Research

Faithful Genome Inheritance

The faithful transmission of genetic material from parents to offspring hinges on a dangerous and specialized cell division program: Meiosis.

During the first stages of meiosis, multiple double strand DNA breaks are intentionally generated on each pair of homologous chromosomes. These dangerous lesions threaten genomic integrity, but are a necessary starting point for a special type of DNA repair called crossover recombination. Crossovers are essential for successful meiosis: they temporarily connect chromosome pairs and enable their orderly segregation in the first meiotic division.

Strikingly, the number of DNA breaks far exceeds the number of productive crossovers. Most breaks are repaired as non-crossovers, which restore genomic integrity, but do not connect homologs. Only an extremely limited subset of breaks initiate crossover formation. Under this strict limitation, each DNA break site selected to initiate crossover formation must reliably mature as a crossover in order to facilitate accurate chromosome segregation. Failure to form crossovers leads to the creation of sperm and egg with an incorrect number of chromosomes and has devastating effects for sexual reproduction, including infertility, pregnancy loss, and birth defects.

Despite over a century of scientific discovery in the field of meiosis, we still know relatively little about the mechanisms underlying robust and reliable crossover formation.

My research aims to elucidate fundamental molecular mechanisms ensuring faithful genome inheritance during sexual reproduction. My driving question is: How do meiotic cells ensure reliable crossover formation?

A graphic showing 3 c. elegans nuclei during meiotic progression. The first nucleus is labeled "Many DNA Breaks". The second is labeled "one crossover site per chromosome pair". And the third is labeled "Each site designated to become a crossover must reliably mature as a crossover". A caption at the bottom of the image reads "How do meiotic cells ensure reliable crossover formation"?

Figure 1: My research aims to understand mechanisms underlying faithful genome inheritance during sexual reproduction. MSH-5 is a conserved meiotic DNA break repair and recombination factor, marking many DNA breaks in the early pachytene stage of meiosis, and marking the single crossover-designated site per chromosome pair in the late pachytene stage. Thus, how do cells ensure that each site selected to initiate crossover formation reliably completes crossover formation?

The microscopic roundworm C. elegans is an excellent model system to study meiosis.

First, key meiotic factors and processes are conserved between C. elegans and humans, enabling discoveries in worms to influence the understanding of human health and reproduction.

Second, the events of meiosis can be readily observed by immunofluorescence staining or live imaging of the worm's germline (See Figure 2). Important to my work, C. elegans is extremely proficient at regulating and ensuring meiotic crossover formation: It relies on the successful maturation of a single crossover-designated site per chromosome pair to enable orderly segregation!

And finally, C. elegans is highly amenable to genetic manipulation and biochemical approaches, providing a powerful system to test mechanisms of meiosis.

This is a scientific graphic that visualizes chromosome dynamics during meiosis in the C. elegans germ line

Figure 2: The stages of meiosis in the context of the worm germ line.

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