RESUMEN
Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.
Asunto(s)
Trastorno del Espectro Autista/genética , Eliminación de Gen , Duplicación de Gen , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Niño , Variaciones en el Número de Copia de ADN , Femenino , Frecuencia de los Genes , Reordenamiento Génico , Sitios Genéticos , Genoma Humano , Técnicas de Genotipaje , Humanos , Mutación INDEL , Masculino , Análisis por Micromatrices , Datos de Secuencia Molecular , Linaje , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.
Asunto(s)
Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Variación Genética , Herencia Paterna , Regiones Promotoras Genéticas/genética , Exones , Regulación de la Expresión Génica , Genoma Humano , Humanos , Mutación , Linaje , ARN no Traducido/genética , Selección Genética , Eliminación de Secuencia , Factores de Transcripción/genéticaRESUMEN
Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Sitios Genéticos/genética , Marcadores Genéticos/genética , Estudio de Asociación del Genoma Completo , Esquizofrenia/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Factores de RiesgoRESUMEN
In over 100 neuroscience genetics reports on SLC6A4 published in the first part of 2012, >40% reported data from genotyping only the serotonin transporter-linked promoter region [5HTTLPR] indel, omitting genotyping of two nearby SNPs that substantially alter 5HTTLPR allele frequencies and functionality. And 25% of these papers did not report ethnicity of the subjects genotyped, another factor that alters allele frequencies. This field thus seems stultified. Improved science for the present and future will be better served by attention to more complete methods for genotyping and subject sample reporting.