We did not identify any early mutations that could serve as direct targets for therapy, since TP53 is notoriously difficult to target in cancer cells without disrupting its function in normal cells.
One possible explanation is that the 2,789 AA-H SNVs are early mutations that were lost from the AB lineage due to late LOH events, a plausible hypothesis given that AB has many private LOH blocks (Additional file 1: Figure S5).
Oncogenic mutations are prevalent in human cancers, and some are thought to represent early mutations that initiate and subsequently drive cancer development.
Given the reviewers' comments on our original submission (reproduced above), we did not recognize that they were requesting that we examine the proportion of early 145K mutations that arose in SE Asia on the phylogeny.
As we described earlier, structural mutations that abolish the helicase activity of Twinkle affected replication of mtDNA in cultured cells and led to strong replication stalling and the accumulation of replication intermediates (22).
If the AA and AB subpopulations derived from the same genome doubling event, which necessarily must have occurred in a single cell, then due to this single cell 'bottleneck' event they should both retain all of the early somatic mutations that were shared between that single cell and the H subpopulation as a whole, yet they clearly do not.
Several lines of evidence indicate that TW10 is the most important target determining the viral load set point: TW10 is the earliest target during primary infection [32]; and among all the described HLA-associated mutations, T242N is the earliest escape mutation that emerges during acute infections [13].
Lancaster says the results echo earlier studies of gene mutations that cause microcephaly, which also affect neural progenitor cells.
The molecular lesions of the mei-218 alleles that we isolated in addition to other known mei-218 alleles are shown in Figure 2 and Table 2. Notably, the mutations in mei-218, mei-218 hfnd, and mei-218 are all early terminations or frameshift mutations that occur within 17 amino acids of an 1186 amino acid protein.
Our data strongly suggest that the TP53 mutation was an early founder mutation that was inherited by all subsequent subpopulations.
