Probabilities of Fitness Consequences for Point Mutations Across the Human Genome

We describe a novel computational method for estimating the probability that a point mutation at each position in a genome will influence fitness. These fitness consequence (fitCons) scores serve as evolution-based measures of potential genomic function. Our approach is to cluster genomic positions into groups exhibiting distinct “fingerprints” based on high-throughput functional genomic data, then to estimate a probability of fitness consequences for each group from associated patterns of genetic polymorphism and divergence. We have generated fitCons scores for three human cell types based on public data from ENCODE. Compared with conventional conservation scores, fitCons scores show considerably improved prediction power for cis-regulatory elements. In addition, fitCons scores indicate that 4.2–7.5% of nucleotides in the human genome have influenced fitness since the human-chimpanzee divergence, and they suggest that recent evolutionary turnover has had limited impact on the functional content of the genome.