Mitochondrial genetic variation in human bioenergetics, adaptation, and adult disease.

OBJECTIVES: Mitochondria are critical for the survival of eukaryotic organisms due to their ability to produce cellular energy, which drives virtually all aspects of host biology. However, the effects of mitochondrial DNA (mtDNA) variation in relation to disease etiology and adaptation within contemporary global human populations remains incompletely understood. METHODS: To develop a more holistic understanding of the role of mtDNA diversity in human adaptation, health, and disease, we investigated mitochondrial biology and bioenergetics. More specifically, we synthesized details from studies of mitochondrial function and variation in the context of haplogroup background, climatic adaptation, and oxidative disease. RESULTS: The majority of studies show that mtDNA variation arose during modern human dispersal around the world. Some of these variants appear to have been positively selected for their adaptiveness in colder climates, with these sequence changes having implications for tissue-specific function and thermogenic capacity. In addition, many variants modulating energy production are also associated with damaging metabolic byproducts and mitochondrial dysfunction, which, in turn, are implicated in the onset and severity of several different adult mitochondrial diseases. Thus, mtDNA variation that governs bioenergetics, metabolism, and thermoregulation may potentially have adverse consequences for human health, depending on the genetic background and context in which it occurs. CONCLUSIONS: Our review suggests that the mitochondrial research field would benefit from independently replicating mtDNA haplogroup-phenotype associations across global populations, incorporating potentially confounding environmental, demographic, and disease covariates into studies of mtDNA variation, and extending association-based studies to include analyses of complete mitogenomes and assays of mitochondrial function.

Characterizing the genetic diversity of the monkey malaria parasite Plasmodium cynomolgi.

Plasmodium cynomolgi is a malaria parasite that typically infects Asian macaque monkeys, and humans on rare occasions. P. cynomolgi serves as a model system for the human malaria parasite Plasmodium vivax, with which it shares such important biological characteristics as formation of a dormant liver stage and a preference to invade reticulocytes. While genomes of three P. cynomolgi strains have been sequenced, genetic diversity of P. cynomolgi has not been widely investigated. To address this we developed the first panel of P. cynomolgi microsatellite markers to genotype eleven P. cynomolgi laboratory strains and 18 field isolates from Sarawak, Malaysian Borneo. We found diverse genotypes among most of the laboratory strains, though two nominally different strains were found to be genetically identical. We also investigated sequence polymorphism in two erythrocyte invasion gene families, the reticulocyte binding protein and Duffy binding protein genes, in these strains. We also observed copy number variation in rbp genes.