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1.
Nat Commun ; 10(1): 1784, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992455

RESUMO

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.


Assuntos
Genoma Humano/genética , Variação Estrutural do Genoma , Genômica/métodos , Haplótipos/genética , Algoritmos , Mapeamento Cromossômico/métodos , Bases de Dados Genéticas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação INDEL , Sequenciamento Completo do Genoma/métodos
3.
Am J Hum Genet ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30503522

RESUMO

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

5.
Nature ; 559(7714): 350-355, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29995854

RESUMO

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.

6.
Nat Commun ; 9(1): 2606, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973585

RESUMO

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

7.
Nat Commun ; 9(1): 1929, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769526

RESUMO

Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.

8.
Nat Genet ; 50(5): 727-736, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29700473

RESUMO

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.

9.
PLoS Genet ; 14(3): e1007293, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29590102

RESUMO

Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (-α3.7 deletion) and ß-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the -α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the -α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the -α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the -α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and ß-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.


Assuntos
Anemia Falciforme/genética , Hemoglobina Falciforme/genética , Traço Falciforme , alfa-Globinas/genética , Adulto , Afro-Americanos , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Estudos de Coortes , Variações do Número de Cópias de DNA , Eritrócitos Anormais , Taxa de Filtração Glomerular , Hemoglobina A Glicada/metabolismo , Humanos , Fenótipo , Adulto Jovem , Talassemia alfa/genética
10.
Nat Neurosci ; 21(7): 1017, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29549319

RESUMO

In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author; it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note; in fact, only names are given. In all versions of the paper, the corresponding author symbols were attached to A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington and Thomas Lehner; they should have been attached, respectively, to Steven E. Hyman, Anjene M. Addington, Thomas Lehner and Nelson B. Freimer. As a result of this shift, the respective contact links in the HTML version did not lead to the indicated individuals. The errors have been corrected in the HTML and PDF versions of the article.

12.
Genome Res ; 27(8): 1450-1459, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28522612

RESUMO

Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional "download and analyze" paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.


Assuntos
Computação em Nuvem , Variação Genética , Genoma Humano , Genômica/métodos , Neoplasias/genética , Software , Bases de Dados Genéticas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
13.
Nature ; 545(7653): 229-233, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28445466

RESUMO

Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use. We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line. Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use.


Assuntos
Genes Dominantes/genética , Genes p53 , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética , Seleção Genética , Proteína Supressora de Tumor p53/genética , Alelos , Contagem de Células , Diferenciação Celular/genética , Divisão Celular/genética , Linhagem Celular , DNA/metabolismo , Análise Mutacional de DNA , Exoma/genética , Células-Tronco Embrionárias Humanas/citologia , Humanos , Perda de Heterozigosidade/genética , Mosaicismo , Neoplasias/genética , Domínios Proteicos , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo
14.
Nat Neurosci ; 19(12): 1563-1565, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27694993

RESUMO

Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Educação , Humanos , Análise e Desempenho de Tarefas
15.
Nat Genet ; 48(6): 593-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27111036

RESUMO

We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.


Assuntos
Cromossomos Humanos Y , Demografia , Haplótipos , Humanos , Masculino , Mutação , Filogenia , Polimorfismo de Nucleotídeo Único
16.
Nat Genet ; 48(4): 359-66, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26901066

RESUMO

One of the first protein polymorphisms identified in humans involves the abundant blood protein haptoglobin. Two exons of the HP gene (encoding haptoglobin) exhibit copy number variation that affects HP protein structure and multimerization. The evolutionary origins and medical relevance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from many recurring deletions, more specifically, reversions of an ancient hominin-specific duplication of these exons. Although this polymorphism has been largely invisible to genome-wide genetic studies thus far, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We further show that these deletions, and a SNP that affects HP expression, appear to drive the strong association of cholesterol levels with SNPs near HP. Recurring exonic deletions in HP likely enhance human health by lowering cholesterol levels in the blood.


Assuntos
Colesterol/sangue , Haptoglobinas/genética , Deleção de Sequência , Sequência de Bases , Éxons , Frequência do Gene , Estudos de Associação Genética , Haplótipos , Humanos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
17.
Nature ; 530(7589): 177-83, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26814963

RESUMO

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.


Assuntos
Complemento C4/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Esquizofrenia/genética , Alelos , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Complemento C4/química , Via Clássica do Complemento , Dendritos/metabolismo , Dosagem de Genes/genética , Regulação da Expressão Gênica/genética , Haplótipos/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , Camundongos , Modelos Animais , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Fatores de Risco , Esquizofrenia/patologia , Sinapses/metabolismo
18.
Nature ; 526(7571): 75-81, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26432246

RESUMO

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Mapeamento Físico do Cromossomo , Sequência de Aminoácidos , Predisposição Genética para Doença , Genética Médica , Genética Populacional , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Haplótipos/genética , Homozigoto , Humanos , Dados de Sequência Molecular , Taxa de Mutação , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Análise de Sequência de DNA , Deleção de Sequência/genética
19.
Nat Genet ; 47(8): 921-5, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26098870

RESUMO

Hundreds of genes reside in structurally complex, poorly understood regions of the human genome. One such region contains the three amylase genes (AMY2B, AMY2A and AMY1) responsible for digesting starch into sugar. Copy number of AMY1 is reported to be the largest genomic influence on obesity, although genome-wide association studies for obesity have found this locus unremarkable. Using whole-genome sequence analysis, droplet digital PCR and genome mapping, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that the AMY1 copy number in an individual's genome is generally even (rather than odd) and partially correlates with nearby SNPs, which do not associate with body mass index (BMI). We measured amylase gene copy number in 1,000 obese or lean Estonians and in 2 other cohorts totaling ∼3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI, yet found no association.


Assuntos
Amilases/genética , Predisposição Genética para Doença/genética , Haplótipos , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Índice de Massa Corporal , Estudos de Coortes , Feminino , Dosagem de Genes , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Adulto Jovem
20.
Genome Res ; 25(6): 792-801, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25883321

RESUMO

Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.


Assuntos
Variação Genética , Genoma Humano , Alelos , Sequência de Aminoácidos , Feminino , Genômica , Haplótipos , Humanos , Mutação INDEL , Masculino , Dados de Sequência Molecular , Taxa de Mutação , Polimorfismo de Nucleotídeo Único , Retroelementos/genética , Alinhamento de Sequência , Análise de Sequência de DNA
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