Abstract
The Dobzhansky-Muller model of incompatibilities explains reproductive isolation between species by incorrect epistatic interactions. Although the mechanisms of speciation are of great interest, no incompatibility has been characterized at the gene level in mammals. The Hybrid sterility 1 gene (Hst1) participates in the arrest of meiosis in F1 males of certain strains from two Mus musculus subspecies, e.g., PWD from M. m. musculus and C57BL/6J (henceforth B6) from M. m. domesticus. Hst1 has been identified as a meiotic PR-domain gene (Prdm9) encoding histone 3 methyltransferase in the male offspring of PWD females and B6 males, (PWD×B6)F1. To characterize the incompatibilities underlying hybrid sterility, we phenotyped reproductive and meiotic markers in males with altered copy numbers of Prdm9. A partial rescue of fertility was observed upon removal of the B6 allele of Prdm9 from the azoospermic (PWD×B6)F1 hybrids, whereas removing one of the two Prdm9 copies in PWD or B6 background had no effect on male reproduction. Incompatibility(ies) not involving Prdm9B6 also acts in the (PWD×B6)F1 hybrids, since the correction of hybrid sterility by Prdm9B6 deletion was not complete. Additions and subtractions of Prdm9 copies, as well as allelic replacements, improved meiotic progression and fecundity also in the progeny-producing reciprocal (B6×PWD)F1 males. Moreover, an increased dosage of Prdm9 and reciprocal cross enhanced fertility of other sperm-carrying male hybrids, (PWD×B6-C3H.Prdm9)F1, harboring another Prdm9 allele of M. m. domesticus origin. The levels of Prdm9 mRNA isoforms were similar in the prepubertal testes of all types of F1 hybrids of PWD with B6 and B6-C3H.Prdm9 despite their different prospective fertility, but decreased to 53% after removal of Prdm9B6. Therefore, the Prdm9B6 allele probably takes part in posttranscriptional dominant-negative hybrid interaction(s) absent in the parental strains.
Highlights
Hybrid sterility is a condition in which two fertile parental forms produce progeny with disturbed gametogenesis
Six copies of the Prdm9C3H allele in a transgene (BAC24) increased reproductive fitness compared to two copies of the same allele (BAC5 transgene) in Prdm9PWD/B6 (PWD6B6)F1 intersubspecific hybrid males ([6] and Table 1), no effect of increased Prdm9 dosage appeared on the intrasubspecific background
Our ‘‘digital genetics‘‘ approach brings a new insight into the interactions of Prdm9 and other hybrid sterility genes participating in the genetic Dobzhansky-Muller incompatibilities (DMIs) and controlling the reproductive fitness of intersubspecific mouse hybrids
Summary
Hybrid sterility is a condition in which two fertile parental forms produce progeny with disturbed gametogenesis. In agreement with the SC data but in contrast to sterile hybrids carrying Prdm9PWD/B6, the chromosome spreads revealed the presence of spermatids in (PWD6B6-Prdm9wt/2)F1 Prdm9PWD/2 males. A sex body was formed in 67% of pachytene spermatocytes of Prdm9PWD/2 hybrids (Figure 2), a higher proportion in comparison to Prdm9PWD/B6 (p,0.001) but lower compared to Prdm9PWD/C3H hybrids (p = 0.001). The Prdm9PWD/C3H hybrid carried a lower ratio of pachytene spermatocytes displaying a sex body than the B6 (p = 0.004) and PWD (p = 0.03) fertile controls. The staining of spermatocyte chromosome spreads with MLH1 and SYCP1 revealed that the proportion of nuclei with fully synapsed pachytene chromosomes carrying over 20 recombination nodules is higher in the Prdm9PWD/2 than in the Prdm9PWD/B6 hybrids (p,0.001). The Prdm9PWD/2 hybrids were similar in this respect to Prdm9PWD/C3H, but both carried less pachytene spermatocytes with completed recombination than B6 and PWD (Table S4). The meiotic phenotypes correlate with the TW-SC-OFM data; the Prdm9PWD/B6, Prdm9PWD/2, and Prdm9PWD/ C3H F1 hybrids display a gradual increase in meiotic progress, yet even the Prdm9PWD/C3H F1 hybrid does not reach the parameters of B6 or PWD
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