Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Nature · 2021 · 2261 citations

• Computer Science
• Biology
• Genetics

. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population

Proceedings of the National Academy of Sciences · 2020 · 110 citations

• Genetics
• Biology
• Evolutionary biology

), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.