Modern concepts of the human mitochondrial genome variability and its role in the shaping of phenotype

Mitochondrial DNA (mtDNA) is a separate part of the genome which is localized in the mitochondria. It encodes 13 subunits of the respiratory chain complexes, as well as ribosomal and transfer RNAs. mtDNA is present in the cell in a large number of copies, its replication is relatively independent of the nuclear genome, it is inherited only through the maternal line, and has high mutation rate. The human mitochondrial genome has a high level of variability in various aspects, including hereditary polymorphism, which may have functional significance. High geographic and ethnic differentiation is characteristic of mtDNA polymorphism in human populations. In addition, mtDNA is characterized by different types of variability, such as the number of copies per cell and different levels of heteroplasmy of pathogenic variants. The purpose of this review is to outline the main trends in human mtDNA studies, its variability and its role in the shaping of phenotypes. Recently, mtDNA studies in populations have shifted to studying the complete mtDNA sequence, and studies of ancient DNA obtained from archaeological excavations are becoming increasingly important. Modern reproductive technologies and genome editing methods are being introduced in the field of mitochondrial diseases. Subunits of respiratory chain proteins encoded by mtDNA are more polymorphic in terms of amino acid sequence compared to subunits encoded by nuclear genes. Modern studies of associations of mtDNA polymorphism with phenotype are aimed at studying the effect of population genetic polymorphism on mitochondrial function, adaptation to environmental conditions, and studying the interaction of the effects of individual variants in one haplotype (epistasis). The study of the contribution of mtDNA polymorphism to the formation of a phenotype, both in health and pathology, faces the problems of assessing the combined effect of several variants. Recent studies have shown that the "genetic background" should be taken into account when assessing the pathogenicity/benignity of a genetic variant in mtDNA. For example, mtDNA belonging to haplogroup J is an unfavorable factor that enhances the effect of mtDNA mutations leading to the development of Leber's hereditary ophthalmopathy. The role of mtDNA polymorphism in predisposition to diseases can be considered within the framework of "thrifty" genotypes. This hypothesis assumes that the human genome is evolutionarily adapted to a traditional lifestyle, and modern changes in the level of human well-being and increased life expectancy lead to a change in the selection pressure, and evolutionarily formed genotypes lose their adaptiveness. In particular, this hypothesis is supported by the fact that mtDNA haplogroup H is associated with an increased risk of cardiovascular diseases, although it is the most common in human populations of European origin. The article contains 26 References. The author is sincerely grateful to her university teachers, lecturers of the Department of Cytology and Genetics of Tomsk State University: Alla Anatolyevna Kozlova, Larisa Ivanovna Potekhina, Svetlana Igorevna Tsitlenok, Svetlana Vasilyevna Pulkina, Yuri Mikhailovich Novikov. The Author declares no conflict of interest.