Use of whole genome and exome sequencing for analysis of mitochondrial DNA variation in the Brazilian population

• Grant number: 25/15637-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2026
• End date: December 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Marcos Roberto Chiaratti
• Grantee: Sérgio Antonio Garcia Pereira Junior
• 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

The human mitochondrial DNA (mtDNA) is a circular, multi-copy, extra-nuclear genome of 16.6 kb comprising two non-coding regions and 37 genes that are essential for mitochondrial function. Subjected to a high mutation rate and due to the absence of recombination, mutant and wild-type mtDNA molecules normally co-exist in the cell determining a condition known as heteroplasmy. Normally, the levels of heteroplasmy are present in most human individuals at below 1%, but can increase to disease-causing levels (i.e., >80%) or influence a range of phenotypes due to mechanisms such as relaxed replication and vegetative segregation. Additionally, given the maternal inheritance of mtDNA, the human population has been subdivided into several haplogroups according to the level of mtDNA sequence variation. However, most large genomic datasets based on whole genome sequencing (WGS) and whole exome sequencing (WES) do not include mtDNA variants due to technical challenges of analyzing mtDNA sequence, mainly explained by the existence of nuclear mitochondrial sequences (NUMTs), which require the use of dedicated pipelines to avoid misalignment and false-positive variant calls. This is of particular importance to Brazil as most studies of mtDNA sequence variation so far have focused on specific Brazilian regions, were based on low-resolution methods, restricted to a short region of mtDNA and involved a restricted number of individuals. In spite of this, recent and ongoing projects have provided high-coverage WGS and WES data of the Brazilian population. In this regard, the objective of the present proposal is to investigate mtDNA variants from at least two Brazilian WGS/WES datasets to assess mtDNA variant and copy number, haplogroup frequency, and association with available phenotypes (i.e., aging and diseases). To this aim, we will leverage from two cohorts of 1,171 (WGS) and 10,000 (WES) individuals from Brazil. We expect that the findings of the present study to contribute to a better understanding of the human mtDNA landscape in Brazil, being of scientific and medical relevance. (AU)