The mutational burden of regulatory function

Genetic mutations provide the raw material for evolution, they are responsible for heritable disease and driving the development of cancer. We have shown that the binding of chromatin and regulatory proteins to DNA can interfere with replication and lead to regions with locally elevated mutation rates. Mechanistically this process appears to involve the trapping of DNA polymerase alpha synthesised DNA in the fully replicated genome; a process we have explored with a novel method, EmRiboSeq, that tracks replicative polymerase activity in vivo. Extending this work we are measuring the patterns of chromatin accessibility and protein binding specifically in the mammalian germline and relating it to the distribution of polymorphism and mutation, to reveal the terrain of replication associated mutations in mice and humans. In related work on promoter evolution we find locally accelerated evolution of promoters active in the germline and consider more broadly the changes, gains and losses of promoters in the evolution of transcriptional regulation.