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Principal Investigator: JEFF J. SEKELSKY
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $544,786
Funding agency: National Institute of General Medical Sciences
ABSTRACT
Recombination is both a means to avoid genome instability and to process that generates genome instability.
In meiosis, DNA double-strand breaks are repaired into crossovers that are essential for accurate
segregation of homologous chromosomes; defects in this process result in sterility or aneuploidy, the major
cause of pregnancy loss and trisomy. Conversely, in mitotically proliferating cells double-strand breaks are a
dangerous class of DNA damage. Repair of breaks in this context is done without making crossovers;
formation of crossovers in mitotic cells can lead to chromosome rearrangements and tumorigenesis.
Research in my laboratory focuses on mechanisms that promote crossovers in meiotic cells and non-
crossover outcomes of repair in mitotic cells. We have made important contributions to understand these
problems for 20 years, during which time I have trained numerous scientists who are active in research and
research-related careers. This proposal sketches out both continued and new directions that will drive the
field forward. These include investigations of how large gaps are repaired (important for designing Cas9
fragment integration experiments and Cas9-based gene drive systems) and how meiotic crossovers are
patterned (important for proper segregation of chromosomes into gametes). We use a combination of
genetics, primarily using Drosophila as a model organism, genomics, biochemistry, cell biology, evolutionary
biology, and mathematical modeling.
Terms: <Aneuploid><Aneuploidy><Biochemistry><Biological Chemistry><Biology><Birth Defects><Body Tissues><CRISPR gene drive><CRISPR-Cas9 gene drive><CRISPR-Cas9 mediated gene drive><CRISPR/Cas9 based gene drive><Cancers><Cas9-based gene drive><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell division><Cells><Cellular Proliferation><Cellular biology><Chromosome Segregation><Chromosomes><Clustered Regularly Interspaced Short Palindromic Repeats gene drive><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Crossing Over><DNA Damage><DNA Double Strand Break><DNA Injury><DNA Recombination><DNA crossover><Dangerousness><Defect><Double Strand Break Repair><Drosophila><Drosophila genus><Gametes><Genetic><Genetic Crossing Over><Genetic Recombination><Genome Instability><Genomic Instability><Genomics><Germ Cells><Germ-Line Cells><Investigation><Laboratories><Malignant Neoplasms><Malignant Tumor><Math Models><Meiosis><Meiotic Recombination><Miscarriage><Mitotic><Mitotic Recombination><Molecular><Oncogenesis><Outcome><Pattern><Pregnancy loss><Process><Recombination><Regulation><Reproductive Cells><Research><Scientist><Sex Cell><Sperm><Spermatozoa><Spontaneous abortion><Sterility><Time><Tissues><Training><Trisomy><career><cell biology><chromosome division><crossover recombination><design><designing><egg><experiment><experimental research><experimental study><experiments><fruit fly><gene drive approach><gene drive strategy><gene drive system><gene drive technology><genomic crossover><initial cell><inter-homolog crossover><malignancy><mathematic model><mathematical model><mathematical modeling><meiotic><meiotic crossover><model organism><neoplasm/cancer><next-generation gene drive><non-sister chromatid exchange><nonsister chromatid exchange><repair><repaired><segregation><sexual cell><sperm cell><sterile><tumorigenesis><zoosperm>