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1.
Nature ; 527(7579): 459-65, 2015 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-26580012

RESUMEN

Acorn worms, also known as enteropneust (literally, 'gut-breathing') hemichordates, are marine invertebrates that share features with echinoderms and chordates. Together, these three phyla comprise the deuterostomes. Here we report the draft genome sequences of two acorn worms, Saccoglossus kowalevskii and Ptychodera flava. By comparing them with diverse bilaterian genomes, we identify shared traits that were probably inherited from the last common deuterostome ancestor, and then explore evolutionary trajectories leading from this ancestor to hemichordates, echinoderms and chordates. The hemichordate genomes exhibit extensive conserved synteny with amphioxus and other bilaterians, and deeply conserved non-coding sequences that are candidates for conserved gene-regulatory elements. Notably, hemichordates possess a deuterostome-specific genomic cluster of four ordered transcription factor genes, the expression of which is associated with the development of pharyngeal 'gill' slits, the foremost morphological innovation of early deuterostomes, and is probably central to their filter-feeding lifestyle. Comparative analysis reveals numerous deuterostome-specific gene novelties, including genes found in deuterostomes and marine microbes, but not other animals. The putative functions of these genes can be linked to physiological, metabolic and developmental specializations of the filter-feeding ancestor.


Asunto(s)
Cordados no Vertebrados/genética , Evolución Molecular , Genoma/genética , Animales , Cordados no Vertebrados/clasificación , Secuencia Conservada/genética , Equinodermos/clasificación , Equinodermos/genética , Familia de Multigenes/genética , Filogenia , Transducción de Señal , Sintenía/genética , Factor de Crecimiento Transformador beta
2.
Nature ; 513(7517): 195-201, 2014 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-25209798

RESUMEN

Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ∼5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.


Asunto(s)
Genoma/genética , Hylobates/clasificación , Hylobates/genética , Cariotipo , Filogenia , Animales , Evolución Molecular , Hominidae/clasificación , Hominidae/genética , Humanos , Datos de Secuencia Molecular , Retroelementos/genética , Selección Genética , Terminación de la Transcripción Genética
3.
Nature ; 467(7311): 52-8, 2010 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-20811451

RESUMEN

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of

Asunto(s)
Variaciones en el Número de Copia de ADN , Genoma Humano , Polimorfismo de Nucleótido Simple , Grupos de Población/genética , Proyecto Genoma Humano , Humanos
4.
Nature ; 455(7216): 1069-75, 2008 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-18948947

RESUMEN

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.


Asunto(s)
Adenocarcinoma Bronquioloalveolar/genética , Neoplasias Pulmonares/genética , Mutación/genética , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Masculino , Proto-Oncogenes/genética
5.
Nature ; 440(7088): 1194-8, 2006 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-16641997

RESUMEN

After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.


Asunto(s)
Cromosomas Humanos Par 3/genética , Animales , Secuencia de Bases , Rotura Cromosómica/genética , Inversión Cromosómica/genética , Mapeo Contig , Islas de CpG/genética , ADN Complementario/genética , Evolución Molecular , Etiquetas de Secuencia Expresada , Proyecto Genoma Humano , Humanos , Macaca mulatta/genética , Datos de Secuencia Molecular , Pan troglodytes/genética , Análisis de Secuencia de ADN , Sintenía/genética
6.
Nature ; 440(7082): 346-51, 2006 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-16541075

RESUMEN

Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease. The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome. Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 4.5% of the human genome. Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages. The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents.


Asunto(s)
Cromosomas Humanos Par 12/genética , Animales , Composición de Base , Islas de CpG/genética , Evolución Molecular , Etiquetas de Secuencia Expresada , Genes/genética , Humanos , Desequilibrio de Ligamiento/genética , Repeticiones de Microsatélite/genética , Datos de Secuencia Molecular , Mutagénesis Insercional/genética , Pan troglodytes/genética , Análisis de Secuencia de ADN , Eliminación de Secuencia/genética , Elementos de Nucleótido Esparcido Corto/genética , Sintenía/genética
7.
Cancer Res ; 76(8): 2197-205, 2016 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-26941285

RESUMEN

The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. Cancer Res; 76(8); 2197-205. ©2016 AACR.


Asunto(s)
Perfilación de la Expresión Génica , Leucemia Mieloide Aguda/genética , Mutación , Adolescente , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Masculino , Recurrencia
8.
Nat Genet ; 43(3): 189-96, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21258341

RESUMEN

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Alelos , Trastornos de la Motilidad Ciliar/genética , Animales , Variación Genética , Humanos , Ratones , Mutación , Linaje , Células Fotorreceptoras/fisiología , Pez Cebra/genética
9.
Nat Commun ; 1: 131, 2010 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-21119644

RESUMEN

Accurately determining the distribution of rare variants is an important goal of human genetics, but resequencing of a sample large enough for this purpose has been unfeasible until now. Here, we applied Sanger sequencing of genomic PCR amplicons to resequence the diabetes-associated genes KCNJ11 and HHEX in 13,715 people (10,422 European Americans and 3,293 African Americans) and validated amplicons potentially harbouring rare variants using 454 pyrosequencing. We observed far more variation (expected variant-site count ∼578) than would have been predicted on the basis of earlier surveys, which could only capture the distribution of common variants. By comparison with earlier estimates based on common variants, our model shows a clear genetic signal of accelerating population growth, suggesting that humanity harbours a myriad of rare, deleterious variants, and that disease risk and the burden of disease in contemporary populations may be heavily influenced by the distribution of rare variants.

10.
Nat Genet ; 41(6): 739-45, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19430481

RESUMEN

Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Variación Genética , Degeneración Retiniana/genética , Alelos , Animales , Síndrome de Bardet-Biedl/genética , Cuerpo Ciliar/fisiopatología , Europa (Continente)/epidemiología , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Humanos , Mutación , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , Degeneración Retiniana/epidemiología , Degeneración Retiniana/prevención & control , Retinitis Pigmentosa/enzimología , Retinitis Pigmentosa/genética , Uveítis/epidemiología , Uveítis/genética , Pez Cebra/genética
11.
J Exp Med ; 205(12): 2711-6, 2008 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-18955567

RESUMEN

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. The importance of granulocyte/macrophage colony-stimulating factor (GM-CSF) in the pathogenesis of PAP has been confirmed in humans and mice, wherein GM-CSF signaling is required for pulmonary alveolar macrophage catabolism of surfactant. PAP is caused by disruption of GM-CSF signaling in these cells, and is usually caused by neutralizing autoantibodies to GM-CSF or is secondary to other underlying diseases. Rarely, genetic defects in surfactant proteins or the common beta chain for the GM-CSF receptor (GM-CSFR) are causal. Using a combination of cellular, molecular, and genomic approaches, we provide the first evidence that PAP can result from a genetic deficiency of the GM-CSFR alpha chain, encoded in the X-chromosome pseudoautosomal region 1.


Asunto(s)
Cromosomas Humanos X/genética , Proteinosis Alveolar Pulmonar/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Animales , Antígeno CD11b/metabolismo , Preescolar , Exones , Femenino , Genotipo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Ratones , Monocitos/citología , Monocitos/metabolismo , Surfactantes Pulmonares/metabolismo , Transducción de Señal/fisiología , Síndrome de Turner
12.
Science ; 316(5822): 222-34, 2007 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-17431167

RESUMEN

The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species.


Asunto(s)
Evolución Molecular , Genoma , Macaca mulatta/genética , Animales , Investigación Biomédica , Femenino , Duplicación de Gen , Reordenamiento Génico , Enfermedades Genéticas Congénitas , Variación Genética , Humanos , Masculino , Familia de Multigenes , Mutación , Pan troglodytes/genética , Análisis de Secuencia de ADN , Especificidad de la Especie
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