Investigating chromosome structure and function across species using Oligopaints and genomics

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Precisely regulating inter-chromosomal interactions in all cell types is absolutely essential. In meiotic germline cells, homologs (maternal and paternal copies of the same chromosome) must come together and pair from end-to-end for accurate genetic recombination and chromosome segregation. Errors in chromosome segregation during meiosis can lead to reduced fertility, miscarriages, or chromosomal disorders in progeny, such as Down Syndrome or Turner Syndrome. Yet, how homologs find each other in 3D nuclear space and form stable linkages with each other remains unclear. This gap in our understanding of chromosome behavior is partially due to the fact that it is extremely challenging to study pairing in mammalian systems, where pairing is restricted to a subset of specialized cells in the germline. Thus, employing multiple model systems and elucidating what aspects of chromosome pairing regulation are conserved across species is essential for making accurate inferences about human biology. Our lab uses a combination of imaging and genomics approaches in insect and mammalian systems to dissect the mechanisms regulating homolog pairing and inter-chromosomal communications across species. Understanding these central aspects of chromosome biology will not only provide insights into how disruption of these processes can result in genome instability, but will provide new avenues for potential therapeutic targets for infertility. One early project in the lab was a collaboration with Dr. Takashi Akera (NHLBI) to investigate a novel meiotic drive locus in mice (published in Current Biology). We designed Oligoapint DNA FISH probes for Dr. Akera’s lab to distinguish between maternal and paternal chromosome copies, where only one allele contained the meiotic drive locus. This locus leads to chromosome missegregation during mouse oocyte production, and we found that it does so by pulling the other allele with it during segregation events to create an “egg-sabotaging” mechanism. This is a novel mechanism of chromosome missegregation and understanding drivers like this help us better understand how infertility can arise in humans. Another project is dissecting chromosome segregation mechanisms in two insect species that don’t pair sister kinetochores during meiosis I, a phenotype called “kinetochore splitting” which leads to aneuploidy (the wrong number of chromosomes) in mammals. Importantly, in human females, kinetochore splitting becomes more prominent and more problematic with age, and yet there are no known mechanisms to overcome this splitting and rescue chromosome segregation. Thus, understanding how these insects have bypassed this challenge could potentially lead to avenues for rescuing such fertility defects in humans. The discovery of this kinetochore splitting phenotype was published in PLOS Genetics, and interrogating the mechanism is on-going. Other upcoming projects in the lab will use a combination of genomics and CRISPR-based genome editing to investigate the regulation of homolog pairing and meiotic recombination across species, events which are completely essential for the accurate formation of egg and sperm cells but are not well understood.