RT Journal Article SR Electronic T1 Probabilities of Fitness Consequences for Point Mutations Across the Human Genome JF bioRxiv FD Cold Spring Harbor Laboratory SP 006825 DO 10.1101/006825 A1 Brad Gulko A1 Melissa J. Hubisz A1 Ilan Gronau A1 Adam Siepel YR 2014 UL http://biorxiv.org/content/early/2014/08/23/006825.abstract AB 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 (fit-Cons) 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 EN-CODE. 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, in contrast to several recent studies, they suggest that recent evolutionary turnover has had limited impact on the functional content of the genome.