A Highly Unstable Recent Mutation in Human mtDNA

An A-to-G transition at position 16247 in the human mtDNA genome denotes haplogroup B4a1a1a and its sublineages. Informally known as the "Polynesian motif," this haplogroup has been widely used as a marker in Oceania of genetic affiliation with the Austronesian expansion. The 16247G allele has arisen only once in the human mtDNA phylogeny, about 7,000 thousand years ago, and is nearly fixed in Remote Oceania. We analyzed 536 complete mtDNA genome sequences from the Solomon Islands from haplogroup B4a1a1 and associated subhaplogroups and found multiple independent back mutations from 16247G to 16247A. We also find elevated levels of heteroplasmy at this position in samples with the 16247G allele, suggesting the ongoing occurrence of somatic back-mutations and/or transmission of heteroplasmy. Moreover, the G allele is predicted to introduce a novel stem-loop structure in the DNA sequence that may be structurally unfavorable, thereby accounting for the remarkable number of back-mutations observed at the 16247G allele in this short evolutionary time span. More generally, haplogroup-calling scripts result in inaccurate haplogroup calls involving the back-mutation and need to be supplemented with other types of analyses; this may be true for other mtDNA lineages because no other lineage has been investigated to the same extent (over 500 complete mtDNA sequences).