The characterization of twenty sequenced human genomes

Area of Science:

• Genomics
• Human Genetics
• Variant Discovery

Background:

• Identifying rare functional genetic variants is crucial for understanding complex diseases.
• High-coverage whole-genome sequencing offers a powerful approach for variant detection.

Purpose of the Study:

• To assess the feasibility of identifying rare, highly-penetrant functional variants using whole-genome sequencing.
• To characterize the landscape of genetic variation in a cohort of individuals with severe hemophilia A and controls.

Main Methods:

• Whole-genome sequencing of ten severe hemophilia A cases and ten control individuals at high coverage.
• Bioinformatic analysis to identify and quantify single nucleotide variants (SNVs) and other genetic alterations.
• Evaluation of variant data for diagnostic utility and discovery potential.

Main Results:

• The genetic basis of severe hemophilia A was readily identifiable within the sequenced data.
• The discovery rate of novel single nucleotide variants (SNVs) per genome stabilized around 144,000 after sequencing 15 individuals.
• An average of 165 homozygous protein-truncating or stop-loss variants were found per genome across diverse gene pathways.

Conclusions:

• High-coverage whole-genome sequencing is effective for identifying causative variants in Mendelian disorders like hemophilia A.
• The study provides a benchmark for the number of novel SNVs expected per genome in human populations.
• The prevalence of homozygous protein-truncating variants highlights potential targets for functional studies and therapeutic development.