We reasoned that the rescue of haematopoiesis in Aldh2−/−Fancd2−/−Trp53−/− mice must be occurring at the cost of genome integrity. Although the level of micronucleated NCEs in the blood of Aldh2−/−Fancd2−/−Trp53−/− mice appeared similar to that of Aldh2−/−Fancd2−/− mice (Extended Data Fig. 8a), we noticed a significant (P 0.0034) increase in chromosome rearrangements in Aldh2−/−Fancd2−/−Trp53−/− mice, as seen by M-FISH analysis of total bone marrow cells (Fig. 6c, Extended Data Fig. 8). However, neither of these analyses tell us whether genome stability is similarly compromised in Aldh2−/−Fancd2−/−Trp53−/− HSCs. We therefore performed transplantation of single HSCs combined with whole-genome sequencing, as described earlier, and observed that p53 deficiency partially rescued the engraftment defect of Aldh2−/−Fancd2−/− HSCs (Fig. 6d). Surprisingly, the genomes of Aldh2−/−Fancd2−/−Trp53−/− stem cells did not carry a greater mutation burden than those of Aldh2−/−Fancd2−/− HSCs (Fig. 6e, f). Indel and rearrangement calls were validated by targeted deep sequencing and PCR, respectively (Extended Data Figs 9, 10 and Methods). One plausible explanation for the lack of increased mutagenesis in Aldh2−/−Fancd2−/−Trp53−/− HSCs is the possibility that the very small number of HSCs
