Poster Presentation ESA-SRB 2023 in conjunction with ENSA

The inter-generational effects of genome-wide genomic instability on fertility (#380)

Jessica M Stringer 1 , Stevan Novakovic 2 , Elissah Granger 2 , Caitlin Harris 2 , Vanessa Tsui 2 , Karla Hutt 1 , Eva R Hoffmann 3 , Davis J McCarthy 4 , Wayne Crismani 2
  1. Ovarian Biology Laboratory, Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  2. DNA Repair and Recombination Laboratory, St Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
  3. DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  4. Bioinformatics and Cellular Genomics, St Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia

Fanconi anemia (FA) is a complex autosomal genetic disorder characterized by bone marrow failure, congenital defects and cancer predisposition resulting from the inability to repair DNA interstrand cross-links and increased genomic instability. Female FA patients have reduced fertility which typically manifests as premature menopause by their early 30s. Gametogenesis is heavily perturbed in Fancm loss-of-function mice (Fancm-/-), consistent with the reproductive defects reported in humans with biallelic FANCM mutations.  Despite the gametogenesis phenotypes in Fancm-/- mutants, both sexes are capable of producing offspring. In humans approximately 15% of female FA patients carry healthy babies to term. Importantly, we can mirror this stochastic and premature menopause fertility phenotype in our mouse models, by inbreeding the same Fancm-/- mutation onto two different mouse backgrounds (C57BL/6J and FVB). In the C57BL/6J mice a stochastic infertility phenotype was observed in the Fancm-/- female mice compared to wildtype controls (wildtype 10/10 vs Fancm-/- 2/5 females had multiple litters). However, the FVB Fancm-/- female mice have fewer litters (wildtype 4.57±1.9 vs Fancm-/- 2.44±1.0, P<0.01) and a significant reduction in age (days) at last litter (wildtype 174.7±63.3 vs Fancm-/- 116.3±25.6, P<0.02) compared to controls, indicative of premature menopause observed in female FA patients. When we cross the two inbred lines together we recover fertility to wildtype levels, however litter number, size and age at last litter diminished over subsequent generations (F3 and F4) of breeding in the Fancm-/- hybrid line compared to wildtype controls. As Fancm-/- results in a genome-wide increase in meiotic crossover frequency, responsible for shuffling the C57BL/6J and FVB genomes, we will use whole genome sequencing of hybrid F4 parents and F5 offspring to map meiotic crossover sites and identify mutations associated with reduced fertility. This analysis will provide novel biomarkers for infertility and premature menopause relevant for FA patients and women in general.