Heteroplasmy and Individual Mitogene Pools: Characteristics and Potential Roles in Ecological Studies

Abstract

The mitochondrial genome (mitogenome or mtDNA), the extrachromosomal genome, is a multicopy circular DNA with high mutation rates due to replication and repair errors. A mitochondrion, cell, tissue, organ, or an individual body may hold multiple variants, both inherited and developed over a lifetime, which make up individual mitogene pools. This phenomenon is also called mtDNA heteroplasmy. MtDNA variants influence cellular and tissular functions and are consequently subjected to selection. Although it has long been recognized that only inheritable germline heteroplasmies have evolutionary significance, non-inheritable somatic heteroplasmies have been overlooked since they directly affect individual fitness and thus indirectly affect the fate of heritable germline variants. This review focuses on the characteristics, dynamics, and functions of mtDNA heteroplasmy and proposes the concept of individual mitogene pools to discuss individual genetic diversity from multiple angles. We provide a unique perspective on the relationship between individual genetic diversity and heritable genetic diversity and guide how the individual mitogene pool with novel genetic markers can be applied to ecological research.

Keywords: MtDNA heteroplasmy; individual mitogene pool; molecular marker.

Figure 1

Hierarchical mosaicism of mtDNA heteroplasmy and nonrandom distribution across nucleotide positions and tissues. (A). All hierarchical levels of life structure, from organelle (mitochondrion), cell, tissue, and organ to the whole body, may contain heteroplasmic variants of mtDNA and show mosaic patterns. (B). Diagram showing the heteroplasmy of a segment of the mitogenome. Multiple copies of mtDNA from a cell or tissue consist of multiple variants revealing polymorphisms at nucleotide sites. The consensus sequence of this fragment is determined by the major nucleotide at each site, while heteroplasmy is revealed by minor nucleotides. The level of heteroplasmy varies from region to region on the mitogenome, highest in D-loop and considerably lower in other regions such as ND₂.

Figure 2

Effects of mtDNA heteroplasmy. Mutations in RNA coding regions may alter the structure, conformation, and melting temperature of transfer RNAs and ribosomal RNAs, and further lead to alteration of membrane potential and reduction in ATP synthesis [11,12,13]. These changes all result in the dysfunction of mitochondria. Meanwhile, mutational variants in protein-coding regions may alter the structure and function of NDs subunits, further impairing the function of the OXPHOS system. Impaired OXPHOS will lead to the accumulation of ROS, acetyl-CoA, pyruvate, and other basic metabolites, and further lead to hypoxia of cells. The hypoxic state of cells stimulates the production of co-transcriptional regulators PGC-1α and other transcription factors like HIF1 and NRF1 and finally enhances the production of mitochondrial transcription factor A (TFAM) that stimulates mitochondrial biogenesis and mtDNA replication. Active mtDNA replication in turn facilitates the production of additional mutational variants. OXPHOS, oxidative phosphorylation; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator 1alpha; HIF1, hypoxia-inducible factor 1-alpha; NRF1, nuclear respiratory factor 1; TFAM, mitochondrial transcription factor A.

Figure 3

Heteroplasmy passing through bottleneck and development of individual mitogene pool. Each ovum contains up to 100,000 copies of mitogenomes with a few variants. The zygote develops into an embryo with a set of tissues and organs. This process involves massive cell proliferation and replication of the mitogenome, and numerous de novo variants are produced. The de novo and inherited variants form a mitogene pool for each organ and the whole body. Each of the primordial germ cells derived from a group of embryonic stem cells inherit a tiny fraction of the mitogene pool of the entire germline through a bottleneck and drastic drift. During the ovum’s development and maturation, the inherited mitogenomes are massively propagated, producing a large number of de novo heteroplasmic variants available to second-generation animals. Nevertheless, de novo variants are always low-frequency, making the majority of variant(s) in an organ the ones inherited from the previous generation.