Ancient mitochondrial DNA pathogenic variants putatively associated with mitochondrial disease

Area of Science:

• Paleogenomics
• Molecular Biology
• Human Genetics

Background:

• Mitochondrial DNA (mtDNA) variants linked to diseases are extensively studied in present-day populations.
• However, their historical prevalence in ancient human populations remains largely unexplored.
• Ancient genomes offer a unique window into the evolutionary history of genetic variations.

Purpose of the Study:

• To investigate the presence and prevalence of pathogenic mtDNA variants in ancient Eurasian populations.
• To analyze the spatiotemporal dynamics and potential evolutionary drivers of these variants.
• To expand the understanding of the origins and historical distribution of disease-associated mtDNA mutations.

Main Methods:

• Utilized the AmtDB database containing 1443 ancient Eurasian mtDNA genomes.
• Assessed clinical significance and pathogenicity of mtDNA variants using online prediction platforms.
• Analyzed geographic distribution, contemporary epidemiological data, and haplogroup associations.

Main Results:

• Identified six "confirmed pathogenic" mtDNA variants in ancient samples, with the oldest dating to 5800-5400 BCE.
• These pathogenic variants showed well-established clinical associations and low frequencies in contemporary populations.
• All detected pathogenic mutations were located in tRNA coding genes, often associated with altered D-loop/T-loop interactions.

Conclusions:

• Pathogenic mtDNA variants associated with mitochondrial diseases existed in ancient human populations.
• The spatiotemporal dynamics of these variants may be influenced by de novo mutations, human migrations, and evolutionary processes.
• This research enhances our understanding of the historical prevalence and evolutionary trajectories of disease-associated mtDNA variants.