Fanconi anaemia (FA) is a rare genetic disorder characterized by bone marrow failure, developmental abnormalities, decreased fertility, and an increased cancer susceptibility. FA is caused by mutations in specific genes involved in a common DNA repair pathway, with disruption of this pathway leading to genomic instability due to the accumulation of unrepaired DNA damage.
Previous work from our team has found that several fertility related traits are negatively impacted in Fancm-deficient mice with FVB or C57BL/6J Fancm-/- backgrounds, suggesting they are under genetic control. Some of these traits include: i) reduced gonad weights; ii) abnormal histological quantification of sperm development; and iii) sub-Mendelian ratios of female and male Fancm-/- mice.
To identify potential genetic modifiers of Fancm-/- phenotypic severity, we created a unique FVB.Fancm-/- x B6.Fancm-/-mouse population with an increased recombination proportion for the fine mapping of the alleles underlying these traits. Specifically, we constructed advanced intercross lines through semi-random breeding over five generations. Various phenotypic measurements were recorded for mice from the five-generation pedigree. These measurements include genomic instability, haematological parameters, litter sizes, gonad weights, and brain weights. Tissue samples were also preserved. Whole genome sequencing of mice from each generation (F1 to F5) was used to identify associations between traits and chromosomal regions corresponding to C57BL/6J or FVBN backgrounds. Several loci were identified that modify the phenotypic severity associated with loss of Fancm function for specific traits. Our next steps will be to identify the allelic variants that modify Fancm-/-phenotypic severity, which may provide new therapeutic targets with a view to ameliorate the symptoms of FA. This project will generate hypotheses for future human research that could be tested prospectively in an observational clinical study.