Evolutionary Implications of the Frequent Horizontal Transfer of Mismatch Repair Genes

Abstract

Mutation and subsequent recombination events create genetic diversity, which is subjected to natural selection. Bacterial mismatch repair (MMR) deficient mutants, exhibiting high mutation and homologous recombination rates, are frequently found in natural populations. Therefore, we have explored the possibility that MMR deficiency emerging in nature has left some "imprint" in the sequence of bacterial genomes. Comparative molecular phylogeny of MMR genes from natural Escherichia coli isolates shows that, compared to housekeeping genes, individual functional MMR genes exhibit high sequence mosaicism derived from diverse phylogenetic lineages. This apparent horizontal gene transfer correlates with hyperrecombination phenotype of MMR-deficient mutators. The sequence mosaicism of MMR genes may be a hallmark of a mechanism of adaptive evolution that involves modulation of mutation and recombination rates by recurrent losses and reacquisitions of MMR gene functions.

Hypermutable Haemophilus influenzae with mutations in mutS are found in cystic fibrosis sputum

“…In H. influenzae, mutants of mutS may be particularly common as mutS is an isolated ORF; in contrast, mutL and mutH are located within operons with several other genes involved in DNA metabolism, protein synthesis and cell envelope functions, and therefore only mutations which do not produce polar effects are more likely to be selected, potentially limiting the frequency of mutL and mutH mutations in nature. A similar explanation has been previously offered to account for the overrepresentation of natural E. coli mutS 2 mutators compared to mutL 2 mutators, with mutL in E. coli being part of an operon subject to polar mutations (Denamur et al, 2000). In addition, in H. influenzae point mutations inactivating MMR activity may be preferred over gene deletions as the remaining DNA sequence following a point mutation may facilitate genetic recombination at a later time to reacquire a functional mutS allele from the environment by lateral transfer.…”

“…Mutants of mutS are more abundant than isolates with mutations in other MMR genes in natural populations of E. coli (LeClerc et al, 1996;Matic et al, 1997). In contrast, in the laboratory environment mutants of other E. coli MMR genes, including mutL, are readily isolated, suggesting certain mutations may be counterselected against in nature due to deleterious effects that are not compensated by advantageous randomly generated mutations (Denamur et al, 2000). We have found several mutations in mutS alleles from our hypermutator panel that were in regions associated with defective MutS activity in E. coli.…”

Dealing with incongruence in phylogenomic analyses

“…olfactive receptors, Niimura & Nei 2006) or HGT (e.g. mutS, Denamur et al 2000). Their history is little, or not at all, influenced by the species tree.…”

Lateral genetic transfer: open issues

“…(d) What is the physical unit of transfer? Lateral origins have been proposed for DNA regions ranging from seven nucleotides (Denamur et al 2000) up to an entire chromosome greater than 3 Mb (Lin et al 2008) in length and constituting stretches of non-coding DNA, portions of genes, intact genes, multi-gene clusters, operons, plasmids, transposable elements and pathogenicity islands. For this reason, we refer to lateral (or horizontal) genetic, not gene, transfer.…”

“…Nonetheless, some examples have been identified in prokaryotes, including within the rrnB operon (Yap et al 1999) and the mutU and mutS genes (Denamur et al 2000); many others are implicit from genome-wide scans of recombination breakpoints (Mau et al 2006). Of two instances of LGT within genes encoding EF-1a (Inagaki et al 2006), one preserves existing domains but the other interrupts domains.…”