DESCRIPTION (provided by applicant): Violations of Mendel's First law occur when segregation of homologous chromosomes in meiosis is nonrandom, termed meiotic drive, which applies to female meiosis because of its inherent asymmetry: only chromosomes that segregate to the egg go into a gamete. Any bias away from random segregation is therefore under strong positive selection and has significant consequences for centromere and karyotype evolution and speciation. The mechanistic basis for the phenomenon is unknown. Nonrandom segregation of Robertsonian (Rb) fusions, which occur between two acrocentric chromosomes (centromere at one end) to form a metacentric (centromere in the middle), can determine whether a species has an acrocentric or metacentric karyotype. Moreover, the direction of the preferential segregation can reverse and drive changes in karyotype and speciation. The overall goal of this proposal is to determine how functional differences between centromeres and meiotic spindle asymmetry lead to nonrandom chromosome segregation, and how the direction of drive is determined. Rb fusions pair with the two homologous acrocentric chromosomes to create a "trivalent" in meiosis I. Meiotic drive requires preferential orientation of the trivalent on an asymmetric spindle and an asymmetric cell division such that one spindle pole preferentially enters the polar body. Mouse oocytes provide an ideal system to address the underlying mechanisms, which are not understood, because it is well established that the fusion preferentially segregates to the polar body in most strains. Based on our preliminary results, we propose that the fusion centromere preferentially captures microtubules from the pole that has more astral microtubules, which determines the orientation of the trivalent. Aim 1 will distinguish between two models for differences in centromere strength. Aim 2 will test the hypothesis that differential microtubule behavior at asymmetric spindle poles drives trivalent orientation and spindle orientation. Aim 3 will address how the direction of meiotic drive is determined. Multiple Rb fusions have become fixed in the Zalende mouse strain, indicating that the direction of drive is almost certainly reversed relative to common lab strains, which provides an ideal experimental system. We will test two possibilities: either spindle orientation relative to the cortex or trivalent orientation on the spindle could reverse (but not both). The results of the proposed experiments will provide the first insight into mechanisms underlying meiotic drive in animals and establish a link between the basic cell biology of chromosome segregation in individual cells and karyotype evolution and speciation in populations. Moreover, the proposal is relevant to human health because Rb fusions are the most common chromosomal abnormality in humans, occurring in ~ 0.1% of meiotic divisions, and are associated with infertility. Rb fusions preferentially segregate to the egg in humans, which means that the abnormalities persist in families that carry them.

PUBLIC HEALTH RELEVANCE: Robertsonian fusions are the most common chromosomal abnormality in humans and are associated with infertility. Because of nonrandom chromosome segregation in the process of making an egg, termed meiotic drive, these fusions tend to persist in the population. The goal of this proposal is to understand mechanisms underlying this nonrandom segregation.