Bilateral BBSRC-FAPESP: molecular mechanisms shaping the germ-line transmission of mtDNA variants

• Grant number: 23/02226-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: May 01, 2024
• End date: April 30, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: BBSRC, UKRI
• Principal Investigator: Marcos Roberto Chiaratti
• Grantee: Marcos Roberto Chiaratti
• Principal researcher abroad: Patrick Francis Chinnery
• Institution abroad: University of Cambridge , England
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• City of the host institution: São Carlos
• Associated research grant(s): 25/13891-8 - Effect of genetic and metabolic alterations on mitochondrial function in oocytes, AP.R
• Associated scholarship(s): 25/09613-2 - Contribution of mitochondrial DNA replication and mitophagy to purifying selection against deleterious mitochondrial mutation in mouse oocytes, BP.IC; 25/07106-6 - Establishment of a new lineage of mice carrying the mitochondrial mutation m.2707G>A, BP.MS; 24/07272-0 - Molecular mechanisms shaping the germ-line transmission of a pathogenic mtDNA variant, BP.PD; 24/07675-8 - Molecular mechanisms shaping the germ-line transmission of a genetic variant affecting mtDNA replication, BP.PD; 24/00564-6 - Popularizing knowledge about mitochondria and their relationship with fertility and diseases, BP.JC

Abstract

Mitochondria are the main source of energy within cells. They are made from over ~1100 proteins which are coded by two different genomes: nuclear DNA and mitochondrial DNA (mtDNA). MtDNA is only inherited from our mother, and codes for 13 mitochondrial proteins that are essential for cell energy production. In humans, mtDNA varies considerably between different people (called mtDNA single nucleotide variants, or mtSNVs). Studying mtDNA in 358,916 individuals in UK Biobank, we have recently shown that mtSNVs influence how healthy organs function, including the kidney and liver, how long we live, and whether we develop common age-related diseases. Thus, knowing how mtDNA variants arise in the human population has important implications for understanding who we are and how we function during life.Analysing data from the 100,000 genomes project, we have shown that our mtDNA is shaped, or 'selected' as it is transmitted from a mother to each child under the influence of the nuclear genome, but it is not known precisely when and how this occurs. In this project we aim to determine the main mechanisms.We will study mice because we have shown that the mechanisms of mtDNA inheritance are very similar to humans, and the experiments we propose are neither feasible nor technically possible in humans. Harnessing new genetic and single-cell techniques, we will study the transmission of mtSNVs at four stages: when egg cells develop, when they mature, during fertilisation, and in early embryonic development.First, we will generate mice transmitting mtSNVs. Next, we will determine whether there is selection at each of the four stages by measuring heteroplasmy in thousands of single cells. We will then use single-cell functional genomic approaches to determine the most likely nuclear genes involved in modulating mtDNA transmission. Finally, we will modify these genes in mice to show that they directly influence mtSNV inheritance.This work will advance our understanding of the fundamental cellular mechanisms driving human mtDNA evolution and genetic diversity in the human population, with implications for health and lifespan. (AU)