Human genetic disease frequently arises from the failure of meiosis to faithfully haploidize the genome, instead giving rise to aneuploidy. Typically, chromosome missegregations and rearrangements appear to stem from problems in the processes that link partner chromosomes during meiotic prophase, i. e., synapsis and crossing over. However, a particularly dynamic chromosome behavior that instead destabilizes inappropriate links has recently been discovered and offers a new perspective for interpreting and understanding the sources of aneuploidy. On entry into meiotic prophase in S. cerevisiae, telomeres connect across the nuclear envelope to elements of the actin cytoskeleton that drag the chromosomes along the nuclear periphery at rates up to ~2 5m/second. In the absence of these rapid prophase movements (RPMs), crossover numbers and positions are aberrant, crossing over between nonhomologous chromosomes is prevalent and meiosis produces a high frequency of aneuploid products. The RPMs are regulated by recombination, the strongest RPMs coinciding with early recombination intermediates, suggesting that RPMs counteract the forces that stabilize recombinational interactions to insure that only allelic interactions are allowed to develop into crossovers. Preliminary results establish a role for the myosin type II gene MYO1 in a subset of the RPMs and suggest that other myosins influence RPMs either directly or by affecting the rate of actin filament treadmilling. New methods of microscopy and analysis will be used to assess the RPMs and the actin cytoskeleton when individual and combinations of myosin proteins are absent. Candidate signal transduction pathway genes will be tested to identify the regulatory functions that coordinate recombination intermediates with the recruitment of different motor molecules.
Aim 1. Determine the roles of myosins in driving and modulating RPMs.
Aim 2. Identify the regulatory functions that modulate the RPMs.
Aim 3. Refine our understanding of how telomeres interact with the force-generating machinery. The proposed work will complement and extend studies in other organisms aimed at understanding how actin promotes chromosome movements and specifically will address our long term goal to understand the mechanisms that keep aberrant meiotic outcomes in check.
Inheritance of incorrect numbers of chromosomes or parts of chromosomes is a significant source of human infertility, morbidity and mortality resulting from genetic disease. Recently, a major, unanticipated process was discovered that controls the fidelity of chromosome transmission in the reproductive cycle. Understanding this new process will provide a new perspective to understand how chromosomes are prepared for inheritance and what makes chromosome transmission fail so frequently in humans.
|Guiraldelli, Michel F; Eyster, Craig; Wilkerson, Joseph L et al. (2013) Mouse HFM1/Mer3 is required for crossover formation and complete synapsis of homologous chromosomes during meiosis. PLoS Genet 9:e1003383|