# Mitochondrial Genetic Variation Across Human Tissues

> **NIH NIH R03** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $82,500

## Abstract

Project Summary
Defects in mitochondrial genes encoding the oxidative phosphorylation (OXPHOS) complexes result in a
spectrum of disease in humans, ranging from severe pediatric syndromes to aging-related diseases. The
catalytic subunits of OXPHOS complexes I and III-IV are encoded by the mitochondrial genome (mtDNA),
which is present in 6-10 copies per mitochondrion. Due to the presence of multiple mitochondria in a cell,
different mtDNAs often co-exist within an individual mitochondrion or population of cells within a tissue, a
condition termed heteroplasmy, resulting in tissue mosaicism. Mitochondrial diseases that present in
adulthood are often the result of the accumulation of mtDNAs carrying a pathogenic variant in the affected
tissue. Whether different heteroplasmic mitochondrial genetic variants exist in different tissues of the
body within the general population is not known. We hypothesize that mtDNA variants and levels (variant
allele frequency, total number of heteroplasmic mtDNA variants) differ across the tissues of the human body
reflective of their germ layer origin. We also hypothesize that the accumulation of heteroplasmic variants within
a given tissue is associated with age. We will utilize whole genome sequencing and RNAseq data previously
collected as part of the Genotype-Tissue Expression project, a dataset consisting of sequencing data spanning
54 tissue sites across the body of 964 individuals collected postmortem. We will create a pipeline to identify
mtDNA variants from both whole genome sequencing and RNAseq reads that will be used to identify tissue-
specific homoplasmic and heteroplasmic mtDNA variants, which we will make publicly available upon
publication. We will compare homoplasmic and heteroplasmic variants across the tissues from the same
individual to identify tissue-specific variants (Aim 1A), and stratify by the germ layer (endoderm, mesoderm,
ectoderm) that gave rise to the tissues (Aim 1B). We will evaluate the association of age (at time of death) with
mtDNA heteroplasmic variant burden (total number of heteroplasmic variants, VAF) for each tissue (Aim 2).
Our study will lend insight into the possible origins of tissue-specific mtDNA variants and whether such variants
alter mitochondrial function, which may be relevant to the development of disease in that tissue. Without an
understanding of the extent to which tissue-specific mtDNA variants exist in the general population, delineating
between benign and pathogenic mtDNA variants in relation to human disease will continue to be a challenge.

## Key facts

- **NIH application ID:** 10911342
- **Project number:** 5R03AG081053-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Jessica L Fetterman
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $82,500
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911342

## Citation

> US National Institutes of Health, RePORTER application 10911342, Mitochondrial Genetic Variation Across Human Tissues (5R03AG081053-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10911342. Licensed CC0.

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