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1.
Eur J Hum Genet ; 27(5): 738-746, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679813

RESUMO

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

2.
Nat Genet ; 50(9): 1327-1334, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30127527

RESUMO

Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.

3.
Proc Natl Acad Sci U S A ; 115(8): E1859-E1866, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29434036

RESUMO

In individuals with autism spectrum disorder (ASD), de novo mutations have previously been shown to be significantly correlated with lower IQ but not with the core characteristics of ASD: deficits in social communication and interaction and restricted interests and repetitive patterns of behavior. We extend these findings by demonstrating in the Simons Simplex Collection that damaging de novo mutations in ASD individuals are also significantly and convincingly correlated with measures of impaired motor skills. This correlation is not explained by a correlation between IQ and motor skills. We find that IQ and motor skills are distinctly associated with damaging mutations and, in particular, that motor skills are a more sensitive indicator of mutational severity than is IQ, as judged by mutational type and target gene. We use this finding to propose a combined classification of phenotypic severity: mild (little impairment of either), moderate (impairment mainly to motor skills), and severe (impairment of both IQ and motor skills).


Assuntos
Transtorno do Espectro Autista/genética , Destreza Motora/fisiologia , Criança , Feminino , Genótipo , Humanos , Masculino , Mutação
4.
Proc Natl Acad Sci U S A ; 114(27): 7073-7076, 2017 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-28630308

RESUMO

We develop a method of analysis [affected to discordant sibling pairs (A2DS)] that tests if shared variants contribute to a disorder. Using a standard measure of genetic relation, test individuals are compared with a cohort of discordant sibling pairs (CDS) to derive a comparative similarity score. We ask if a test individual is more similar to an unrelated affected than to the unrelated unaffected sibling from the CDS and then, sum over such individuals and pairs. Statistical significance is judged by randomly permuting the affected status in the CDS. In the analysis of published genotype data from the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) cohorts of children with autism spectrum disorder (ASD), we find strong statistical significance that the affected are more similar to the affected than to the unaffected of the CDS (P value ∼ 0.00001). Fathers in multiplex families have marginally greater similarity (P value = 0.02) to unrelated affected individuals. These results do not depend on ethnic matching or gender.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Irmãos , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Simulação por Computador , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
5.
Nat Protoc ; 11(12): 2529-2548, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27854363

RESUMO

As the second most common type of variation in the human genome, insertions and deletions (indels) have been linked to many diseases, but the discovery of indels of more than a few bases in size from short-read sequencing data remains challenging. Scalpel (http://scalpel.sourceforge.net) is an open-source software for reliable indel detection based on the microassembly technique. It has been successfully used to discover mutations in novel candidate genes for autism, and it is extensively used in other large-scale studies of human diseases. This protocol gives an overview of the algorithm and describes how to use Scalpel to perform highly accurate indel calling from whole-genome and whole-exome sequencing data. We provide detailed instructions for an exemplary family-based de novo study, but we also characterize the other two supported modes of operation: single-sample and somatic analysis. Indel normalization, visualization and annotation of the mutations are also illustrated. Using a standard server, indel discovery and characterization in the exonic regions of the example sequencing data can be completed in ∼5 h after read mapping.


Assuntos
Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação INDEL , Alelos , Genômica , Humanos , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único
6.
Am J Hum Genet ; 98(1): 58-74, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26749308

RESUMO

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 = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.


Assuntos
Transtorno Autístico/genética , DNA/genética , Genoma Humano , Exoma , Feminino , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único
7.
Proc Natl Acad Sci U S A ; 112(41): E5600-7, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26401017

RESUMO

We previously computed that genes with de novo (DN) likely gene-disruptive (LGD) mutations in children with autism spectrum disorders (ASD) have high vulnerability: disruptive mutations in many of these genes, the vulnerable autism genes, will have a high likelihood of resulting in ASD. Because individuals with ASD have lower fecundity, such mutations in autism genes would be under strong negative selection pressure. An immediate prediction is that these genes will have a lower LGD load than typical genes in the human gene pool. We confirm this hypothesis in an explicit test by measuring the load of disruptive mutations in whole-exome sequence databases from two cohorts. We use information about mutational load to show that lower and higher intelligence quotients (IQ) affected individuals can be distinguished by the mutational load in their respective gene targets, as well as to help prioritize gene targets by their likelihood of being autism genes. Moreover, we demonstrate that transmission of rare disruptions in genes with a lower LGD load occurs more often to affected offspring; we show transmission originates most often from the mother, and transmission of such variants is seen more often in offspring with lower IQ. A surprising proportion of transmission of these rare events comes from genes expressed in the embryonic brain that show sharply reduced expression shortly after birth.


Assuntos
Transtorno Autístico/genética , Bases de Dados Genéticas , Exoma , Pool Gênico , Modelos Genéticos , Mutação , Criança , Pré-Escolar , Feminino , Humanos , Masculino
8.
Cold Spring Harb Mol Case Stud ; 1(1): a000422, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27148569

RESUMO

Autism spectrum disorders (ASDs) are a group of developmental disabilities that affect social interaction and communication and are characterized by repetitive behaviors. There is now a large body of evidence that suggests a complex role of genetics in ASDs, in which many different loci are involved. Although many current population-scale genomic studies have been demonstrably fruitful, these studies generally focus on analyzing a limited part of the genome or use a limited set of bioinformatics tools. These limitations preclude the analysis of genome-wide perturbations that may contribute to the development and severity of ASD-related phenotypes. To overcome these limitations, we have developed and utilized an integrative clinical and bioinformatics pipeline for generating a more complete and reliable set of genomic variants for downstream analyses. Our study focuses on the analysis of three simplex autism families consisting of one affected child, unaffected parents, and one unaffected sibling. All members were clinically evaluated and widely phenotyped. Genotyping arrays and whole-genome sequencing were performed on each member, and the resulting sequencing data were analyzed using a variety of available bioinformatics tools. We searched for rare variants of putative functional impact that were found to be segregating according to de novo, autosomal recessive, X-linked, mitochondrial, and compound heterozygote transmission models. The resulting candidate variants included three small heterozygous copy-number variations (CNVs), a rare heterozygous de novo nonsense mutation in MYBBP1A located within exon 1, and a novel de novo missense variant in LAMB3. Our work demonstrates how more comprehensive analyses that include rich clinical data and whole-genome sequencing data can generate reliable results for use in downstream investigations.

9.
Science ; 350(6265): 1262-6, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26785492

RESUMO

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.


Assuntos
Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Malformações do Sistema Nervoso/genética , Neurogênese/genética , Encéfalo/anormalidades , Encéfalo/metabolismo , Criança , Anormalidades Congênitas/genética , Exoma/genética , Humanos , Mutação , Prognóstico , Processamento de RNA/genética , Fatores de Processamento de RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Transcrição Genética
10.
Genome Med ; 6(10): 89, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25426171

RESUMO

BACKGROUND: INDELs, especially those disrupting protein-coding regions of the genome, have been strongly associated with human diseases. However, there are still many errors with INDEL variant calling, driven by library preparation, sequencing biases, and algorithm artifacts. METHODS: We characterized whole genome sequencing (WGS), whole exome sequencing (WES), and PCR-free sequencing data from the same samples to investigate the sources of INDEL errors. We also developed a classification scheme based on the coverage and composition to rank high and low quality INDEL calls. We performed a large-scale validation experiment on 600 loci, and find high-quality INDELs to have a substantially lower error rate than low-quality INDELs (7% vs. 51%). RESULTS: Simulation and experimental data show that assembly based callers are significantly more sensitive and robust for detecting large INDELs (>5 bp) than alignment based callers, consistent with published data. The concordance of INDEL detection between WGS and WES is low (53%), and WGS data uniquely identifies 10.8-fold more high-quality INDELs. The validation rate for WGS-specific INDELs is also much higher than that for WES-specific INDELs (84% vs. 57%), and WES misses many large INDELs. In addition, the concordance for INDEL detection between standard WGS and PCR-free sequencing is 71%, and standard WGS data uniquely identifies 6.3-fold more low-quality INDELs. Furthermore, accurate detection with Scalpel of heterozygous INDELs requires 1.2-fold higher coverage than that for homozygous INDELs. Lastly, homopolymer A/T INDELs are a major source of low-quality INDEL calls, and they are highly enriched in the WES data. CONCLUSIONS: Overall, we show that accuracy of INDEL detection with WGS is much greater than WES even in the targeted region. We calculated that 60X WGS depth of coverage from the HiSeq platform is needed to recover 95% of INDELs detected by Scalpel. While this is higher than current sequencing practice, the deeper coverage may save total project costs because of the greater accuracy and sensitivity. Finally, we investigate sources of INDEL errors (for example, capture deficiency, PCR amplification, homopolymers) with various data that will serve as a guideline to effectively reduce INDEL errors in genome sequencing.

11.
Nature ; 515(7526): 216-21, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25363768

RESUMO

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Predisposição Genética para Doença/genética , Mutação/genética , Fases de Leitura Aberta/genética , Criança , Análise por Conglomerados , Exoma/genética , Feminino , Genes , Humanos , Testes de Inteligência , Masculino , Reprodutibilidade dos Testes
12.
Circ Res ; 115(10): 884-896, 2014 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-25205790

RESUMO

RATIONALE: Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis. OBJECTIVE: To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD. METHODS AND RESULTS: We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6×10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions. CONCLUSIONS: We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.


Assuntos
Variações do Número de Cópias de DNA/genética , Exoma/genética , Frequência do Gene/genética , Cardiopatias Congênitas/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Estudos de Coortes , Redes Reguladoras de Genes/genética , Cardiopatias Congênitas/diagnóstico , Humanos , Dados de Sequência Molecular
13.
Nat Methods ; 11(10): 1033-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25128977

RESUMO

We present an open-source algorithm, Scalpel (http://scalpel.sourceforge.net/), which combines mapping and assembly for sensitive and specific discovery of insertions and deletions (indels) in exome-capture data. A detailed repeat analysis coupled with a self-tuning k-mer strategy allows Scalpel to outperform other state-of-the-art approaches for indel discovery, particularly in regions containing near-perfect repeats. We analyzed 593 families from the Simons Simplex Collection and demonstrated Scalpel's power to detect long (≥30 bp) transmitted events and enrichment for de novo likely gene-disrupting indels in autistic children.


Assuntos
Análise Mutacional de DNA/métodos , Exoma , Mutação INDEL , Algoritmos , Biologia Computacional/métodos , DNA/química , Bases de Dados Genéticas , Humanos , Mutação , Linguagens de Programação , Alinhamento de Sequência , Software
14.
J Chem Inf Model ; 54(8): 2286-93, 2014 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-25026390

RESUMO

Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descriptors for a set of antifungal compounds ("drugs") previously examined for interaction. Analyzing the relationship between molecular weight, lipophilicity, H-bond donor, and H-bond acceptor values for drugs and their propensity to show pairwise antifungal drug synergy, we found that combinations of two lipophilic drugs had a greater tendency to show drug synergy. We developed a more refined decision tree model that successfully predicted drug synergy in stringent cross-validation tests based on only lipophilicity of drugs. Our predictions achieved a precision of 63% and allowed successful prediction for 58% of synergistic drug pairs, suggesting that this phenomenon can extend our understanding for a substantial fraction of synergistic drug interactions. We also generated and analyzed a large-scale synergistic human toxicity network, in which we observed that combinations of lipophilic compounds show a tendency for increased toxicity. Thus, lipophilicity, a simple and easily determined molecular descriptor, is a powerful predictor of drug synergy. It is well established that lipophilic compounds (i) are promiscuous, having many targets in the cell, and (ii) often penetrate into the cell via the cellular membrane by passive diffusion. We discuss the positive relationship between drug lipophilicity and drug synergy in the context of potential drug synergy mechanisms.


Assuntos
Antifúngicos/química , Modelos Estatísticos , Animais , Antifúngicos/farmacologia , Benzamidas/química , Benzamidas/toxicidade , Benzilatos/química , Benzilatos/toxicidade , Árvores de Decisões , Sinergismo Farmacológico , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Humanos , Interações Hidrofóbicas e Hidrofílicas , Naftalenos/química , Naftalenos/farmacologia , Nortropanos/química , Nortropanos/toxicidade , Pentamidina/química , Pentamidina/farmacologia , Terbinafina , Triprolidina/química , Triprolidina/toxicidade
15.
Chem Biol ; 21(4): 541-551, 2014 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-24704506

RESUMO

One drug may suppress the effects of another. Although knowledge of drug suppression is vital to avoid efficacy-reducing drug interactions or discover countermeasures for chemical toxins, drug-drug suppression relationships have not been systematically mapped. Here, we analyze the growth response of Saccharomyces cerevisiae to anti-fungal compound ("drug") pairs. Among 440 ordered drug pairs, we identified 94 suppressive drug interactions. Using only pairs not selected on the basis of their suppression behavior, we provide an estimate of the prevalence of suppressive interactions between anti-fungal compounds as 17%. Analysis of the drug suppression network suggested that Bromopyruvate is a frequently suppressive drug and Staurosporine is a frequently suppressed drug. We investigated potential explanations for suppressive drug interactions, including chemogenomic analysis, coaggregation, and pH effects, allowing us to explain the interaction tendencies of Bromopyruvate.


Assuntos
Antifúngicos/farmacologia , Piruvatos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Bioensaio , Interações de Medicamentos , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae/citologia , Estaurosporina/farmacologia , Relação Estrutura-Atividade
16.
Nat Rev Genet ; 15(2): 133-41, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24430941

RESUMO

The identification of the genetic components of autism spectrum disorders (ASDs) has advanced rapidly in recent years, particularly with the demonstration of de novo mutations as an important source of causality. We review these developments in light of genetic models for ASDs. We consider the number of genetic loci that underlie ASDs and the relative contributions from different mutational classes, and we discuss possible mechanisms by which these mutations might lead to dysfunction. We update the two-class risk genetic model for autism, especially in regard to children with high intelligence quotients.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Predisposição Genética para Doença/genética , Modelos Genéticos , Mutação , Criança , Transtornos Globais do Desenvolvimento Infantil/psicologia , Feminino , Humanos , Inteligência , Masculino , Fatores Sexuais
17.
Neuron ; 74(2): 285-99, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22542183

RESUMO

Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Proteína do X Frágil de Retardo Mental/genética , Predisposição Genética para Doença , Mutação/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/etiologia , Pré-Escolar , Saúde da Família , Feminino , Dosagem de Genes , Estudos de Associação Genética , Humanos , Masculino , Modelos Moleculares , Pais , Fenótipo
18.
Genome Biol ; 12(9): R97, 2011 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-21958622

RESUMO

BACKGROUND: Human exome resequencing using commercial target capture kits has been and is being used for sequencing large numbers of individuals to search for variants associated with various human diseases. We rigorously evaluated the capabilities of two solution exome capture kits. These analyses help clarify the strengths and limitations of those data as well as systematically identify variables that should be considered in the use of those data. RESULTS: Each exome kit performed well at capturing the targets they were designed to capture, which mainly corresponds to the consensus coding sequences (CCDS) annotations of the human genome. In addition, based on their respective targets, each capture kit coupled with high coverage Illumina sequencing produced highly accurate nucleotide calls. However, other databases, such as the Reference Sequence collection (RefSeq), define the exome more broadly, and so not surprisingly, the exome kits did not capture these additional regions. CONCLUSIONS: Commercial exome capture kits provide a very efficient way to sequence select areas of the genome at very high accuracy. Here we provide the data to help guide critical analyses of sequencing data derived from these products.


Assuntos
Exoma , Kit de Reagentes para Diagnóstico/normas , Análise de Sequência de DNA/métodos , Algoritmos , Sequência de Bases , Linhagem Celular , Biologia Computacional , Sequência Consenso , DNA/genética , Biblioteca Gênica , Genoma Humano , Projeto HapMap , Humanos , Anotação de Sequência Molecular , Fases de Leitura Aberta , Sensibilidade e Especificidade
19.
Neuron ; 70(5): 886-97, 2011 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-21658582

RESUMO

To explore the genetic contribution to autistic spectrum disorders (ASDs), we have studied genomic copy-number variation in a large cohort of families with a single affected child and at least one unaffected sibling. We confirm a major contribution from de novo deletions and duplications but also find evidence of a role for inherited "ultrarare" duplications. Our results show that, relative to males, females have greater resistance to autism from genetic causes, which raises the question of the fate of female carriers. By analysis of the proportion and number of recurrent loci, we set a lower bound for distinct target loci at several hundred. We find many new candidate regions, adding substantially to the list of potential gene targets, and confirm several loci previously observed. The functions of the genes in the regions of de novo variation point to a great diversity of genetic causes but also suggest functional convergence.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Variações do Número de Cópias de DNA/genética , Saúde da Família , Deleção de Genes , Predisposição Genética para Doença/genética , Neurotransmissores/genética , Criança , Pré-Escolar , Bases de Dados de Ácidos Nucleicos/estatística & dados numéricos , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Masculino , Modelos Estatísticos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fenótipo , Probabilidade , Irmãos
20.
Neuron ; 70(5): 898-907, 2011 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-21658583

RESUMO

Identification of complex molecular networks underlying common human phenotypes is a major challenge of modern genetics. In this study, we develop a method for network-based analysis of genetic associations (NETBAG). We use NETBAG to identify a large biological network of genes affected by rare de novo CNVs in autism. The genes forming the network are primarily related to synapse development, axon targeting, and neuron motility. The identified network is strongly related to genes previously implicated in autism and intellectual disability phenotypes. Our results are also consistent with the hypothesis that significantly stronger functional perturbations are required to trigger the autistic phenotype in females compared to males. Overall, the presented analysis of de novo variants supports the hypothesis that perturbed synaptogenesis is at the heart of autism. More generally, our study provides proof of the principle that networks underlying complex human phenotypes can be identified by a network-based functional analysis of rare genetic variants.


Assuntos
Transtorno Autístico/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Sinapses/genética , Algoritmos , Área Sob a Curva , Transtorno Autístico/patologia , Mapeamento Cromossômico , Análise por Conglomerados , Variações do Número de Cópias de DNA/genética , Bases de Dados Genéticas/estatística & dados numéricos , Feminino , Humanos , Funções Verossimilhança , Masculino , Modelos Neurológicos , Fenótipo , Filogenia , Densidade Pós-Sináptica/genética , Reprodutibilidade dos Testes
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