Molecular mechanisms shaping the germ-line transmission of a pathogenic mtDNA variant

• Grant number: 24/07272-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2024
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: BBSRC, UKRI
• Principal Investigator: Marcos Roberto Chiaratti
• Grantee: Ana Rita Tavares Krause
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Associated research grant: 23/02226-8 - Bilateral BBSRC-FAPESP: molecular mechanisms shaping the germ-line transmission of mtDNA variants, AP.TEM

Abstract

Mitochondria are the principal source of cellular energy which is produced by oxidative phosphorylation (OXPHOS) leading to the production of adenosine triphosphate (ATP). Thirteen essential OXPHOS proteins are synthesised within the mitochondrion from mitochondrial DNA (mtDNA) which is exclusively inherited down the maternal line. MtDNA is highly polymorphic in humans, but the single nucleotide variants (mtSNVs) are not randomly distributed throughout the molecule. Family and population studies indicate that selective forces have shaped the mtDNA genetic landscape. Studying 358,916 individuals in UK Biobank we recently showed that mtSNVs influence common physiological parameters including kidney and liver function, our height and lifespan. Thus, understanding how mtSNVs arise and are propagated has important implications for human health and longevity. Most cells contain thousands of mtDNA molecules, and new mutations initially only affect a proportion of the mtDNA pool (heteroplasmy). Analysing 100,000 genomes project data, we have recently shown evidence of selection for and against heteroplasmic mtDNA variants. This was detectable between a mother and their child, and contributed to the genetic architecture of mtDNA at the population level. Precisely when and how the selection occurs is not known. We aim to determine the principal mechanisms influencing the inheritance of a pathogenic heteroplasmic mtDNA variant between a mother and her offspring. This work will be carried out in mice because mtDNA transmission in mice closely resembles humans, and the experiments we propose are not possible in humans.