Oxford researchers find path to partly restore fertility of male hybrid offspring

The male offspring of hybrids--the product of mating between different species or subspecies-- are often sterile. The mule, a cross between a horse and a donkey, is a familiar example.

A team of scientists from Oxford University in the United Kingdom investigated why this occurs, and how genetic manipulation might be used to restore, or partially restore, fertility. Their research appears in the journal Molecular Biology and Evolution, December 2021.

Hybrid infertility is important to understand because it plays a role in evolution by limiting speciation.

The researchers worked with two subspecies of the house mouse, Mus musculus domesticus and M. musculus musculus, that interbreed. Previous studies had identified the gene PRDM9 as critical in mammalian meiosis and important in determining hybrid infertility in subspecies.

There are two roles for PRDM9 that have been identified. First, the gene controls the positioning of the double-strand breaks that initiate the recombination between the maternal and paternal chromosomes that form pairs when fertilization occurs in a cell.

Second, and less well understood, PRDM9 plays a role in binding the two chromosomes for the process of synapsis, the pairing of maternal and paternal chromosomes during meiosis, the cell division of reproduction.

Chance mutation and double-strand breaks that accumulate over time eliminate many of the binding sites for PRDM9 and thereby disrupt the process of synapsis.

Here, authors focus on the improper line-up (synapsis) that occurs between chromosomes which can cause sterility. They describe the relationship between spermatogenesis and synapsis as a “cliff edge” meaning there must be at least 50% synapsis for effective sperm production to occur. 

Intervening on hybrid infertility

The researchers used genetic manipulation to intervene on the failed binding process by introducing a human PRDM9 sequence, called a humanized allele, into sterile hybrids offspring of Mus musculus domesticus and M. musculus musculus. They also used another engineered allele from a third mouse species, M. musculus castaneus, called CAST.

They were able to identify the particular chromosome recombination site that failed and to insert the humanized allele in the sterile hybrid. 

The researchers reported, "Cytological analysis of meiotic chromosomes revealed that levels of chromosomal autosomal synapsis were significantly improved by the introduction of either" the humanized PRDM9 allele or the CAST allele. 

As the researchers note, however, the change of alleles was not able to completely reverse the process of sterility.

Their results suggest further areas for looking at reproductive barriers in hybrid offspring and the researchers report other possible blocks related to hybrid infertility. One of this is abnormal head shape of sperm in hybrids.

"Despite the persistence of these additional reproductive blocks, the data establish for the first time that PRDM9 is, and remains, a key but reversible part of the hybrid infertility between these two species," the researchers wrote.

The researchers conclude, "With manipulation of a single gene, we are able to rescue aspects of the infertility that has arisen between two species separated by 1.5 My of evolution."

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Benjamin Davies et al. "Altering the Binding Properties of PRDM9 Partially Restores Fertility across the Species Boundary," Molecular Biology and Evolution (December 2021). DOI: 10.1093/molbev/msab269