Extra-haplotype rescue mosaicism mediates multi-lineage functional restoration in a monogenic condition
Year: 2026
Type: preprint
Abstract: 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.
Source: Research Square
Authors: Wayne Crismani, Caitlin Harris, Michael Sharp, Chirantani Mukherjee, Stevan Novakovic, Elissah Granger, Roser Pujol, Gerard Muñoz-Pujol, Elva Shi, Karen Dun, Cesar Salinas-La Rosa, Zhen Hou Xu, Mark Pertile, Krystle Standen, Rebecca Walsh, Andrew Deans, Davis McCarthy, Eunike Velleuer-Carlberg, Katerina Vlahos, Sara Howden, Andrew Elefanty, Elizabeth Ng, Jonathan Moses, Holly Pearson, David Gallego-Ortega, Adayapalam Nandini, Adam Nelson, Lisa Worgan, Jordi Surralles
Institutions: Monash University, Hospital de Sant Pau, Institut de Recerca Sant Pau, St Vincent's Hospital Melbourne, Victorian Clinical Genetics Services, Murdoch Children's Research Institute, NSW Health Pathology, St Vincents Institute of Medical Research, Heinrich Heine University Düsseldorf, Royal Children's Hospital, Australian Red Cross Lifeblood, University of Technology Sydney, Sydney Children’s Hospitals Network, Royal Prince Alfred Hospital, Universitat Autònoma de Barcelona
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7170133915