Conflict-driven aneuploidy and genomic instability caused by meiotic proteins

项目摘要/摘要

PROJECT SUMMARY/ ABSTRACT Chromosome segregation can fail and generate cells with too many or too few chromosomes, a condition known as aneuploidy. Aneuploidy is a driving force in cancer progression and most cancers exhibit an abnormal karyotype. Aneuploidy is also the leading cause of infertility and congenital birth defects, such as Down syndrome. Because of the prevalence of aneuploidy in cancer and infertility, it is paramount to understand the causes of inaccurate chromosome segregation. Some components of the chromosome segregation machinery are among the fastest evolving genes in the genome. This rapid evolution is paradoxical as the process of chromosome segregation is essential and largely conserved. It is thought that conflicts caused by genetic parasites, found throughout eukaryotes, could be one cause of this rapid evolution. Meiotic drivers are one such type of intragenomic parasites that selfishly promote their own transmission into gametes. The overall goal of this proposal is to identify mechanisms that cause aneuploidy and infertility. The proposed aims will address three important questions: 1) What are the molecular mechanisms utilized by meiotic drivers? 2) Do meiotic drivers promote the formation of aneuploid gametes? 3) What causes errors in chromosome segregation? My work recently identified fission yeast wtf genes as a tractable model system in which to study meiotic drive. For my thesis dissertation (Aim 1), I will test if the genetic conflict caused by these meiotic drivers could affect the chromosome segregation machinery and thus the frequency of aneuploid gametes. Additionally, I will test if a high frequency of meiotic drivers in a population could promote the evolution of low fidelity chromosome segregation. During my postdoctoral research (Aim 2), I will apply the insights gained in my thesis research to address if the meiotic components of the chromosome segregation machinery can contribute to errors in mitotic chromosome segregation in humans. In addition, I will test if the untimely expression of meiotic genes contributes to the aneuploidy seen in cancer cells. To achieve these goals, I will use interdisciplinary approaches such as genetics, theoretical evolution, confocal microscopy, and cytogenetics. The completion of these aims will expand our understanding of the causes of aneuploidy and infertility, as well as the impact that genetic conflict has on genome integrity. The proposed research represents a unique contribution to the field of chromosome segregation and cancer research.