RESUMO
We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.
Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Linhagem , Mapas de Interação de Proteínas/genética , Animais , Criança , Bases de Dados Genéticas , Modelos Animais de Doenças , Feminino , Deleção de Genes , Guanilato Quinases/genética , Humanos , Padrões de Herança/genética , Aprendizado de Máquina , Masculino , Núcleo Familiar , Regiões Promotoras Genéticas/genética , Receptores de Mineralocorticoides/genética , Fatores de Risco , Proteínas Supressoras de Tumor/genética , Sequenciamento Completo do Genoma , Peixe-Zebra/genéticaRESUMO
Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio [OR] = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts.
Assuntos
Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Cromossomos Humanos Par 2/genética , Estudos de Coortes , Bases de Dados Genéticas , Éxons/genética , Feminino , Duplicação Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredutases/genética , Penetrância , Regiões Promotoras Genéticas/genética , Fatores de Risco , Deleção de Sequência/genética , Irmãos , Proteínas Supressoras de Tumor/genética , Regiões não Traduzidas/genética , Oxidorredutase com Domínios WWRESUMO
PURPOSE: To map the canine rcd2 retinal degeneration locus. Rod-cone dysplasia type 2 (rcd2), an early-onset autosomal recessive form of progressive retinal atrophy (PRA), is phenotypically similar to early-onset forms of retinitis pigmentosa collectively termed Leber congenital amaurosis and segregates naturally in the collie breed of dog. Multiple genes have previously been evaluated as candidates for rcd2, but all have been excluded. METHODS: A set of informative experimental pedigrees segregating the rcd2 phenotype was produced. A genome-wide scan of these pedigrees using a set of 241 markers was undertaken. To refine the localized homology between canine and human maps, an RH map of the identified rcd2 region was built using a 3000 cR panel. A positional candidate gene strategy was then undertaken to begin to evaluate potentially causative genes. RESULTS: A locus responsible for the rcd2 phenotype was mapped to CFA7 in a region corresponding to human chromosome 1, region q32.1-q32.2. Maximum linkage was observed between rcd2 and marker FH3972 (theta = 0.02; lod = 25.53), and the critical region was flanked by markers FH2226 and FH3972. As CRB1 is the closest gene on human chromosome 1q known to cause retinal degeneration, canine gene-specific markers for CRB1 were developed, and this gene was excluded as a positional candidate for rcd2. CONCLUSIONS: The rcd2 locus represents a novel retinal degeneration gene. It is anticipated that when identified, this gene will offer new insights into retinal developmental and degenerative processes, and new opportunities for exploring experimental therapies.
Assuntos
Cromossomos Humanos Par 1/genética , Cromossomos de Mamíferos/genética , Doenças do Cão/genética , Ligação Genética , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/veterinária , Animais , Atrofia , Mapeamento Cromossômico , Cães , Proteínas do Olho/genética , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Linhagem , Mapeamento de Híbridos Radioativos , Degeneração Retiniana/genéticaRESUMO
The purebred dog population consists of >300 partially inbred genetic isolates or breeds. Restriction of gene flow between breeds, together with strong selection for traits, has led to the establishment of a unique resource for dissecting the genetic basis of simple and complex mammalian traits. Toward this end, we present a comprehensive radiation hybrid map of the canine genome composed of 3,270 markers including 1,596 microsatellite-based markers, 900 cloned gene sequences and ESTs, 668 canine-specific bacterial artificial chromosome (BAC) ends, and 106 sequence-tagged sites. The map was constructed by using the RHDF5000-2 whole-genome radiation hybrid panel and computed by using MULTIMAP and TSP/CONCORDE. The 3,270 markers map to 3,021 unique positions and define an average intermarker distance corresponding to 1 Mb. We also define a minimal screening set of 325 highly informative well spaced markers, to be used in the initiation of genome-wide scans. The well defined synteny between the dog and human genomes, established in part as a function of this work by the identification of 85 conserved fragments, will allow follow-up of initial findings of linkage by selection of candidate genes from the human genome sequence. This work continues to define the canine system as the method of choice in the pursuit of the genes causing mammalian variation and disease.
Assuntos
Genoma , Células Híbridas/efeitos da radiação , Animais , Cromossomos Artificiais Bacterianos , Cricetinae , Cães , Etiquetas de Sequências Expressas , Repetições de Microssatélites , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We are interested in the collagen gene superfamily and its involvement in hereditary diseases of the human and domestic dog. Presented here is radiation hybrid mapping of the type I and type IV collagen gene subfamilies on the most recent version of the canine map. The col1A1 gene was mapped to chromosome 9, col1A2 was mapped to chromosome 14, col4A1 and col4A2 were mapped to chromosome 22 and col4A3 and col4A4 were mapped to chromosome 25. The col4A5 and col4A6 genes, while linked to one another, are not linked in the present version of the canine map but likely are present on the X chromosome. These data provide an insight into the molecular evolution of these subfamilies and increase the number of mapped genes in discrete regions of the canine genome.