The genetic architecture of the DDK syndrome: an early embryonic lethal phenotype in the mouse Public Deposited

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  • March 22, 2019
  • Ideraabdullah, Folami Yetunde
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
  • The DDK syndrome is a polar early embryonic lethal phenotype that occurs when DDK females are mated to males of other inbred mouse strains. Lethality is parent of origin dependent and results from an incompatibility between an ooplasmic DDK factor and a non- DDK paternal gene, both of which map to the Ovum mutant (Om) locus on chromosome 11. Here, I utilize naturally occurring genetic variation in classical and wild-derived inbred strains to characterize the genetic architecture of the DDK syndrome. I show that genetic variation among wild-derived strains is uniformly distributed and significantly higher than previously reported for other mammalian species. The high levels of diversity present among laboratory strains suggests that the effective population size of the Mus lineage has been relatively large and constant over a long period of time. Overall, these findings demonstrate that wild-derived inbred strains are a valuable resource for genetic studies. By utilizing this resource in recombination mapping and association mapping experiments, we have reduced the candidate interval for the paternal gene of the DDK syndrome to a 23 kb region encompassing a single gene. We have also defined a candidate interval for the gene encoding the maternal factor, and demonstrated that the maternal and paternal components of the DDK syndrome are non-allelic. I have identified three Mus musculus domesticus wild-derived strains carrying modifiers that completely rescue the DDK syndrome lethality. In at least two of these strains, the major modifier loci are unlinked to Om and rescue lethality in a parent of origin dependent manner that is independent of allelic exclusion at Om. Taken together, these data reveal that the DDK syndrome requires a specific combination of alleles at multiple loci. The fact that all of these alleles, with the exception of the allele encoding the maternal DDK factor, segregate in natural populations of mice suggests that they may be part of an important molecular pathway. In conclusion, further characterization of the genes responsible for this rescue phenotype will not only provide significant insight into the DDK syndrome, it should also increase our understanding of the molecular framework underlying early mammalian development.
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  • In Copyright
  • Pardo-Manuel Pardo-Pardo-Manuel de Villena, Fernando
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  • University of North Carolina at Chapel Hill
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