The mismatch repair system contributes to meiotic sterility in an interspecific yeast hybrid.

Abstract

The mismatch repair system is the major barrier to genetic recombination during interspecific sexual conjugation in prokaryotes. The existence of this anti‐recombination activity has implications for theories of evolution and the isolation of species. To determine if this phenomenon occurs in eukaryotes, the effect of a deficiency of mismatch repair on the meiotic sterility of an interspecific hybrid of Saccharomyces cerevisiae and the closely related species Saccharomyces paradoxus was examined. The results demonstrate that the rare viable spores from these hybrids have high frequencies of aneuploidy and low frequencies of genetic exchange. Hybrids lacking mismatch repair genes PMS1 or MSH2 display increased meiotic recombination, decreased chromosome non‐disjunction and improved spore viability. These observations are consistent with the proposal that the mismatch repair system is an element of the genetic barrier between eukaryotic species. We suggest that an anti‐recombination activity during meiosis contributes towards the establishment of post‐zygotic species barriers.

Biochemistry and genetics of eukaryotic mismatch repair.

“…The available data indicate that mutations in S. cerevisiae MLHl and PMSl cause a similar, strong general mutator phenotype that is virtually the same as that caused by mutations in MSH2; no differences in the mutator phenotypes caused by pmsl and mlhl mutations have yet been published (Williamson et al 1985;Bishop et al 1987;Strand et al 1993;Prolla et al 1994a;Jeyaprakash et al 1996). Interestingly, in a recent study on the effects of m s h 2 msh3, and pmsl (human pms2) mutations on crossing over between divergent DNA sequences, PMSl (human PMS2) appeared to play significantly less of a role in suppressing homologous recombination than MSH2 (Datta et al 1996;Hunter et al 1996). This suggests that defects in PMS1 (human PMS2) might not be equivalent to defects in other mismatch repair genes (unfortunately MLHI was not evaluated in these studies; Datta et al 1996;Hunter et al 1996).…”

“…Interestingly, in a recent study on the effects of m s h 2 msh3, and pmsl (human pms2) mutations on crossing over between divergent DNA sequences, PMSl (human PMS2) appeared to play significantly less of a role in suppressing homologous recombination than MSH2 (Datta et al 1996;Hunter et al 1996). This suggests that defects in PMS1 (human PMS2) might not be equivalent to defects in other mismatch repair genes (unfortunately MLHI was not evaluated in these studies; Datta et al 1996;Hunter et al 1996). Analysis of human tumor cell lines with mutations in either MLHI or PMS2 support this view: Such cell lines have a strong, global microsatellite instability phenotype, and extracts prepared from such cell (Parsons et al 1993;Bhattacharyya et al 1994;Shibata et al 1994;Boyer et al 1995;Li and Modrich 1995;Risinger et al 1995).…”

“…These data may reflect trivial possibilities such as founder effects (NystromLahti et al 1995), or DNA sequence contexts may make MLHl more mutable than PMS2. Alternately, these data raise the intriguing possibilities that MLHl and PMS2 do not play equivalent roles in the cell even though they are subunits of the same complex (see above discussion of Datta et al 1996;Hunter et al 1996), that pms2 mutations confer a selective disadvantage to the population compared to mlhl mutations (Baker et al 1995), or that like S. cerevisiae MSH3 and MSH6, there is a function that is redundant with PMS2. The resolution of this question could provide important information about how mismatch repair defects give rise to cancer susceptibility.…”

Sensing of DNA non‐homology lowers the initiation of meiotic recomination in yeast

“…in somatic pairing), this mechanism might be extremely useful in cells containing a genome with repeated DNA sequences, because it would prevent potential ectopic DNA/DNA interactions leading to chromosomal translocations when gene conversion events are associated with reciprocal exchanges. In this perspective, this meiotic process, which monitors the initiation of recombination and behaves as an anti-initiation mechanism, would precede the anti-recombinogenic properties of the mismatch repair mutS/L system found in bacteria (Rayssiguier et al 1989;Humbert et al 1995) and in yeast (Hunter et al 1996). Altogether, these processes would be implicated in the maintenance of chromosomal stability, in the monitoring of sequence divergence, and in the establishment of the genetic barrier between species (Wagner & Radman 1993).…”

“…Recent studies involving interspecific Saccharomyces hybrids indicate that sequence divergence leads to a decrease of genetic exchange in meiosis, and inviability within the progeny (Resnick et al 1989;Hunter et al 1996). As in bacteria (Rayssiguier et al 1989), this effect of sequence divergence is under the control of the mismatch repair system PMS1/MSH2 (Hunter et al 1996) probably acting as an antirecombination process that detects sequence divergence in heteroduplex intermediate molecules. The present report reveals the existence of another process sensing the presence of local sequence non-homology between the homologous chromosomes, and acting during the initiation of recombination.…”