The roles of replication-transcription conflict in mutagenesis and evolution of genome organization.

Jeremy W Schroeder,Jue D Wang,Lyle A Simmons,T Sabari Sankar

doi:10.1371/journal.pgen.1008987

Abstract

Replication-transcription conflicts promote mutagenesis and give rise to evolutionary signatures, with fundamental importance to genome stability ranging from bacteria to metastatic cancer cells. This review focuses on the interplay between replication-transcription conflicts and the evolution of gene directionality. In most bacteria, the majority of genes are encoded on the leading strand of replication such that their transcription is co-directional with the direction of DNA replication fork movement. This gene strand bias arises primarily due to negative selection against deleterious consequences of head-on replication-transcription conflict. However, many genes remain head-on. Can head-on orientation provide some benefit? We combine insights from both mechanistic and evolutionary studies, review published work, and analyze gene expression data to evaluate an emerging model that head-on genes are temporal targets for adaptive mutagenesis during stress. We highlight the alternative explanation that genes in the head-on orientation may simply be the result of genomic inversions and relaxed selection acting on nonessential genes. We seek to clarify how the mechanisms of replication-transcription conflict, in concert with other mutagenic mechanisms, balanced by natural selection, have shaped bacterial genome evolution.

Highlights

Studies of mutagenesis in bacteria have revealed conserved biological processes influencing mutation rate across all domains of life and identified sources of bacterial evolution against host defense, peer competition, and antibiotic exposure
Historical studies of bacterial mutations by Luria and Delbruck led to a conclusive demonstration that spontaneous mutations generate the genetic diversity to allow survival of subsequent selective pressure [1]
Mutations do not arise uniformly across the genome, because multiple mechanisms for mutagenesis exist and the effect of each mechanism depends on the genomic context of a given locus [2]

Summary

Introduction

Studies of mutagenesis in bacteria have revealed conserved biological processes influencing mutation rate across all domains of life and identified sources of bacterial evolution against host defense, peer competition, and antibiotic exposure. The rate of base-pair substitution in bacteria varies around 3 × 10−10 per nucleotide replicated per generation, depending on the type of substitution and sequence context [22,37] Both the Zhang group and the Merrikh group, disagreeing in the numbers, provide evidence for many inversion events resulting in co-directional to head-on changes of gene orientation [17,21]. This hotspot is identical in nature and position to a promoter hotspot previously identified in a head-on oriented mutation reporter in E. coli [38] This striking similarity in mutagenic signature identified in two phylogenetically distant bacteria (E. coli and B. subtilis), using two different reporter systems, supports the widespread existence of promoter substitutions due to head-on replication-transcription conflict. These analyses indicate that head-on genes are not special in their patterns of differential expression when compared with co-directional genes

Conclusions

Findings

Methods