LCMB_WGS_HSPC
Aldh2-/- Adh5-/- mice fail to degrade endogenous formaldehyde, develop bone marrow failure and exhibit increased cancer predisposition despite intact DNA repair. Pilot work has shown increased mutation accumulation in a small number of HSPC colonies from aged mice of this genotype showing some similarity with commonly observed mutational signatures, and analysis of the VAF distribution from bulk granulocyte WGS suggests (oligo)clonal granulopoiesis by 26 weeks of age. In light of recent biochemical and mass spectrometry findings suggesting formaldehyde lesions, while reversible, can persist for months in vivo, we believe they constitute plausible candidates for the persistent mutagenic lesions recently discovered in human stem cells. Furthermore, we now know that formaldehyde catabolism is important for maintaining organ function in other tissues including liver, kidney and brain, which in mass spectrometry experiments show a considerably higher formaldehyde adduct burden than bone marrow.  This project will thus (a) look in granular detail at the clonal architecture and mutation pattern in DNA from HS(P)C colonies from aged Aldh2-/- Adh5-/- mice to assess clonal evolution and look for potential phylogeny-violating variants, and (b) look at mutagenesis  in other tissues that show higher formaldehyde burden but not readily amenable to clonal colony growth using nanorate sequencing.
This project will (a) look in granular detail at the clonal architecture and mutation pattern in DNA from HS(P)C colonies from aged Aldh2-/- Adh5-/- mice to assess clonal evolution and look for potential phylogeny-violating variants, and (b) look at mutagenesis  in other tissues that show higher formaldehyde burden but not readily amenable to clonal colony growth using nanorate sequencing.