Genetic Analysis of Meiotic Drive Systems in the Mouse Using Genotyping Arrays

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  • October 10, 2018
Creator
  • Didion, John
    • Affiliation: School of Medicine, Curriculum in Bioinformatics and Computational Biology
Abstract
  • Mendel's laws are key to our understanding of genetics and evolution. The Law of Segregation states that alleles at each genetic locus segregate randomly to the gametes such that each parental allele has an equal chance of passing to offspring. Though the processes governing chromosomal segregation are among the best conserved in eukaryotic biology, there are multiple examples of alleles that depart significantly from Mendelian inheritance ratios (transmission ratio distortion, TRD) and cannot be explained by natural selection on organismal fitness. Such deviations are thought to result from intragenomic conflict, in which selfish genetic elements have evolved mechanisms to propagate regardless of their effect on fitness. Meiotic drive is a type of intragenomic conflict in which a selfish allele is able to exploit asymmetric meiosis in order to have a significantly greater than random chance of being transmitted to the gamete. In mammals, only female meiosis is asymmetric due to the requirement that most of the cellular volume is transferred to a single haploid oocyte that is able to develop into an embryo upon fertilization. In some meiotic drive systems, non-random segregation is observed at or near the centromere. The Centromeric Drive theory predicts that meiotic drive acting on competing centromeric alleles leads to fixation of chromosomal rearrangements and thereby evolution of karyotypes with possible implications for speciation. In other meiotic drive systems, the locus exhibiting non-random segregation is not in direct linkage to the centromere. In order to characterize genetic factors that influence non-random chromosome segregation, I studied two different populations of the western house mouse (Mus musculus domesticus), each of which exhibited a different type of meiotic drive. First, there are over 100 chromosomal races of the house mouse, each of which has fixed one or more Robertsonian (Rb) translocations (fusions between acrocentric chromosomes). It has been hypothesized that the karyotypic diversity of the house mouse is due to a segregating meiotic drive system in which the ancestral allele favors transmission of acrocentric chromosomes to the oocyte while the derived allele favors metacentric chromosomes. I conducted a genome-wide association study of karyotypically divergent wild mice and identified a locus on Chr 13 that was significantly associated with accumulation of Rb translocations. Second, I characterized a novel meiotic drive system in the Collaborative Cross and Diversity Outbred mouse populations. I found a large region of Chr 2 in a wild-derived strain, WSB/EiJ, is preferentially transmitted during female meiosis when in heterozygosity with alleles from several other classical inbred strains. We identified a promising candidate causal allele, a 127 kb copy number variant with 33 additional copies in WSB/EiJ. We mapped the candidate allele to a 900 kb region that is distal to the single copy that exists in the mouse reference genome. There was striking similarity in both the number of copies and the sequence similarity between WSB/EiJ and SPRET/EiJ, a strain derived from a different species (Mus spretus), which also exhibits Chr 2 TRD in crosses with C57BL/6J. I also found that both the presence and level of meiotic drive were variable and dependent on genetic background. Some backgrounds exhibited drive approaching 100%, a level unprecedented in mammalian meiotic drive systems. We identified multiple QTL that approached significant associated with the presence and level of TRD in a relatively small sample of CC and DO hybrid females. This work contributes substantially to the understanding of meiotic drive, provides several important methods, data sets and mouse resources, and may have future implications for evolutionary theory, human health and biotechnological applications.
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  • In Copyright
Advisor
  • Pardo-Manuel Pardo-Pardo-Manuel de Villena, Fernando
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2014
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