RESUMEN
Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
Asunto(s)
Perros/genética , Evolución Molecular , Genoma/genética , Genómica , Haplotipos/genética , Animales , Secuencia Conservada/genética , Enfermedades de los Perros/genética , Perros/clasificación , Femenino , Humanos , Hibridación Genética , Masculino , Ratones , Mutagénesis/genética , Polimorfismo de Nucleótido Simple/genética , Ratas , Elementos de Nucleótido Esparcido Corto/genética , Sintenía/genéticaRESUMEN
With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of approximately 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health.
Asunto(s)
Mapeo Cromosómico , Perros/genética , Ligamiento Genético , Color del Cabello/genética , Factor de Transcripción Asociado a Microftalmía/genética , Polimorfismo de Nucleótido Simple , Animales , Cruzamiento , Femenino , Genoma , Haplotipos , Masculino , Melanocitos/citología , Melanocitos/metabolismo , Mutación/genética , Regiones Promotoras GenéticasRESUMEN
We mapped histone H3 lysine 4 di- and trimethylation and lysine 9/14 acetylation across the nonrepetitive portions of human chromosomes 21 and 22 and compared patterns of lysine 4 dimethylation for several orthologous human and mouse loci. Both chromosomes show punctate sites enriched for modified histones. Sites showing trimethylation correlate with transcription starts, while those showing mainly dimethylation occur elsewhere in the vicinity of active genes. Punctate methylation patterns are also evident at the cytokine and IL-4 receptor loci. The Hox clusters present a strikingly different picture, with broad lysine 4-methylated regions that overlay multiple active genes. We suggest these regions represent active chromatin domains required for the maintenance of Hox gene expression. Methylation patterns at orthologous loci are strongly conserved between human and mouse even though many methylated sites do not show sequence conservation notably higher than background. This suggests that the DNA elements that direct the methylation represent only a small fraction of the region or lie at some distance from the site.
Asunto(s)
Cromatina/genética , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 22/genética , Histonas/genética , Proteínas de Homeodominio/genética , Acetilación , Animales , Cromatina/metabolismo , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 21/metabolismo , Cromosomas Humanos Par 22/metabolismo , Genoma , Histonas/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Lisina/metabolismo , Metilación , Ratones , Receptores de Interleucina-4/genéticaRESUMEN
Most inbred laboratory mouse strains are known to have originated from a mixed but limited founder population in a few laboratories. However, the effect of this breeding history on patterns of genetic variation among these strains and the implications for their use are not well understood. Here we present an analysis of the fine structure of variation in the mouse genome, using single nucleotide polymorphisms (SNPs). When the recently assembled genome sequence from the C57BL/6J strain is aligned with sample sequence from other strains, we observe long segments of either extremely high (approximately 40 SNPs per 10 kb) or extremely low (approximately 0.5 SNPs per 10 kb) polymorphism rates. In all strain-to-strain comparisons examined, only one-third of the genome falls into long regions (averaging >1 Mb) of a high SNP rate, consistent with estimated divergence rates between Mus musculus domesticus and either M. m. musculus or M. m. castaneus. These data suggest that the genomes of these inbred strains are mosaics with the vast majority of segments derived from domesticus and musculus sources. These observations have important implications for the design and interpretation of positional cloning experiments.