Laboratory of Chromosome Dynamics and Evolution

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

Genetic elements compete for transmission to the next generation through meiosis, when haploid gametes are created from a diploid parent. Although Mendel's Law of Segregation states that each genetic element has an equal chance to transmit to the gametes, it is increasingly clear that this law is often violated by selfish elements. This non-Mendelian transmission of selfish elements in meiosis is called meiotic drive with significant impacts on chromosome evolution and sexual reproduction. To reveal the molecular basis underlying non-Mendelian segregation, we currently focus on selfish R2d2, a non-centromeric locus on mouse chromosome 2. This selfish element shows over 90% transmission ratio distortion with mild embryonic lethality. The underlying cell biological basis for both biased segregation in female meiosis and the embryonic lethality is unknown. To study the dynamics of the R2d2 locus during female meiosis, we implemented a FISH technique called Oligo-paint to the mouse oocyte system in collaboration with the Elissa Lai lab in NIDDK. Oligo-paint of the R2d2 locus allows us to analyze if the R2d2 locus has different chromatin structure compared to the neighboring regions and perform IF-FISH to screen what proteins are recruited to the R2d2 locus to cheat the segregation process. In the past year, we analyzed the aneuploid rate of chromosome 2, which carries the R2d2 locus and found that the R2d2 cheating can lead to the production of aneuploid egg. This result shed light on the mechanisms of the fitness costs associated with this meiotic drive system. Meiotic drive is fundamental to sexual reproduction and has been recognized as a powerful force in genetics and evolutionary biology since first described in maize in 1942. The underlying mechanisms have long been mysterious to cell biologists. This project tackles this exciting problem, all the way from developing experimental systems to revealing how selfish elements challenge Mendel and affect fertility. Moreover, our work will lead to a deeper understanding of the interactions between chromosomes and spindle microtubules. These interactions are highly error-prone in humans and a major cause of infertility, which could be caused by selfish behaviors of meiotic drivers.