Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout aging

Area of Science:

• Evolutionary Biology
• Genetics
• Cell Biology

Background:

• Mitochondrial genomes (mt-genomes) co-evolve with nuclear genomes and are shaped by selection in the female germline.
• Understanding how nuclear-mitochondrial genetic mismatch influences somatic evolution during aging is crucial.

Approach:

• Utilized ultra-sensitive Duplex Sequencing to analyze approximately 2.5 million mt-genomes across five mitochondrial haplotypes and three tissues in young and aged mice.
• Cataloged ~1.2 million mitochondrial somatic and ultra-low frequency inherited mutations, identifying 81,097 unique mutations.

Key Points:

• Identified haplotype-specific mutational patterns and hotspots, notably the Light Strand Origin of Replication.
• Rodents display a distinct mitochondrial somatic mutational spectrum (rich in G>T/C>A mutations) compared to primates.
• Somatic mutations in protein-coding genes show signatures of negative selection, and somatic reversion mutations re-align mito-nuclear ancestry.

Conclusions:

• Mitochondrial genomes represent a dynamically evolving subcellular population influenced by somatic mutation and selection throughout an organism's lifespan.
• Mismatched nuclear and mitochondrial ancestry significantly impacts somatic mt-genome evolution during aging.