I have come across three reports in the last few days that help me think about the question: How many genomes is enough? My conclusion – we need a lot! Here are some thoughts and objective data that support this conclusion.
(1) Clinical sequencing for rare disease – JAMA reported compelling evidence that exome sequencing identified a molecular diagnosis for patients (Editorial here). One study investigated 2000 consecutive patients who had exome sequencing at one academic medical center over 2 years (here). Another study investigated 814 consecutive pediatric patients over 2.5 years (here). Both groups report that ~25% of patients were “solved” by exome sequencing. All patients had a rare clinical presentation that strongly suggested a genetic etiology.
(2) Inactivating NPC1L1 mutations protect from coronary heart diease – NEJM reported an exome sequencing study in ~22,000 case-control samples to search for coronary heart disease (CHD) genes, with follow-up of a specific inactivating mutation (p.Arg406X in the gene NPC1L1) in ~91,000 case-control samples (here). The data suggest that naturally occurring mutations that disrupt NPC1L1 function are associated with reduced LDL cholesterol levels and reduced risk of CHD. The statistics were not overwhelming despite the large sample size (P=0.008, OR=0.47). …