Copyright zyxwvutsrqponm 0 1991 by the Genetics Society of America A Novel Mouse Chromosome 17 Hybrid Sterility Locus: Implications for the Origin of zyxw t Haplotypes Stephen H. Pilder, Michael F. Hammer' and zyx Lee M. Silver Department zyxwvutsr of Molecular Biology, Princeton University, Princeton, New Jersey 08544-1014 zyx Manuscript received January zyxwv 2 1, 199 zyxw 1 Accepted for publication May 1 1, 199 1 ABSTRACT T h e effects of heterospecific combinations of mouse chromosome 17 on male fertility and trans- mission ratio were investigated through a series of breeding studies. Animals were bred to carry complete chromosome 17 homologs, or portions thereof, from three different sources-Mus domesticus, Mus spretus and t haplotypes. These chromosome 17 combinations were analyzed for fertility within the context of a M. domesticus or M. spretus genetic background. Two new forms of hybrid sterility were identified. First, the heterospecific combination of M. spretus and t haplotype homologs leadsto complete male sterility on both M. spretus and M. domesticus genetic backgrounds. This is an example of symmetrical hybrid sterility. Second, the presence of a single M. domesticus chromosome 17 homolog within a M. spretus background causes sterility, however, the same combination of chromosome 17 homologs does not cause sterility within the M. domesticus background. This is a case of asymmetrical hybrid sterility. Through an analysis of recombinant chromosomes, it was possible to map the M. domesticus, M. spretus and t haplotype alleles responsible for these two hybrid sterility phenotypes to the same novel locus (Hybrid sterility-4). Previous structural studies had led to the hypothesis that the ancestral t haplotype originated through an introgression event from M. spretus or a related species. If this were true, one might expect that (1) M. spretus homologs would be transmitted at a non- Mendelian ratio within the M. domesticus background, and (2) t haplotypes would be transmitted at a ratio closer to Mendelian within the M. spretus background. The functional data generated in the current study indicate that neither of these predictions is fulfilled, and thus, the M. spretus introgression hypothesis appears to be unlikely. M OST naturally occurring populations of the house mouse (which include the sibling species Mus musculus, Mus domesticus, as well as others) are polymorphic for a selfish chromosomal entity known as a zyxwvutsrqp t haplotype. A t haplotype occupies a zyxwvu 20 cM region at the proximal end of chromosome 17 and it maintains its structural integrity through a series of four inversions that block recombination with the wild-type homolog (Committee for Mouse Chromo- some 17 1991 ; Figure 1A). t Haplotypes are main- tained at relatively high levels in natural populations through the expression of a male-specific phenotype of transmission ratio distortion (TRD) by which 95% or more of the offspring from heterozygous +/t males receive the t-bearing chromosome (SILVER 1985). Al- though TRD provides a powerful selective advantage, t haplotypes have not become fixed in the mouse genome because males homozygous for the t-form of the chromosome are completely sterile. From map- ping studies, it appears likely that this recessive steril- ity phenotype is a consequence of homozygosity for the same t genes that are involved in the dominant TRD phenotype (LYON 1986). In addition, most (but ' Current address: Museum of Comparative Zoology, Harvard University, Cambridge, Massachusetts 021 38. Genetics 149: 237-246 (September, 1991) not all) naturally occurring t haplotypes carry recessive embryonic lethal mutations that also counteract TRD (BENNETT 1975). These three selective forces-TRD, sterility and lethality-balance each other out giving rise to equilibrium allele frequencies of 5-1 5% in most populations that have been studied (FICUEROA et al. 1988a). Since their discovery over 60 years ago, the origin and evolution of these unusual genetic entities has intrigued many investigators. Until the last decade, the question of t haplotype derivation hadbeen a complete enigma. However,with the ability to use DNA probes to compare t haplotypes with other forms of chromosome 17, it became possible to begin to unravel this puzzle in the context of a model shown in Figure 1B. The crux of this model is asfollows: first, all current-day t haplotypes derive from a single ancestor; second, t haplotypes diverged apart from the line leading to the M. domesticus form of chromo- some 17 between 1 and 6 million years ago, prior to the divergence of the various strongly commensal mouse species from each other, but not prior to the divergence of the M . domesticus line from the M. spretus line (DELARBRE et al. 1988; HAMMER, SCHI- MENTI and SILVER 1989). Finally, once the primordial