Structural variation and the evolution of the mouse genome Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 20, 2019
Creator
  • Morgan, Andrew
    • Affiliation: School of Medicine, Curriculum in Bioinformatics and Computational Biology
Abstract
  • Genetic variation in populations is governed by four basic forces: mutation, recombination, natural selection and genetic drift. Mutation is the source of new alleles, which are assorted among chromosomes by recombination. Selection and drift dictate the magnitude and direction of changes in allele frequency over time. These forces are intimately linked to meiosis, and asymmetries in meiosis create the opportunity for intragenomic conflict: competition between selfish alleles at the same locus for transmission to progeny. Such conflicts manifest as selection at the population level but subvert the Darwinian concept of fitness. The aim of this thesis is to characterize three of the four basic forces — recombination, mutation and intragenomic conflict — using the house mouse as a model system. I focus on the role of large segmental duplications, long tracts of repeated sequence that make up approximately 10% of mammalian genomes and are the site of the preponderance of structural variation between individuals. First I use two laboratory populations, the Collaborative Cross and the Diversity Outbred, to analyze the effects of sex and genetic background on the rate of recombination. I discover that (crossover) recombination is strongly suppressed in both sexes near large multiallelic copy-number variants. Second I reconstruct in detail the evolution of one such variant, R2d2. I show that R2d2 represents an ancient duplication that has been amplified to more than 100 copies in some lineages of European mice. Alleles with high copy number (R2d2HC) are associated with suppressed recombination but have an extremely high mutation rate. They are also selfish, having risen to high frequency in wild and laboratory populations by meiotic drive, in spite of their deleterious effect on reproductive fitness. Finally I perform the first comprehensive survey of sequence and structural variation on the mouse Y chromosome. I show that Y chromosomes have reduced sequence diversity relative to neutral expectations due to a strong population bottleneck in the recent past. I find that Y chromsomes vary dramatically in copy number of testis-specific genes, possibly as a side effect of past intragenomic conflict with the X chromosome.
Date of publication
Keyword
DOI
Resource type
Rights statement
  • In Copyright
Advisor
  • Pardo-Manuel Pardo-Pardo-Manuel de Villena, Fernando
  • Pomp, Daniel
  • McMillan, Leonard
  • Churchill, Gary
  • Magnuson, Terry
  • Petes, Thomas D.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
Language
Parents:

This work has no parents.

Items