Feasibility and impact of haplogroup matching for mitochondrial replacement treatment

Abstract

Mitochondrial replacement technology (MRT) aims to reduce the risk of serious disease in children born to women who carry pathogenic mitochondrial DNA (mtDNA) variants. By transplanting nuclear genomes from eggs of an affected woman to enucleated eggs from an unaffected donor, MRT creates new combinations of nuclear and mtDNA. Based on sets of shared sequence variants, mtDNA is classified into ~30 haplogroups. Haplogroup matching between egg donors and women undergoing MRT has been proposed as a means of reducing mtDNA sequence divergence between them. Here we investigate the potential effect of mtDNA haplogroup matching on clinical delivery of MRT and on mtDNA sequence divergence between donor/recipient pairs. Our findings indicate that haplogroup matching would limit the availability of egg donors such that women belonging to rare haplogroups may have to wait > 4 years for treatment. Moreover, we find that intra‐haplogroup sequence variation is frequently within the range observed between randomly matched mtDNA pairs. We conclude that haplogroup matching would restrict the availability of MRT, without necessarily reducing mtDNA sequence divergence between donor/recipient pairs. image Haplogroup‐defining mtDNA sequence variants do not preclude within‐haplogroup variation. Comparison of variant counts between haplogroup matched and random mtDNA pairings indicates that matching would not necessarily reduce sequence divergence between egg donors and women undergoing MRT. Women belonging to rare haplogroups may have to wait several years for a suitable haplogroup matched egg donor. High levels of sequence divergence within many rare haplogroups limits the potential of haplogroup matching to reduce sequence divergence between egg donors and women belonging to rare haplogroups.