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1.
Nature ; 570(7762): 514-518, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31217584

RESUMO

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

3.
Hum Mutat ; 39(11): 1713-1720, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30311373

RESUMO

The Clinical Genome Resource (ClinGen) Ancestry and Diversity Working Group highlights the need to develop guidance on race, ethnicity, and ancestry (REA) data collection and use in clinical genomics. We present quantitative and qualitative evidence to characterize: (1) acquisition of REA data via clinical laboratory requisition forms, and (2) information disparity across populations in the Genome Aggregation Database (gnomAD) at clinically relevant sites ascertained from annotations in ClinVar. Our requisition form analysis showed substantial heterogeneity in clinical laboratory ascertainment of REA, as well as marked incongruity among terms used to define REA categories. There was also striking disparity across REA populations in the amount of information available about clinically relevant variants in gnomAD. European ancestral populations constituted the majority of observations (55.8%), allele counts (59.7%), and private alleles (56.1%) in gnomAD at 550 loci with "pathogenic" and "likely pathogenic" expert-reviewed variants in ClinVar. Our findings highlight the importance of implementing and supporting programs to increase diversity in genome sequencing and clinical genomics, as well as measuring uncertainty around population-level datasets that are used in variant interpretation. Finally, we suggest the need for a standardized REA data collection framework to be developed through partnerships and collaborations and adopted across clinical genomics.

4.
Elife ; 62017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28895531

RESUMO

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic BioMe biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.


Assuntos
Doenças do Colágeno/epidemiologia , Doenças do Colágeno/genética , Colágenos Fibrilares/genética , Epidemiologia Molecular , Linhagem , Adolescente , Adulto , Idoso , Criança , Feminino , Genótipo , Heterozigoto , Hispano-Americanos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Doenças Musculoesqueléticas/epidemiologia , Doenças Musculoesqueléticas/genética , Cidade de Nova Iorque/epidemiologia , Cidade de Nova Iorque/etnologia , Sequenciamento Completo do Genoma , Adulto Jovem
5.
Nat Genet ; 49(5): 700-707, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28394350

RESUMO

Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.


Assuntos
Perfilação da Expressão Gênica/métodos , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Locos de Características Quantitativas/genética , Processamento Alternativo , Mapeamento Cromossômico , Saúde da Família , Feminino , Predisposição Genética para Doença/genética , Genética Populacional , Genótipo , Humanos , Itália , Masculino , Polimorfismo de Nucleotídeo Único , Sítio de Iniciação de Transcrição
6.
Genetics ; 198(2): 561-75, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25146970

RESUMO

In multicellular organisms, genetic programs guide cells to adopt cell fates as tissues are formed during development, maintained in adults, and repaired after injury. Here we explore how a small molecule in the environment can switch a genetic program from one fate to another. Wild-type Caenorhabditis elegans XX adult hermaphrodites make oocytes continuously, but certain mutant XX adults make sperm instead in an otherwise hermaphrodite soma. Thus, puf-8; lip-1 XX adults make only sperm, but they can be switched from sperm to oocyte production by treatment with a small-molecule MEK inhibitor. To ask whether this chemical reprogramming is common, we tested six XX sperm-only mutants, but found only one other capable of cell fate switching, fbf-1; lip-1. Therefore, reprogramming competence relies on genotype, with only certain mutants capable of responding to the MEK inhibitor with a cell fate change. To gain insight into the molecular basis of competence for chemical reprogramming, we compared polyadenylated transcriptomes of competent and noncompetent XX sperm-only mutants in the absence of the MEK inhibitor and hence in the absence of cell fate reprogramming. Despite their cellular production of sperm, competent mutants were enriched for oogenic messenger RNAs relative to mutants lacking competence for chemical reprogramming. In addition, competent mutants expressed the oocyte-specific protein RME-2, whereas those lacking competence did not. Therefore, mutants competent for reprogramming possess an intersexual molecular profile at both RNA and protein levels. We suggest that this intersexual molecular signature is diagnostic of an intermediate network state that poises the germline tissue for changing its cellular fate in response to environmental cues.


Assuntos
Caenorhabditis elegans/genética , Transcriptoma , Animais , Butadienos/farmacologia , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Feminino , Expressão Gênica , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Mutação , Nitrilos/farmacologia , Oócitos/metabolismo , Especificidade de Órgãos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Processos de Determinação Sexual , Espermatozoides/metabolismo
7.
G3 (Bethesda) ; 4(9): 1765-72, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25060624

RESUMO

The nematode Caenorhabditis elegans is an important model for studies of germ cell biology, including the meiotic cell cycle, gamete specification as sperm or oocyte, and gamete development. Fundamental to those studies is a genome-level knowledge of the germline transcriptome. Here, we use RNA-Seq to identify genes expressed in isolated XX gonads, which are approximately 95% germline and 5% somatic gonadal tissue. We generate data from mutants making either sperm [fem-3(q96)] or oocytes [fog-2(q71)], both grown at 22°. Our dataset identifies a total of 10,754 mRNAs in the polyadenylated transcriptome of XX gonads, with 2748 enriched in spermatogenic gonads, 1732 enriched in oogenic gonads, and the remaining 6274 not enriched in either. These spermatogenic, oogenic, and gender-neutral gene datasets compare well with those of previous studies, but double the number of genes identified. A comparison of the additional genes found in our study with in situ hybridization patterns in the Kohara database suggests that most are expressed in the germline. We also query our RNA-Seq data for differential exon usage and find 351 mRNAs with sex-enriched isoforms. We suggest that this new dataset will prove useful for studies focusing on C. elegans germ cell biology.


Assuntos
Caenorhabditis elegans/genética , Oócitos/metabolismo , Espermatozoides/metabolismo , Processamento Alternativo , Animais , Sequência de Bases , Caenorhabditis elegans/metabolismo , Bases de Dados de Ácidos Nucleicos , Gônadas/metabolismo , Masculino , Dados de Sequência Molecular , RNA de Helmintos/genética , Análise de Sequência de RNA , Transcriptoma
8.
Nucleic Acids Res ; 36(14): 4788-96, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18653534

RESUMO

Among bacterial topoisomerase I enzymes, a conserved methionine residue is found at the active site next to the nucleophilic tyrosine. Substitution of this methionine residue with arginine in recombinant Yersinia pestis topoisomerase I (YTOP) was the only substitution at this position found to induce the SOS response in Escherichia coli. Overexpression of the M326R mutant YTOP resulted in approximately 4 log loss of viability. Biochemical analysis of purified Y. pestis and E. coli mutant topoisomerase I showed that the Met to Arg substitution affected the DNA religation step of the catalytic cycle. The introduction of an additional positive charge into the active site region of the mutant E. coli topoisomerase I activity shifted the pH for optimal activity and decreased the Mg(2+) binding affinity. This study demonstrated that a substitution outside the TOPRIM motif, which binds Mg(2+)directly, can nonetheless inhibit Mg(2+) binding and DNA religation by the enzyme, increasing the accumulation of covalent cleavage complex, with bactericidal consequence. Small molecules that can inhibit Mg(2+) dependent religation by bacterial topoisomerase I specifically could be developed into useful new antibacterial compounds. This approach would be similar to the inhibition of divalent ion dependent strand transfer by HIV integrase in antiviral therapy.


Assuntos
DNA Topoisomerases Tipo I/química , Escherichia coli/enzimologia , Magnésio/química , Yersinia pestis/enzimologia , Substituição de Aminoácidos , Arginina/química , Arginina/genética , Sítios de Ligação , Catálise , Cátions Bivalentes/química , Clivagem do DNA , DNA Topoisomerases Tipo I/genética , DNA Topoisomerases Tipo I/metabolismo , Concentração de Íons de Hidrogênio , Metionina/química , Metionina/genética , Modelos Moleculares , Resposta SOS (Genética)
9.
Nucleic Acids Res ; 36(3): 1017-25, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18096618

RESUMO

The TOPRIM DXDXXG residues of type IA and II topoisomerases are involved in Mg(II) binding and the cleavage-rejoining of DNA. Mutation of the strictly conserved glycine to serine in Yersinia pestis and Escherichia coli topoisomerase I results in bacterial cell killing due to inhibition of DNA religation after DNA cleavage. In this study, all other substitutions at the TOPRIM glycine of Y. pestis topoisomerase I were examined. While the Gly to Ala substitution allowed both DNA cleavage and religation, other mutations abolished DNA cleavage. DNA cleavage activity retained by the Gly to Ser mutant could be significantly enhanced by a second mutation of the methionine residue adjacent to the active site tyrosine. Induction of mutant topoisomerase with both the TOPRIM glycine and active site region methionine mutations resulted in up to 40-fold higher cell killing rate when compared with the single TOPRIM Gly to Ser mutant. Bacterial type IA topoisomerases are potential targets for discovery of novel antibiotics. These results suggest that compounds that interact simultaneously with the TOPRIM motif and the molecular surface around the active site tyrosine could be highly efficient topoisomerase poisons through both enhancement of DNA cleavage and inhibition of DNA rejoining.


Assuntos
DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/genética , DNA/metabolismo , Glicina/química , Serina/química , Motivos de Aminoácidos , Substituição de Aminoácidos , Sítios de Ligação , DNA Topoisomerases Tipo I/metabolismo , Escherichia coli/enzimologia , Glicina/genética , Magnésio/química , Metionina/química , Metionina/genética , Mutação , Fenótipo , Resposta SOS (Genética) , Serina/genética , Tirosina/química , Valina/genética , Yersinia pestis/enzimologia
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