protocol detailing the capture and subsequent sequencing of >2000 genomic targets from 192 samples, representative of a single lane on the Illumina HiSeq 2000 platform...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27803192/interchromosomal-core-duplicons-drive-both-evolutionary-instability-and-disease-susceptibility-of-the-chromosome-8p23-1-region
#9
Kiana Mohajeri, Stuart Cantsilieris, John Huddleston, Bradley J Nelson, Bradley P Coe, Catarina D Campbell, Carl Baker, Lana Harshman, Katherine M Munson, Zev N Kronenberg, Milinn Kremitzki, Archana Raja, Claudia Rita Catacchio, Tina A Graves, Richard K Wilson, Mario Ventura, Evan E Eichler
Recurrent rearrangements of Chromosome 8p23.1 are associated with congenital heart defects and developmental delay. The complexity of this region has led to inconsistencies in the current reference assembly, confounding studies of genetic variation. Using comparative sequence-based approaches, we generated a high-quality 6.3-Mbp alternate reference assembly of an inverted Chromosome 8p23.1 haplotype. Comparison with nonhuman primates reveals a 746-kbp duplicative transposition and two separate inversion events that arose in the last million years of human evolution...
November 2016: Genome Research
https://www.readbyqxmd.com/read/27708267/a-high-quality-human-reference-panel-reveals-the-complexity-and-distribution-of-genomic-structural-variants
#10
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
https://www.readbyqxmd.com/read/27584858/human-adaptation-and-evolution-by-segmental-duplication
#11
REVIEW
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...
December 2016: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/27580710/analysis-of-exome-sequencing-data-sets-reveals-structural-variation-in-the-coding-region-of-abo-in-individuals-of-african-ancestry
#12
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
https://www.readbyqxmd.com/read/27487209/emergence-of-a-homo-sapiens-specific-gene-family-and-chromosome-16p11-2-cnv-susceptibility
#13
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
https://www.readbyqxmd.com/read/27356984/long-read-sequencing-and-de-novo-assembly-of-a-chinese-genome
#14
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
https://www.readbyqxmd.com/read/27298360/brain-white-matter-structure-and-comt-gene-are-linked-to-second-language-learning-in-adults
#15
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
https://www.readbyqxmd.com/read/27207956/large-deletions-at-the-shox-locus-in-the-pseudoautosomal-region-are-associated-with-skeletal-atavism-in-shetland-ponies
#16
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
https://www.readbyqxmd.com/read/27053122/an-incomplete-understanding-of-human-genetic-variation
#17
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
https://www.readbyqxmd.com/read/27034376/long-read-sequence-assembly-of-the-gorilla-genome
#18
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
https://www.readbyqxmd.com/read/26942287/disruption-of-pogz-is-associated-with-intellectual-disability-and-autism-spectrum-disorders
#19
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
https://www.readbyqxmd.com/read/26917491/molecular-subtyping-and-improved-treatment-of-neurodevelopmental-disease
#20
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...
February 25, 2016: Genome Medicine
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