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Implications of human evolution and admixture for mitochondrial replacement therapy.

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Mitochondrial replacement therapy allows healthy births but raises safety concerns. Studies show human nuclear and mitochondrial DNA can coexist, suggesting this therapy is safe for reproductive purposes.

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Area of Science:

  • Genetics
  • Evolutionary Biology
  • Reproductive Medicine

Background:

  • Mitochondrial replacement (MR) therapy combines nuclear DNA from a mother with mitochondria from a donor to prevent mitochondrial disorders.
  • Concerns exist regarding potential incompatibilities between nuclear and mitochondrial genomes, known as the nuclear-mitochondrial mismatch hypothesis.
  • Previous studies in model organisms suggested potential issues with mismatched genomes.

Purpose of the Study:

  • To investigate the nuclear-mitochondrial mismatch hypothesis in humans.
  • To assess the safety of MR therapy by examining natural nuclear-mitochondrial genome combinations in human populations.

Main Methods:

  • Analyzed nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) sequences from 2,504 individuals in the 1000 Genomes Project (1KGP).
  • Conducted a replication analysis using mtDNA haplotypes from 1,043 individuals in the Human Genome Diversity Project (HGDP).
  • Compared nDNA and mtDNA divergence and evaluated mtDNA haplotype distributions within and between populations.

Main Results:

  • Nuclear and mitochondrial DNA sequence divergence levels were highly correlated, supporting co-evolution.
  • Identified numerous instances of individuals carrying nuclear and mitochondrial genomes from divergent populations.
  • Observed mismatched genome combinations even in populations with low admixture levels.

Conclusions:

  • Mismatched nuclear and mitochondrial genomes can coexist in healthy individuals, indicating they are not deleterious.
  • Natural human nuclear-mitochondrial mismatches do not appear to be subject to strong purifying selection.
  • The safety of mitochondrial replacement therapy is unlikely to be jeopardized by potential nuclear-mitochondrial mismatches.