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Rescue of the mouse DDK syndrome by parent-of-origin-dependent modifiers
Folami Y Ideraabdullah1, Kuikwon Kim, Daniel Pomp
1Department of Genetics, Curriculum in Genetics and Molecular Biology, Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
Abstract:
When females of the DDK inbred mouse strain are mated to males of other strains, 90-100% of the resulting embryos die during early embryonic development. This DDK syndrome lethality results from incompatibility between an ooplasmic DDK factor and a non-DDK paternal gene, which map to closely linked loci on chromosome 11. It has been proposed that the expression of the gene that encodes the ooplasmic factor is subject to allelic exclusion in oocytes. Previous studies have demonstrated the existence of recessive modifiers that increase lethality in the C57BL/6 and BALB/c strains. These modifiers are thought to skew the choice of allele undergoing allelic exclusion in the oocytes of heterozygous females. In the present study, we demonstrate the presence of modifiers in three Mus musculus domesticus wild-derived strains, PERA, PERC, and RBA. These modifiers completely rescued DDK syndrome lethality. We mapped the major locus that is responsible for rescue in PERA and PERC crosses to proximal chromosome 13 and named this locus Rmod1 (Rescue Modifier of the DDK Syndrome 1). Our experiments demonstrate that PERA or PERC alleles at Rmod1 rescue lethality independently of allelic exclusion. In addition, rescue of the lethal phenotype depends on the parental origin of the Rmod1 alleles; transmission through the dam leads to rescue, while transmission through the sire has no effect.
Insights
Genetic incompatibility causes early embryo death in DDK mice. Modifiers in wild-derived strains rescue this lethality by acting independently of allelic exclusion, with maternal inheritance being key.
Area of Science:
- Developmental Biology
- Genetics
- Reproductive Biology
Background:
- DDK syndrome causes high embryonic lethality due to ooplasmic DDK factor and paternal gene incompatibility.
- Allelic exclusion in oocytes is proposed to regulate the expression of the ooplasmic factor.
- Previous studies identified recessive modifiers increasing lethality in C57BL/6 and BALB/c strains.
Purpose of the Study:
- To investigate modifiers in Mus musculus domesticus wild-derived strains that rescue DDK syndrome lethality.
- To map the genetic locus responsible for rescue and understand its mechanism of action.
- To determine the role of parental origin in the rescue phenotype.
Main Methods:
- Cross-breeding DDK mice with wild-derived strains (PERA, PERC, RBA).
- Phenotypic analysis of embryonic development and lethality.
- Genetic mapping of modifier loci.
- Analysis of allele-specific expression and parental imprinting.
Main Results:
- Wild-derived strains PERA and PERC possess modifiers that completely rescue DDK syndrome lethality.
- A major rescue locus, Rmod1, was mapped to proximal chromosome 13 in PERA and PERC crosses.
- Rescue by Rmod1 alleles is independent of allelic exclusion and depends on maternal transmission.
Conclusions:
- Maternal transmission of specific alleles at the Rmod1 locus on chromosome 13 rescues DDK syndrome lethality.
- The rescue mechanism operates independently of the proposed allelic exclusion process.
- This study identifies novel genetic factors and mechanisms influencing interstrain reproductive incompatibility in mice.
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