Mitochondrial DNA in Human Diversity and Health: From the Golden Age to the Omics Era

Abstract

Mitochondrial DNA (mtDNA) is a small fraction of our hereditary material. However, this molecule has had an overwhelming presence in scientific research for decades until the arrival of high-throughput studies. Several appealing properties justify the application of mtDNA to understand how human populations are-from a genetic perspective-and how individuals exhibit phenotypes of biomedical importance. Here, I review the basics of mitochondrial studies with a focus on the dawn of the field, analysis methods and the connection between two sides of mitochondrial genetics: anthropological and biomedical. The particularities of mtDNA, with respect to inheritance pattern, evolutionary rate and dependence on the nuclear genome, explain the challenges of associating mtDNA composition and diseases. Finally, I consider the relevance of this single locus in the context of omics research. The present work may serve as a tribute to a tool that has provided important insights into the past and present of humankind.

Keywords: aDNA; aging; diseases; forensics; haplogroup; human population genetics; longevity; mitogenome; phylogeny; phylogeography.

Figure 1

A simplified mtDNA phylogeny. Coalescence ages [point estimates (95% CI)] were retrieved from [21,56,66,67]. All estimates were based on mtDNA complete sequences, and the calibration rate is that proposed by Soares et al. [19], except for mtMRCA (most recent common mitochondrial ancestor).

Figure 2

A temporal overview of mtDNA studies in the literature. (a) Number of mtDNA studies published per year retrieved from PubMed from 1980 to the present (keywords: “mitochondrial DNA & human populations”, accessed on 8 May 2023); (b) this panel shows the number of publications, from 1993 to the present, that analyzed human variability with massive genotyping (keywords: “genome wide analysis and human populations”) and NGS methods (keywords: “next-generation sequencing and human populations”); (c) timeline of milestones in mitochondrial studies (in red) with respect to key episodes in human genetics (in blue). Arrows represent different methodologies used for analyzing human mitochondrial diversity as described in the text, and the time span in which they dominate mtDNA research. Abbreviations: GWAS (genome wide association analysis), CR (control region) and HGDP (Human Genome Diversity Project).