Implications of human evolution and admixture for mitochondrial replacement therapy.
Mitochondrial replacement (MR) therapy is a new assisted reproductive technology that allows women with mitochondrial disorders to give birth to healthy children by combining their nuclei with mitochondria from unaffected egg donors. Evolutionary biologists have raised concerns about the safety of MR therapy based on the extent to which nuclear and mitochondrial genomes are observed to co-evolve within natural populations, i.e. the nuclear-mitochondrial mismatch hypothesis. In support of this hypothesis, a number of previous studies on model organisms have provided evidence for incompatibility between nuclear and mitochondrial genomes from divergent populations of the same species.



We tested the nuclear-mitochondrial mismatch hypothesis for humans by observing the extent of naturally occurring nuclear-mitochondrial mismatch seen for 2,504 individuals across 26 populations, from 5 continental populations groups, characterized as part of the 1000 Genomes Project (1KGP). We also performed a replication analysis on mitochondrial DNA (mtDNA) haplotypes for 1,043 individuals from 58 populations, characterized as part of the Human Genome Diversity Project (HGDP). Nuclear DNA (nDNA) and mtDNA sequences from the 1KGP were directly compared within and between populations, and the population distributions of mtDNA haplotypes derived from both sequence (1KGP) and genotype (HGDP) data were evaluated. Levels of nDNA and mtDNA pairwise sequence divergence are highly correlated, consistent with their co-evolution among human populations. However, there are numerous cases of co-occurrence of nuclear and mitochondrial genomes from divergent populations within individual humans. Furthermore, pairs of individuals with closely related nuclear genomes can have highly divergent mtDNA haplotypes. Supposedly mismatched nuclear-mitochondrial genome combinations are found not only within individuals from populations known to be admixed, where they may be expected, but also from populations with low overall levels of observed admixture.



These results show that mitochondrial and nuclear genomes from divergent human populations can co-exist within healthy individuals, indicating that mismatched nDNA-mtDNA combinations are not deleterious or subject to purifying selection. Accordingly, human nuclear-mitochondrial mismatches are not likely to jeopardize the safety of MR therapy.
School of Biology, Georgia Institute of Technology, Atlanta, GA, USA.|PanAmerican Bioinformatics Institute, Cali, Colombia.|Applied Bioinformatics Laboratory, Atlanta, GA, USA.
Lavanya
L
Rishishwar
School of Biology, Georgia Institute of Technology, Atlanta, GA, USA. king.jordan@biology.gatech.edu.|PanAmerican Bioinformatics Institute, Cali, Colombia. king.jordan@biology.gatech.edu.|Applied Bioinformatics Laboratory, Atlanta, GA, USA. king.jordan@biology.gatech.edu.
I King
0000-0003-4996-2203
IK
Jordan
D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D019143:Evolution, Molecular; D005787:Gene Frequency; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D016045:Human Genome Project; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics / Q000628:therapy; D000069321:Mitochondrial Replacement Therapy; D010802:Phylogeny
D004272:DNA, Mitochondrial; D004247:DNA
Population genomics; Three-person baby; mtDNA