A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 3 10-28. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10-28 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C. © The Author 2010. Published by Oxford University Press. All rights reserved

Functional impact of global rare copy number variation in autism spectrum disorders

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (<1%frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P=0.012), especially so for loci previously implicated in either ASDand/or intellectual disability (1.69 fold, P=3.4×310-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways. © 2010 Macmillan Publishers Limited. All rights reserved

Preserving accuracy in GenBank

GenBank, the public repository for nucleotide and protein sequences, is a critical resource for molecular biology, evolutionary biology, and ecology. While some attention has been drawn to sequence errors, common annotation errors also reduce the value of this database. In fact, for organisms such as fungi, which are notoriously difficult to identify, up to 20% of DNA sequence records may have erroneous lineage designations in GenBank. Gene function annotation in protein sequence databases is similarly error-prone. Because identity and function of new sequences are often determined by bioinformatic analyses, both types of errors are propagated into new accessions, leading to long-term degradation of the quality of the database. Currently, primary sequence data are annotated by the authors of those data, and can only be reannotated by the same authors. This is inefficient and unsustainable over the long term as authors eventually leave the field. Although it is possible to link third-party databases to GenBank records, this is a short-term solution that has little guarantee of permanence. Similarly, the current third-party annotation option in GenBank (TPA) complicates rather than solves the problem by creating an identical record with a new annotation, while leaving the original record unflagged and unlinked to the new record. Since the origin of public zoological and botanical specimen collections, an open system of cumulative annotation has evolved, whereby the original name is retained, but additional opinion is directly appended and used for filing and retrieval. This was needed as new specimens and analyses allowed for reevaluation of older specimens and the original depositors became unavailable. The time has come for the public sequence database to incorporate a community-curated, cumulative annotation process that allows third parties to improve the annotations of sequences when warranted by published peer-reviewed analyses.Fil: Bidartondo, Martin I.. Imperial College London; Reino Unido. Royal Botanic Gardens; Reino UnidoFil: Bruns, Thomas D.. University of California at Berkeley; Estados UnidosFil: Blackwell, Meredith. Louisiana State University; Estados UnidosFil: Edwards, Ivan. University of Michigan; Estados UnidosFil: Taylor, Andy F. S.. Swedish University of Agricultural Sciences; SueciaFil: Bianchinotti, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur; ArgentinaFil: Padamsee, Mahajabeen. University of Minnesota; Estados UnidosFil: Callac, Philippe. Institut National de la Recherche Agronomique; FranciaFil: Lima, Nelson. Universidade do Minho; PortugalFil: White, Merlin M.. Boise State University; Estados UnidosFil: Barreau Daly, Camila. Centre National de la Recherche Scientifique; Francia. Institut National de la Recherche Agronomique; FranciaFil: Juncai, M. A.. Chinese Academy of Sciences; República de ChinaFil: Buyck, Bart. Museum National d'Histoire Naturelle; FranciaFil: Rabeler, Richard K.. University of Michigan; Estados UnidosFil: Liles, Mark R.. Auburn University; Estados UnidosFil: Estes, Dwayne. Austin Peay State University; Estados UnidosFil: Carter, Richard. Valdosta State University; Estados UnidosFil: Herr Jr., J. M.. University of South Carolina; Estados UnidosFil: Chandler, Gregory. University of North Carolina; Estados UnidosFil: Kerekes, Jennifer. University of California at Berkeley; Estados UnidosFil: Cruse Sanders, Jennifer. Salem College Herbarium; Estados UnidosFil: Galán Marquez, R.. Universidad de Alcalá; EspañaFil: Horak, Egon. Zurich Herbarium; SuizaFil: Fitzsimons, Michael. University of Chicago; Estados UnidosFil: Döering, Heidi. Royal Botanic Gardens; Reino UnidoFil: Yao, Su. China Center of Industrial Culture Collection; ChinaFil: Hynson, Nicole. University of California at Berkeley; Estados UnidosFil: Ryberg, Martin. University Goteborg; SueciaFil: Arnold, A. E.. University of Arizona; Estados UnidosFil: Hughes, Karen. University of Tennessee; Estados Unido