RESUMO
There are bioethical, institutional, economic, legal, and cultural obstacles to creating the robust-precompetitive-data resource that will be required to advance the vision of "precision medicine," the ability to use molecular data to target therapies to patients for whom they offer the most benefit at the least risk. Creation of such an "information commons" was the central recommendation of the 2011 report Toward Precision Medicine issued by a committee of the National Research Council of the USA (Committee on a Framework for Development of a New Taxonomy of Disease; National Research Council. Toward precision medicine: building a knowledge network for biomedical research and a new taxonomy of disease. 2011). In this commentary, I review the rationale for creating an information commons and the obstacles to doing so; then, I endorse a path forward based on the dynamic consent of research subjects interacting with researchers through trusted mediators. I assert that the advantages of the proposed system overwhelm alternative ways of handling data on the phenotypes, genotypes, and environmental exposures of individual humans; hence, I argue that its creation should be the central policy objective of early efforts to make precision medicine a reality.
Assuntos
Atenção à Saúde/organização & administração , Genética Humana/tendências , Medicina de Precisão/tendências , Genoma Humano , Genética Humana/ética , Genética Humana/organização & administração , Humanos , Tecnologia da Informação , Fenótipo , Medicina de Precisão/métodos , PrivacidadeAssuntos
Testes Genéticos/tendências , Genética Médica/tendências , Genética Populacional/tendências , Análise de Sequência de DNA/tendências , Animais , Líquidos Corporais/microbiologia , Criança , Síndrome de Down/genética , Epigênese Genética , Saúde da Família/tendências , Genética Forense/tendências , Genoma Bacteriano/genética , Humanos , Metagenômica/tendências , Neoplasias/diagnóstico , Neoplasias/genética , Análise de Sequência de DNA/economia , Análise de Sequência de DNA/estatística & dados numéricos , Águas Residuárias/microbiologiaRESUMO
Fulfilling the promise of the genetic revolution requires the analysis of large datasets containing information from thousands to millions of participants. However, sharing human genomic data requires protecting subjects from potential harm. Current models rely on de-identification techniques in which privacy versus data utility becomes a zero-sum game. Instead, we propose the use of trust-enabling techniques to create a solution in which researchers and participants both win. To do so we introduce three principles that facilitate trust in genetic research and outline one possible framework built upon those principles. Our hope is that such trust-centric frameworks provide a sustainable solution that reconciles genetic privacy with data sharing and facilitates genetic research.
Assuntos
Privacidade Genética , Genoma Humano , Genômica/legislação & jurisprudência , Consentimento Livre e Esclarecido , Confiança , Pesquisa Participativa Baseada na Comunidade , HumanosRESUMO
The central preoccupation of human genetics is an effort to understand the genotypic basis of human phenotypic diversity. Although recent progress in identifying the genes that, when mutated, underlie major genetic diseases has been rapid, knowledge of the genetic influences on the vast range of variable, and at least partially heritable, traits that constitute the "normal" range of human phenotypic variation lags. Spectacular advances in our knowledge of human genetic variation have laid the groundwork for a synthesis of insights from medical genetics, population genetics, molecular evolution, and the study of human origins that places basic constraints on models of human genetic individuality. Balancing selection, local adaptation, mutation-selection balance, and founder effects have all extensively shaped contemporary genetic variation. Long-term-balancing selection appears largely to reflect the consequences of host-pathogen arms races. Local adaptation has been widespread-and involved responses to a plethora of selective pressures, some identifiable but most unknown. However, it appears to be a combination of mutation-selection balance and founder effects that largely accounts for genetic individuality. If true, this inference has major implications for future research programs in human genetics.
Assuntos
Variação Genética , Animais , Evolução Molecular , Genética Médica/história , Genoma Humano , Haplótipos , História do Século XX , Humanos , Modelos Genéticos , Mutação , Seleção Genética , Análise de Sequência de DNARESUMO
Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. Here we explore variation on an intermediate scale--particularly insertions, deletions and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1,695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number between individuals. Complete sequencing of 261 structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence map of human structural variation--a standard for genotyping platforms and a prelude to future individual genome sequencing projects.
Assuntos
Variação Genética/genética , Genoma Humano/genética , Mapeamento Físico do Cromossomo , Análise de Sequência de DNA , Inversão Cromossômica/genética , Eucromatina/genética , Deleção de Genes , Geografia , Haplótipos , Humanos , Mutagênese Insercional/genética , Polimorfismo de Nucleotídeo Único/genética , Grupos Raciais/genética , Reprodutibilidade dos TestesRESUMO
Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.
Assuntos
Genoma Humano , Instabilidade Genômica , Mutação , Polimorfismo Genético , Pareamento de Bases , Linhagem Celular Tumoral , Biologia Computacional , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Valores de Referência , Análise de Sequência de DNARESUMO
It is well known that average levels of population structure are higher on the X chromosome compared to autosomes in humans. However, there have been surprisingly few analyses on the spatial distribution of population structure along the X chromosome. With publicly available data from the HapMap Project and Perlegen Sciences, we show a strikingly punctuated pattern of X chromosome population structure. Specifically, 87% of X-linked HapMap SNPs within the top 1% of F(ST) values cluster into five distinct loci. The largest of these regions spans 5.4 Mb and contains 66% of the most highly differentiated HapMap SNPs on the X chromosome. We demonstrate that the extreme clustering of highly differentiated SNPs on the X chromosome is not an artifact of ascertainment bias, nor is it specific to the populations genotyped in the HapMap Project. Rather, additional analyses and resequencing data suggest that these five regions have been substrates of recent and strong adaptive evolution. Finally, we discuss the implications that patterns of X-linked population structure have on the evolutionary history of African populations.
Assuntos
População Negra/genética , Cromossomos Humanos X , Evolução Molecular , Genética Populacional , Grupos Populacionais/genética , Alelos , Bases de Dados Genéticas , Frequência do Gene , Genoma Humano , Genótipo , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Estados UnidosRESUMO
We have established strong linkage evidence that supports mapping autosomal-dominant sensory/motor neuropathy with ataxia (SMNA) to chromosome 7q22-q32. SMNA is a rare neurological disorder whose phenotype encompasses both the central and the peripheral nervous system. In order to identify a gene responsible for SMNA, we have undertaken a comprehensive genomic evaluation of the region of linkage, including evaluation for repeat expansion and small deletions or duplications, capillary sequencing of candidate genes, and massively parallel sequencing of all coding exons. We excluded repeat expansion and small deletions or duplications as causative, and through microarray-based hybrid capture and massively parallel short-read sequencing, we identified a nonsynonymous variant in the human interferon-related developmental regulator gene 1 (IFRD1) as a disease-causing candidate. Sequence conservation, animal models, and protein structure evaluation support the involvement of IFRD1 in SMNA. Mutation analysis of IFRD1 in additional patients with similar phenotypes is needed for demonstration of causality and further evaluation of its importance in neurological diseases.
Assuntos
Ataxia/genética , Cromossomos Humanos Par 7/genética , Predisposição Genética para Doença , Neuropatia Hereditária Motora e Sensorial/genética , Proteínas Imediatamente Precoces/genética , Humanos , Mutação , LinhagemRESUMO
The genome sequence of the aceticlastic methanoarchaeon Methanosaeta concilii GP6, comprised of a 3,008,626-bp chromosome and an 18,019-bp episome, has been determined and exhibits considerable differences in gene content from that of Methanosaeta thermophila.
Assuntos
Genoma Arqueal , Metano/metabolismo , Methanosarcinaceae/genética , Methanosarcinaceae/metabolismo , Sequência de Bases , DNA Arqueal/genética , Methanosarcinaceae/classificação , Dados de Sequência Molecular , Análise de Sequência de DNAAssuntos
Genoma Humano/genética , Genômica/métodos , Análise de Sequência de DNA/métodos , Aconselhamento Genético , Predisposição Genética para Doença/genética , Genética Médica/tendências , Genômica/economia , Genômica/tendências , Projeto Genoma Humano , Humanos , Individualidade , Masculino , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA/economiaRESUMO
Large-insert genome analysis (LIGAN) is a broadly applicable, high-throughput technology designed to characterize genome-scale structural variation. Fosmid paired-end sequences and DNA fingerprints from a query genome are compared to a reference sequence using the Genomic Variation Analysis (GenVal) suite of software tools to pinpoint locations of insertions, deletions, and rearrangements. Fosmids spanning regions that contain new structural variants can then be sequenced. Clonal pairs of Pseudomonas aeruginosa isolates from four cystic fibrosis patients were used to validate the LIGAN technology. Approximately 1.5 Mb of inserted sequences were identified, including 743 kb containing 615 ORFs that are absent from published P. aeruginosa genomes. Six rearrangement breakpoints and 220 kb of deleted sequences were also identified. Our study expands the "genome universe" of P. aeruginosa and validates a technology that complements emerging, short-read sequencing methods that are better suited to characterizing single-nucleotide polymorphisms than structural variation.
Assuntos
Fibrose Cística/microbiologia , Impressões Digitais de DNA/métodos , Análise Mutacional de DNA/métodos , Genoma Bacteriano , Pseudomonas aeruginosa/genética , Sequência de Bases , Variação Genética , Humanos , Dados de Sequência Molecular , Mutagênese Insercional , Pseudomonas aeruginosa/isolamento & purificação , Recombinação Genética , Deleção de SequênciaRESUMO
Fundamental biological knowledge and the technology to acquire it have been immeasurably advanced by past efforts to understand and manipulate the genomes of model organisms. Has the utility of bacteria, yeast, worms, flies, mice, plants, and other models now peaked and are humans poised to become the model organism of the future? The Genetics Society of America recently convened its 2006 meeting entitled "Genetic Analysis: Model Organisms to Human Biology" to examine the future role of genetic research. (Because of time limitations, the meeting was unable to cover the substantial contributions and future potential of research on model prokaryotic organisms.) In fact, the potential of model-organism-based studies has grown substantially in recent years. The genomics revolution has revealed an underlying unity between the cells and tissues of eukaryotic organisms from yeast to humans. No uniquely human biological mechanisms have yet come to light. This common evolutionary heritage makes it possible to use genetically tractable organisms to model important aspects of human medical disorders such as cancer, birth defects, neurological dysfunction, reproductive failure, malnutrition, and aging in systems amenable to rapid and powerful experimentation. Applying model systems in this way will allow us to identify common genes, proteins, and processes that underlie human medical conditions. It will allow us to systematically decipher the gene-gene and gene-environment interactions that influence complex multigenic disorders. Above all, disease models have the potential to address a growing gap between our ability to collect human genetic data and to productively interpret and apply it. If model organism research is supported with these goals in mind, we can look forward to diagnosing and treating human disease using information from multiple systems and to a medical science built on the unified history of life on earth.
Assuntos
Genética , Animais , Epigênese Genética , Variação Genética , Humanos , Modelos Animais , Modelos Genéticos , Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/metabolismo , Células-Tronco/metabolismoAssuntos
Genoma Humano , Genômica/normas , Projeto Genoma Humano/história , Mapeamento Físico do Cromossomo/normas , Pesquisadores/normas , Biotecnologia/economia , Biotecnologia/história , Biotecnologia/normas , Ética Profissional , Genômica/economia , Genômica/história , História do Século XX , Projeto Genoma Humano/economia , Projeto Genoma Humano/organização & administração , Humanos , Mapeamento Físico do Cromossomo/história , Mapeamento Físico do Cromossomo/métodos , Setor Público , Pesquisadores/psicologiaRESUMO
BACKGROUND: Methylotrophy describes the ability of organisms to grow on reduced organic compounds without carbon-carbon bonds. The genomes of two pink-pigmented facultative methylotrophic bacteria of the Alpha-proteobacterial genus Methylobacterium, the reference species Methylobacterium extorquens strain AM1 and the dichloromethane-degrading strain DM4, were compared. METHODOLOGY/PRINCIPAL FINDINGS: The 6.88 Mb genome of strain AM1 comprises a 5.51 Mb chromosome, a 1.26 Mb megaplasmid and three plasmids, while the 6.12 Mb genome of strain DM4 features a 5.94 Mb chromosome and two plasmids. The chromosomes are highly syntenic and share a large majority of genes, while plasmids are mostly strain-specific, with the exception of a 130 kb region of the strain AM1 megaplasmid which is syntenic to a chromosomal region of strain DM4. Both genomes contain large sets of insertion elements, many of them strain-specific, suggesting an important potential for genomic plasticity. Most of the genomic determinants associated with methylotrophy are nearly identical, with two exceptions that illustrate the metabolic and genomic versatility of Methylobacterium. A 126 kb dichloromethane utilization (dcm) gene cluster is essential for the ability of strain DM4 to use DCM as the sole carbon and energy source for growth and is unique to strain DM4. The methylamine utilization (mau) gene cluster is only found in strain AM1, indicating that strain DM4 employs an alternative system for growth with methylamine. The dcm and mau clusters represent two of the chromosomal genomic islands (AM1: 28; DM4: 17) that were defined. The mau cluster is flanked by mobile elements, but the dcm cluster disrupts a gene annotated as chelatase and for which we propose the name "island integration determinant" (iid). CONCLUSION/SIGNIFICANCE: These two genome sequences provide a platform for intra- and interspecies genomic comparisons in the genus Methylobacterium, and for investigations of the adaptive mechanisms which allow bacterial lineages to acquire methylotrophic lifestyles.
Assuntos
Genoma Bacteriano/genética , Methylobacterium/genética , Methylobacterium/metabolismo , Acil Coenzima A/metabolismo , Formaldeído/metabolismo , Genoma Bacteriano/fisiologia , Metanol/metabolismo , Metilaminas/metabolismo , Modelos Biológicos , Modelos GenéticosRESUMO
The human genome sequence has been finished to very high standards; however, more than 340 gaps remained when the finished genome was published by the International Human Genome Sequencing Consortium in 2004. Using fosmid resources generated from multiple individuals, we targeted gaps in the euchromatic part of the human genome. Here we report 2,488,842 bp of previously unknown euchromatic sequence, 363,114 bp of which close 26 of 250 euchromatic gaps, or 10%, including two remaining euchromatic gaps on chromosome 19. Eight (30.7%) of the closed gaps were found to be polymorphic. These sequences allow complete annotation of several human genes as well as the assignment of mRNAs. The gap sequences are 2.3-fold enriched in segmentally duplicated sequences compared to the whole genome. Our analysis confirms that not all gaps within 'finished' genomes are recalcitrant to subcloning and suggests that the paired-end-sequenced fosmid libraries could prove to be a rich resource for completion of the human euchromatic genome.
Assuntos
Cromossomos Humanos Par 19 , Genoma Humano , Sequência de Bases , Clonagem Molecular , Eucromatina , Biblioteca Gênica , Vetores Genéticos , Projeto Genoma Humano , Humanos , Dados de Sequência Molecular , Polimorfismo GenéticoRESUMO
BACKGROUND: Francisella tularensis subspecies tularensis and holarctica are pathogenic to humans, whereas the two other subspecies, novicida and mediasiatica, rarely cause disease. To uncover the factors that allow subspecies tularensis and holarctica to be pathogenic to humans, we compared their genome sequences with the genome sequence of Francisella tularensis subspecies novicida U112, which is nonpathogenic to humans. RESULTS: Comparison of the genomes of human pathogenic Francisella strains with the genome of U112 identifies genes specific to the human pathogenic strains and reveals pseudogenes that previously were unidentified. In addition, this analysis provides a coarse chronology of the evolutionary events that took place during the emergence of the human pathogenic strains. Genomic rearrangements at the level of insertion sequences (IS elements), point mutations, and small indels took place in the human pathogenic strains during and after differentiation from the nonpathogenic strain, resulting in gene inactivation. CONCLUSION: The chronology of events suggests a substantial role for genetic drift in the formation of pseudogenes in Francisella genomes. Mutations that occurred early in the evolution, however, might have been fixed in the population either because of evolutionary bottlenecks or because they were pathoadaptive (beneficial in the context of infection). Because the structure of Francisella genomes is similar to that of the genomes of other emerging or highly pathogenic bacteria, this evolutionary scenario may be shared by pathogens from other species.
Assuntos
Francisella tularensis/genética , Francisella tularensis/patogenicidade , Elementos de DNA Transponíveis , Evolução Molecular , Francisella tularensis/classificação , Genoma Bacteriano , Humanos , Mutação , Pseudogenes , VirulênciaAssuntos
Variação Genética , Genoma Humano , Mutação , Evolução Biológica , Variação Estrutural do Genoma , Humanos , Seleção GenéticaRESUMO
Comparisons between haplotypes from affected patients and the human reference genome are frequently used to identify candidates for disease-causing mutations, even though these alignments are expected to reveal a high level of background neutral polymorphism. This limits the scope of genetic studies to relatively small genomic intervals, because current methods for distinguishing potential causal mutations from neutral variation are inefficient. Here we describe a new strategy for detecting mutations that is based on comparing affected haplotypes with closely matched control sequences from healthy individuals, rather than with the human reference genome. We use theory, simulation, and a real data set to show that this approach is expected to reduce the number of sequence variants that must be subjected to follow-up analysis by at least a factor of 20 when closely matched control sequences are selected from a reference panel with as few as 100 control genomes. We also define a reference data resource that would allow efficient application of this strategy to large critical intervals across the genome.
Assuntos
Doenças Genéticas Inatas/genética , Genoma Humano , Haplótipos , Mutação , Alelos , Estudos de Casos e Controles , Simulação por Computador , Bases de Dados Genéticas , Frequência do Gene , Genômica/métodos , Genômica/estatística & dados numéricos , Humanos , Modelos Genéticos , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Recombinação GenéticaRESUMO
The contribution of large-scale and intermediate-size structural variation (ISV) to human genetic disease and disease susceptibility is only beginning to be understood. The development of high-throughput genotyping technologies is one of the most critical aspects for future studies of linkage disequilibrium (LD) and disease association. Using a simple PCR-based method designed to assay the junctions of the breakpoints, we genotyped seven simple insertion and deletion polymorphisms ranging in size from 6.3 to 24.7 kb among 90 CEPH individuals. We then extended this analysis to a larger collection of samples (n=460) by application of an oligonucleotide extension-ligation genotyping assay. The analysis showed a high level of concordance ( approximately 99%) when compared with PCR/sequence-validated genotypes. Using the available HapMap data, we observed significant LD (r2=0.74-0.95) between each ISV and flanking single nucleotide polymorphisms, but this observation is likely to hold only for similar simple insertion/deletion events. The approach we describe may be used to characterize a large number of individuals in a cost-effective manner once the sequence organization of ISVs is known.