CompletedGenetics & Molecular BiologyCells, Biochemistry & Physiology

Nuclear genomic control of mitochondrial DNA heteroplasmy in humans: population genetics & disease

FunderWellcomeCharity-funded
Recipient organisationUniversity of Cambridge
Funding£2.2M
PeriodOct 2018 — Oct 2023

In plain English

AI plain-English summary

Every time a woman passes her mitochondrial DNA to her child, the genetic dice are rolled again—and for roughly one in 5,000 people, that roll lands on a severe, often untreatable disease. Mitochondrial DNA mutates about 15 times faster than nuclear DNA, yet only a small fraction of the genome shows variation in the population. No one knows exactly how new mutations arise or why some become common while others vanish. This project aims to answer both questions by focusing on a “genetic bottleneck” that occurs during female germ cell development—a process that can dramatically shift the proportion of mutated mitochondrial DNA from one generation to the next. The researchers will define the mechanism of that bottleneck, identify the nuclear signal that controls it, and determine whether selection for or against particular mutations happens at the level of the cell, the mitochondrion, or the DNA molecule itself. This is fundamental science: it will not produce a treatment tomorrow. But understanding how mitochondrial variation arises and spreads is a prerequisite for designing therapies that could prevent or reverse mitochondrial diseases—conditions that currently have few options beyond symptom management.

View original technical description
Human mitochondrial DNA (mtDNA) mutates ~15-fold faster than nuclear genome, but only ~5% of the 16.5Kb mtDNA shows genetic variation in the population. Severe mtDNA mutations cause diseases affecting ~1 in 5000, but it is not known how new genetic variants arise, and why some are more common than others. We aim to address these two questions, building on pilot data implicating a mechanism acting on mtDNA during female germ cell development. Most humans inherit a mixed population of mtDNA (heteroplasmy) from their mother, and the proportion of mutated molecules can either increase or decrease within one generation due to a ‘genetic bottleneck’. This accelerates the segregation of alleles during early germ-cell development. We aim to: (a) define the mechanism of the bottleneck in germ cells; (b) identify the nuclear transcriptional signal controlling the bottleneck; (c) determine whether selection for/against particular mtDNA mutations occurs at the level of the cell, mitochondrion, or mtDNA molecule; and, (d) identify nuclear genes modulating the rate of segregation and selection. Together this work will define the fundamental biology driving mtDNA genetic variation in the human population, explain how this leads to mitochondrial diseases, and identity new approaches to prevent and treat these disorders.

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Researchers

Patrick F. Chinnery (EPMC Awardee)

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Original classification

Principal Research Fellowship (New)

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