RESUMEN
We report on the sequencing of 10,545 human genomes at 30×-40× coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome can be sequenced confidently. This high-confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present the distribution of over 150 million single-nucleotide variants in the coding and noncoding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries on average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct high-resolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.
Asunto(s)
Genoma Humano , Genómica , Secuenciación Completa del Genoma , Mapeo Cromosómico , Biología Computacional/métodos , Bases de Datos de Ácidos Nucleicos , Predisposición Genética a la Enfermedad , Variación Genética , Genómica/métodos , Humanos , Sistemas de Lectura Abierta , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados , Regiones no TraducidasRESUMEN
Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10-11). We identified 113 (10.7%) among 1,054 unrelated individuals in the cohort who carried heterozygous rare variants likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn errors of metabolism or other pediatric genetic conditions. This study extends the map of loci influencing the metabolome and highlights the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Metaboloma/genética , Adulto , Anciano , Sangre , Exoma/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Sitios de Carácter CuantitativoRESUMEN
The genetic mechanisms mediating longevity and maximum lifespan of the human species are likely different than those explaining differences in life expectancy and healthspan across individuals. Both of these perspectives are important and can be separated and explored using genomic data.