Homologous chromosome pairing is a central process underlying Mendelian inheritance, but while many genetic studies have revealed genes involved in homology recognition and recombination, the physical process by which the chromosomes come together inside the densely packed nucleus remains poorly understood. Telomeres of meiotic chromosomes are anchored on the nuclear envelope and attached to the cytoskeleton, which exerts randomly directed pulling forces. A key question is how randomly directed forces can facilitate the homology search process. Using a series of computational models, we have shown that randomly directed telomere forces can in theory promote search in several ways: driving superdiffusive motion of chromatin, overcoming entanglement, unpairing incorrectly paired regions to improve fidelity, and opposing entropic de-mixing of chromosomes. We propose to test these distinct predicted functions using live cell imaging and quantitative image analysis, combined with yeast genetics to alter the forces applied to the chromosomes. Our results should impact not only the understanding of meiotic homolog pairing as a physical process, but also the physical biology of chromosome motion in general as well as the broad concept of active random motion in biology.

Public Health Relevance

Project Relevance/Narrative Chromosome missegregation during meiosis is directly tied to human infertility and is also the leading known genetic cause for mental retardation and developmental disabilities. This work investigates the mechanisms in place to ensure faithful chromosome pairing during meiosis since in order for chromosomes to segregate faithfully, they must first find their homologous partner. Such research may lead to new ideas for treatment of infertility or to development of diagnostic tests to detect potential problems of chromosome segregation early on before expensive medical and surgical treatments are attempted.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM137126-01
Application #
9942883
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Resat, Haluk
Project Start
2020-04-03
Project End
2024-03-31
Budget Start
2020-04-03
Budget End
2021-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118