Using the ancestral recombination graph to study the history of rare variants in founder populations

Gene genealogies represent the shared ancestry of a sample and are often encoded as ancestral recombination graphs (ARGs). It has recently become possible to infer these gene genealogies from sequencing or genotyping data and use them for many evolutionary and statistical genetics applications. Here, we use the ARG inference software ARG-needle and the pedigree imputation software ISGen to impute and trace the transmission of disease variants in founder populations where long shared haplotypes allow for accurate timing of relatedness. We applied these methods to the population of Quebec, where multiple founder events led to an uneven distribution of pathogenic variants across regions and where extensive population pedigrees are available via the BALSAC project. We validated this approach with nine founder mutations for the Saguenay-Lac-Saint-Jean region, demonstrating high accuracy for mutation age, imputation, and regional frequency estimation. We used imputed carrier status in a longitudinal cohort to highlight heterozygote effects for known recessive alleles. These heterozygote effects, together with regional frequency estimates, can inform the design of screening programs.