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Natural selection shapes the genetic architecture of many human traits. However, the prevalence of different modes of selection on genomic regions associated with variation in traits remains poorly understood. To address this, we developed an efficient computational framework to calculate enrichment of different evolutionary measures among regions associated with complex traits. We applied the framework to summary statistics from >900 genome-wide association studies (GWASs) and 11 evolutionary measures of sequence constraint, population differentiation, and allele age while accounting for linkage disequilibrium, allele frequency, and other potential confounders. We demonstrate that this framework yields consistent results across GWASs with variable sample sizes, numbers of trait-associated SNPs, and analytical approaches. The resulting evolutionary atlas maps diverse signatures of selection on genomic regions associated with complex human traits on an unprecedented scale. We detected positive enrichment for sequence conservation among trait-associated regions for the majority of traits (>77% of 290 high power GWASs), which was most dominant in reproductive traits. Many traits also exhibited substantial enrichment for population differentiation and recent positive selection, especially among hair, skin, and pigmentation traits. In contrast, we detected widespread negative enrichment for balancing selection (51% GWASs) and no evidence of enrichment for selection signals in regions associated with late-onset Alzheimer’s disease. These results support a pervasive role for negative selection on regions of the human genome that contribute to variation in complex traits, but also demonstrate where diverse modes of selection have shaped trait-associated loci. This atlas of signatures of different modes of natural selection across the diversity of available GWASs will enable exploration of the relationship between the genetic architecture and selection in the human genome.

Replicative DNA helicases expose the two strands of the double helix to the replication apparatus, but accessory helicases are often needed to help forks move past naturally occurring hard-to-replicate sites, such as tightly bound proteins, RNA/DNA hybrids, and DNA secondary structures. Although the Schizosaccharomyces pombe 5’-to-3’ DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry. Of the 621 high confidence Pfh1-binding sites in wild type cells, about 40% were sites of fork slowing (as marked by high DNA polymerase occupancy) and/or DNA damage (as marked by high levels of phosphorylated H2A). The replication and integrity of tRNA and 5S rRNA genes, highly transcribed RNA polymerase II genes, and nucleosome depleted regions were particularly Pfh1-dependent. The association of Pfh1 with genomic integrity at highly transcribed genes was S phase dependent, and thus unlikely to be an artifact of high transcription rates. Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase. Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner. Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites. These data provide insight into mechanisms by which this evolutionarily conserved helicase helps preserve genome integrity., Author Summary Progression of the DNA replication machinery is challenged in every S phase by active transcription, tightly bound protein complexes, and formation of stable DNA secondary structures. Using genome-wide analyses, we show that the evolutionarily conserved fission yeast Pfh1 DNA helicase promotes fork progression and suppresses DNA damage at natural sites of fork pausing, which occur at “hard-to-replicate” sites. Our data suggest that Pfh1 interacts with the replication apparatus. First, mass spectrometry revealed that Pfh1 interacts with many components of the replication machinery. Second, Pfh1 and the leading strand DNA polymerase occupy many common regions genome-wide, not only hard-to-replicate sites, but also sites whose replication is not Pfh1-dependent. The human genome encodes a Pfh1 homolog, hPIF1, and contains all of the same hard-to-replicate features that make fission yeast DNA replication dependent upon Pfh1. Thus, human cells likely also require replicative accessory DNA helicases to facilitate replication at hard-to-replicate sites, and hPIF1 is a good candidate for this role.