Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues

Area of Science:

• Genetics and Genomics
• Aging Research
• Mitochondrial Biology

Background:

• Mitochondrial DNA (mtDNA) mutations are linked to various diseases.
• Understanding mtDNA mutation origins and accumulation with age is crucial but hindered by sequencing errors.
• Duplex sequencing offers a high-accuracy method for studying mtDNA mutations.

Purpose of the Study:

• To investigate the origins and accumulation patterns of mtDNA mutations in primate somatic tissues and oocytes across aging.
• To assess the impact of age on mtDNA mutation rates and identify mutation hotspots.
• To explore the role of selection on mtDNA variants in aging primates.

Main Methods:

• Employed duplex sequencing to obtain high-quality mtDNA sequences from liver, skeletal muscle, and single oocytes of rhesus macaques aged 1-23 years.
• Analyzed de novo mutations in somatic tissues and germline cells (oocytes) to minimize selection effects.
• Investigated mutation hotspots, particularly the light-strand origin of replication (OriL).

Main Results:

• Identified 17,637 tissue-specific de novo mtDNA mutations, with frequencies increasing significantly in liver and muscle over 20 years.
• Oocyte mutation frequency rose until age 9 but stabilized thereafter, indicating maintained mtDNA quality in older animals.
• The OriL region was identified as a mutation hotspot in aging liver tissue, with variants potentially affecting replication efficiency.

Conclusions:

• Mitochondrial DNA mutations accumulate with age in primate somatic tissues, but oocytes exhibit stable mtDNA quality beyond reproductive age.
• The OriL is a key hotspot for age-related mtDNA mutations, impacting replication.
• Positive selection acts on protein-coding mtDNA variants in somatic tissues, potentially mitigating mitochondrial dysfunction and offering insights into delayed reproduction.