Molecular characterization of a maternal effect hybrid lethality locus on the chromosome II between Caenorhabditis briggsae and C. nigoni

Recurrent miscarriage (RM) affects approximately 1% of couples, characterized by the consecutive loss of three or more pregnancies. Although all diagnosis parameters for both parents are normal, the underlying causes for approximately a half of RM cases remain enigmatic, suggesting some hidden genetic conflicts between the parental genomes that render them incompatible - a phenomenon termed hybrid incompatibility (HI). HI usually leads to a loss or reduction in viability, lethality, and/or sterility in hybrid progeny, which plays a vital role in maintaining genetic stability within a species
by limiting genetic exchanges with other species or population. Dissecting the genetic and molecular mechanism of HI remains a central task for evolutionary biology. Identifying the HI genes poses a great challenge as they often lack selective pressure, resulting in minimal conservation across species, which makes traditional mapping methods unsuitable for mapping HI genes. While HI is more prevalent between closely related species than between different populations of the same species, mapping HI loci between species is frequently complicated by suppressed recombination due to the limited homology in their genomes.
In our previous study on hybrid incompatibility between the nematode species Caenorhabditis briggsae and C. nigoni, we identified an HI locus closely linked to chromosome II's left arm. Specifically, when the C. briggsae locus is homozygous in the hybrid embryo with C. briggsae as father, it results in complete embryo death, whereas similar hybrid embryos with C. nigoni father are viable although the two types of hybrids share the nuclear genomes. This pattern of inheritance suggests that the C. nigoni locus may encode a toxin-antidote (TA) pair. The maternally deposited toxin will kill hybrid embryos in the absence of zygotic expression of the antidote gene, which is commonly tightly linked to the toxin gene. Through thorough crossing experiments, we managed to map the HI locus to an interval of approximately 850 Kbps. Our recent development of a targeted recombination technique using CRISPR/Cas9 has enabled us to further refine this interval without being limited by homology. This proposal aims to narrow down the interval from around 850 Kbps to about 50 Kbps and molecularly clone the TA pair responsible for hybrid embryonic lethality. Uncovering these genetic elements will not only elucidate the mechanisms underlying the complete embryonic lethality in hybrids but also shed light on the genetic foundations of RM.