RESUMO
Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.
Assuntos
Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 4/genética , Animais , Composição de Bases , Sequência de Bases , Centrômero/genética , Sequência Conservada/genética , Ilhas de CpG/genética , Eucromatina/genética , Etiquetas de Sequências Expressas , Duplicação Gênica , Variação Genética/genética , Genômica , Humanos , Dados de Sequência Molecular , Mapeamento Físico do Cromossomo , Polimorfismo Genético/genética , Primatas/genética , Proteínas/genética , Pseudogenes/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA não Traduzido/análise , RNA não Traduzido/genética , Recombinação Genética/genética , Análise de Sequência de DNARESUMO
CONTEXT: The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing. OBJECTIVE: To apply whole-genome sequencing to a patient without any significant family history of cancer but with suspected increased cancer susceptibility because of multiple primary tumors to identify rare or novel germline variants in cancer susceptibility genes. DESIGN, SETTING, AND PARTICIPANT: Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer (negative for BRCA1 and BRCA2 mutations) and therapy-related acute myeloid leukemia (t-AML) and analyzed with the following: whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, RNA expression profiling, and spectral karyotyping. MAIN OUTCOME MEASURES: Structural variants, copy number alterations, single-nucleotide variants, and small insertions and deletions (indels) were detected and validated using the described platforms. RESULTS; Whole-genome sequencing revealed a novel, heterozygous 3-kilobase deletion removing exons 7-9 of TP53 in the patient's normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single-nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient's leukemia genome. CONCLUSION: Whole-genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.
Assuntos
Genes p53/genética , Predisposição Genética para Doença , Leucemia Mieloide Aguda/genética , Análise de Sequência de DNA , Deleção de Sequência , Adulto , Idade de Início , Neoplasias da Mama/terapia , Cistadenocarcinoma Seroso/terapia , DNA de Neoplasias/genética , Feminino , Genoma Humano/genética , Humanos , Leucemia Mieloide Aguda/etiologia , Neoplasias Ovarianas/terapia , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor p53/genéticaRESUMO
Human chromosome 7 has historically received prominent attention in the human genetics community, primarily related to the search for the cystic fibrosis gene and the frequent cytogenetic changes associated with various forms of cancer. Here we present more than 153 million base pairs representing 99.4% of the euchromatic sequence of chromosome 7, the first metacentric chromosome completed so far. The sequence has excellent concordance with previously established physical and genetic maps, and it exhibits an unusual amount of segmentally duplicated sequence (8.2%), with marked differences between the two arms. Our initial analyses have identified 1,150 protein-coding genes, 605 of which have been confirmed by complementary DNA sequences, and an additional 941 pseudogenes. Of genes confirmed by transcript sequences, some are polymorphic for mutations that disrupt the reading frame.
Assuntos
Cromossomos Humanos Par 7 , Animais , Sequência de Bases , Duplicação Gênica , Humanos , Camundongos , Dados de Sequência Molecular , Mapeamento Físico do Cromossomo , Proteínas/genética , Pseudogenes , RNA não Traduzido , Análise de Sequência de DNA , Especificidade da Espécie , Síndrome de Williams/genéticaRESUMO
Here we present a draft genome sequence of the nematode Pristionchus pacificus, a species that is associated with beetles and is used as a model system in evolutionary biology. With 169 Mb and 23,500 predicted protein-coding genes, the P. pacificus genome is larger than those of Caenorhabditis elegans and the human parasite Brugia malayi. Compared to C. elegans, the P. pacificus genome has more genes encoding cytochrome P450 enzymes, glucosyltransferases, sulfotransferases and ABC transporters, many of which were experimentally validated. The P. pacificus genome contains genes encoding cellulase and diapausin, and cellulase activity is found in P. pacificus secretions, indicating that cellulases can be found in nematodes beyond plant parasites. The relatively higher number of detoxification and degradation enzymes in P. pacificus is consistent with its necromenic lifestyle and might represent a preadaptation for parasitism. Thus, comparative genomics analysis of three ecologically distinct nematodes offers a unique opportunity to investigate the association between genome structure and lifestyle.
Assuntos
Mapeamento Cromossômico , Besouros/parasitologia , Genes de Helmintos , Genoma Helmíntico , Intestinos/parasitologia , Nematoides/fisiologia , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/genética , Evolução Molecular , Éxons/genética , Interações Hospedeiro-Parasita , Íntrons/genética , Dados de Sequência Molecular , Filogenia , Homologia de Sequência de AminoácidosRESUMO
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.
Assuntos
Evolução Molecular , Genoma , Macaca mulatta/genética , Animais , Pesquisa Biomédica , Feminino , Duplicação Gênica , Rearranjo Gênico , Doenças Genéticas Inatas , Variação Genética , Humanos , Masculino , Família Multigênica , Mutação , Pan troglodytes/genética , Análise de Sequência de DNA , Especificidade da EspécieRESUMO
The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.