Mitochondrial genetic variation in the evolution of humans and metabolism of cancer

Abstract

Mitochondria act as the cell’s powerhouse for aerobic energy production. Mitochondria carry their own genetic material (mtDNA), which is maternally inherited and has a high mutation rate. Hence the mtDNA is an ideal genetic tool to trace human evolution and migrations, and a candidate for somatic mutation studies in cancer. These aspects of mitochondrial genetics form the two main foci of this thesis.

Southern Africa is known to encompass the world’s greatest genomic diversity, and genetic, anthropological, and archaeological studies support the region as a candidate for the origin of modern humans. In summary, this study used mitochondrial genomes to identify great maternal diversity in the Southern Bantu. Haplogroup distributions in each population suggest a migration route from the Bantu homeland in Western Africa, across Central Africa to the Eastern Great Lakes region, and down the Eastern side of Southern Africa, absorbing indigenous Khoesan lineages to their present day home resulting in the Southern Bantu of today. This study also identified new mtDNA haplogroups, many of which are among the earliest diverging lineages. This study contributes to the global mitochondrial haplogroup diversity knowledge bank.

The role of mitochondrial genetic mutations was studied in the context of altered metabolism in cancer, where biosynthesis and maintenance of redox capacity is favoured over energy production via oxidative phosphorylation in tumour cells. 24 somatic mutations were identified in the mitochondrial genomes of 12 patient-derived pancreatic cancer tumour cell lines, most of which were nonsynonymous and located in coding regions for electron transport chain (ETC) subunits or important control regions, in addition to another 18 mutations in nuclear genes predicted to have important mitochondrial or metabolic function. Additionally, significant variation was observed in metabolic phenotype between normal pancreatic cells and tumour cells, including decreased oxygen consumption in tumours, altered metabolomic profiles with an upregulation in biosynthetic pathways such as fatty acid synthesis in tumour cells, and reduced expression of various mitochondrial electron transport chain subunits in tumours. These findings may inform development of new therapeutic strategies targeting these pathways.