Mitochondrial DNA mosaicism in normal human somatic cells.

Area of Science:

• Genetics
• Cell Biology
• Aging Research

Background:

• Somatic cells accumulate genomic alterations during aging.
• Understanding of mitochondrial DNA (mtDNA) mosaicism and its age-related accumulation is limited.

Purpose of the Study:

• To investigate the origins and dynamics of mtDNA mosaicism in human somatic cells.
• To characterize the landscape of mtDNA variants across different cell types and donors.

Main Methods:

• Analysis of 2,096 clones from three cell types across 31 donors.
• Identification and quantification of mtDNA variants with heteroplasmy levels.
• Assessment of variant sharing across embryonic lineages.

Main Results:

• Identified 6,451 mtDNA variants (heteroplasmy >0.3%), predominantly unique to individual clones.
• Discovered 409 shared variants (6%), indicating origin from fertilized egg heteroplasmy.
• Observed replication-strand bias in the mutational spectrum, suggesting mtDNA replication as a key mutational process.
• Estimated mtDNA mutation rate at 5.0 × 10^-8 per base pair and turnover frequency of 10-20 per year.

Conclusions:

• mtDNA mosaicism arises from both stochastic, age-related acquisition and inheritance from the fertilized egg.
• mtDNA replication is a significant driver of mutations, shaping mosaicism over a lifetime.
• The expansion of mtDNA-truncating mutations is suppressed, influencing functional consequences.