Recombination suppression of mouse t-haplotypes due to chromatin mismatching.

We show here that recombination occurs at the normal rate in compound female mice containing two different complementing lethal haplotypes (th17/tw12) where there is a long stretch of homologous t-mutant chromatin. Thus the recombination suppression of a complete t-haplotype cannot be due to an intrinsic factor(s) which suppresses along the length of its own chromosome but is due to 'mismatching' of wild-type and mutant chromatin. Naturally occurring t-haplotypes of mouse chromosome 17 have several interesting genetic properties. First, they are always transmitted from males in much higher proportions than mendelian expectation; presumably this accounts for the maintenance of lethal and semilethal t-haplotypes at polymorphic levels in populations of wild mice. t-Haplotypes also show recombination suppression. The conventional map distance between genetic markers T and tf is 7-12 cM, whereas in (t/+) heterozygotes for naturally occurring t-haplotypes, recombination is suppressed and T and tf seem to be separated by only 0.1-0.5 cM (ref. 1). The region of recombination suppression extends to and includes the major histocompatibility complex (H-2). Thus t and H-2 effectively travel as a single unit-- a 'super gene'. Although recombination suppression is known to be accompanied by failure of chiasmata formation, the mechanism underlying the suppression has remained an enigma. Lyon suggested a disorder of t-heterochromatin and more recently a change in 'intercalary' middle repetitive DNA. She proposed that either t-chromatin is intrinsically incapable of participating in crossing-over, or chiasma formation is prevented because of mismatching and mispairing of normal and abnormal chromatin. We have measured recombinant between two chromosomes which carried extensive overlapping segments of t-chromatin. We report here that in this configuration, recombination occurs at a normal rate, and thus we conclude that cross-over suppression is due to mismatching.