Abstract
<title>Abstract</title> <p>Fanconi anaemia (FA) is a heritable DNA repair disorder in which somatic genetic rescue is frequently observed and selected, conferring improved haematopoietic outcomes. Here we identify a distinct class of genetic rescue which we term extra-haplotype rescue mosaicism, in which an additional parental allele enables functional rescue through allelic combination rather than sequence-level reversion mutations. This rescue event arose at an early post-zygotic time point therefore creating the potential for mosaicism in all primary germ layers. Mechanistically, the event involved the incorporation of the second polar body and a third chromosome set enabling a functional FA/BRCA DNA repair pathway. This event produced two co-existing cellular populations: a diploid lineage (46,XY) with a classical FA-deficient DNA repair phenotype, and a triploid lineage (69,XXY) with restored FA/BRCA DNA repair pathway function. Embryonic mosaicism enabled tissue-specific selection of the rescued FA-proficient triploid lineage. This rescue reflects an apparent tropism for genotypes with a functional FA/BRCA pathway, in the tissues which are exquisitely sensitive to loss of the FA/BRCA pathway, particularly the haematopoietic system and the oral mucosa. These findings are consistent with a model of mosaicism where one allelic combination can be selectively expanded over another based on a survival advantage, a phenomenon recapitulated in experimental modelling. Together, this model suggests that similar embryonic rescue events may occur in other monogenic conditions subject to selective pressures.</p>