Mouse t haplotypes are variant forms of chromosome 17 that exist at high frequendes in worldwide populations of several species of house mouse. They are known to differ from wild-type chromosomes with respect to two relative inversions referred to as proximal and distal. An untested assumption has been that these two inversions originated in the chromosomal lineage lading to present-day t haplotypes. To investigate the evolutionary origins of these inversions and the possibility of additional inversions, interspecific crosses were performed between Mus spretus or Mus abbotti and laboratory strains of Mus domesticus that carried wild-type and t haplotypes forms of chromosome 17. The results provide evidence for the existence of two additional nonoverlapping inversions-one between the proximal and distal inversions and one between the centromere and the proximal inversion. These four inversions span nearly the entire region of t haplotype recombination suppression. Considering the distribution of these inversions among the species studied as well as the organization of the D17Leh66 family of DNA elements, we infer that the proximal inversion occurred on the lineage leading to the common ancestor ofM. domesticus and M. abbott, and that the other three inversions occurred on the separate lineage leading to present-day t haplotypes.Alternative models for the evolution of t haplotypes are discussed in light of these fndings.Two forms of the proximal region of mouse chromosome 17 are found in natural populations of house mice. One form is considered wild type (+) and the other is known as a t haplotype (t) (1, 2). A t haplotype is able to propagate itself at the expense of its wild-type meiotic partner, in a clear departure from Mendel's first law. The integrity of a complete t haplotype is maintained by a suppression of recombination along its 15-centimorgan (cM) length from the DI7Leh48 locus to the H-2 complex (Fig. 1). These chromosomes have been identified in several house mouse species including Mus domesticus, Mus musculus (3), Mus molossinus (4), and Mus bactrianus (unpublished data). In surveys of M. domesticus from many geographical locations, t haplotypes have been found at frequencies between 10%o and 20%1o, even though they carry genes that cause homozygous male sterility, and some also carry embryonic lethal mutations (5, 6).The major selective force driving t haplotypes in populations is the high ratio of transmission from +/t heterozygous males (7). Genetic experiments have demonstrated the existence of at least five independent loci involved in this transmission ratio distortion (TRD) (refs. 8 and 9; see Fig. 1). In general, only t haplotypes with a complete set of TRD loci are transmitted at high ratios, and only high-ratio t haplotypes survive for significant periods of time in natural populations (7). Because the TRD loci are spread across a 15-cM chromosomal region, the continued presence of t haplotypes in populations depends as much on recombination suppression as on TRD.The discovery o...