Heteroplasmy: Definition, role, mechanism, techniques

Heteroplasmy might not be a household term, but its significance in genetics and personalized medicine is unquestionable. As scientists uncover more about the human genome, understanding phenomena like heteroplasmy become increasingly important. 

In this blog post, we will delve into the world of heteroplasmy, exploring its meaning, role in genetic diversity, implications for human health, and how it is detected and quantified.

So whether you’re a curious reader looking to understand more about human genetics, a student trying to get a grip on complex concepts, or a healthcare professional seeking to understand how genetic diversity impacts health, this comprehensive guide will help you understand heteroplasmy and its significance in the genetic world.

What is heteroplasmy?

Heteroplasmy is a genetic phenomenon referring to the presence of more than one type of mitochondrial DNA (mtDNA) within a cell or individual [1].

The term is derived from the words ‘hetero,’ meaning different, and ‘plasma,’ referring to the material in a living cell. Essentially, heteroplasmy refers to the existence of genetic diversity within the cells of a single organism.

Our cells house small powerhouses known as mitochondria, which are unique because they have their DNA, separate from the nuclear DNA we inherit from our parents. Mitochondrial DNA is solely inherited from our mothers, but variations in this DNA can occur due to a process called mutation.

When a cell divides, each new cell may receive a different mix of mutated and normal mitochondrial DNA, leading to a condition called heteroplasmy. The degree of heteroplasmy can greatly affect health and disease in an individual. 

For instance, if a certain mutation causes disease and a cell contains more of the mutated mtDNA than normal, it may result in disease manifestation.

What is the role of mitochondrial DNA in heteroplasmy?

Mitochondrial DNA (mtDNA) plays a central role in heteroplasmy. Unlike nuclear DNA, inherited from both parents, mtDNA is passed down exclusively from the mother [2]. Each cell contains hundreds to thousands of mitochondria, and each mitochondrion holds multiple copies of mtDNA.

Mitochondria are the energy powerhouses of cells, critical for various metabolic functions. Their unique DNA codes for crucial proteins that contribute to these functions.

However, unlike nuclear DNA, mtDNA is more exposed to reactive oxygen species produced as byproducts of energy generation, making it more susceptible to mutations.

When a mutation occurs in mtDNA, it does not necessarily affect all copies of the mtDNA in a mitochondrion. This leads to a condition where a single mitochondrion, cell, or organism contains a mixture of mutant and normal mtDNA – a state known as heteroplasmy.

The distribution of mutant and normal mtDNA can vary widely between cells and tissues within the same organism due to mitochondria’s independent division and replication.

This variation can lead to differing degrees of heteroplasmy, impacting the phenotype of cells and tissues and by extension, contributing to individual health and disease outcomes.

Understanding the role of mitochondrial DNA in heteroplasmy provides a window into the complexity of genetic variation and its effects on cellular function, health, and disease.

It underlines the importance of studying this phenomenon and how it contributes to our genetic makeup.

How does heteroplasmy contribute to genetic diversity?
Photograph: macrovector/Freepik

How does heteroplasmy contribute to genetic diversity?

Genetic diversity drives evolution, adaptation, and survival across generations. It gives rise to the variations in traits and characteristics we observe within species, including humans. 

Heteroplasmy contributes significantly to this diversity at a cellular and individual level. The concept of heteroplasmy introduces a unique form of diversity within our cells. 

As mentioned, heteroplasmy refers to normal and mutated mtDNA within a cell or individual. The proportion of these mtDNA types can vary from cell to cell, tissue to tissue, and between individuals, contributing to the observed genetic diversity.

This variation in mtDNA sequences and the resulting heteroplasmy introduce additional complexity to our genetic makeup.

The differing degrees of heteroplasmy across cells and tissues can affect the expression of mitochondrial genes, leading to variations in mitochondrial function and metabolic output. 

This can contribute to the diversity of cellular characteristics and phenotypes, even within the same individual.

At the population level, heteroplasmy contributes to genetic diversity by introducing new mtDNA variants that can be passed down through generations [3]. 

These variants can influence individuals’ health, survival, and reproductive success, thereby shaping the genetic landscape of populations over time.

Thus, heteroplasmy significantly contributes to genetic diversity, shaping our individual and population-level genetic identities and influencing various biological functions and health outcomes. 

It highlights the complexity of our genetic makeup and the intricate relationships between our genes, health, and environment.

Case studies highlighting genetic diversity because of heteroplasmy

Heteroplasmy is a complex genetic phenomenon studied extensively, and numerous case studies have illustrated its contribution to genetic diversity. Let’s look at two of these cases to understand how heteroplasmy can drive genetic variation.

Case Study 1: The Leber’s Hereditary Optic Neuropathy (LHON)

Leber’s Hereditary Optic Neuropathy (LHON) is a genetic disease that causes sudden vision loss in young adults, primarily males [4]. This condition is linked to mutations in mitochondrial DNA, highlighting a case of heteroplasmy. 

In families with LHON, different members may carry different proportions of the mutation, leading to variations in disease expression. Some individuals may experience severe vision loss, while others might remain asymptomatic. 

This case study underscores the role of heteroplasmy in generating genetic and phenotypic diversity, even within families.

Case Study 2: Mitochondrial DNA and Aging

A study published in the journal “Aging Cell” in 2018 shed light on the role of heteroplasmy in aging. Researchers found that human blood cells’ heteroplasmy level (the proportion of mutated mtDNA) increased with age. 

Importantly, the type of mtDNA mutations, and hence the level of heteroplasmy, varied significantly among individuals, which could contribute to the observed differences in aging and longevity among people. 

This study is a striking example of how heteroplasmy contributes to genetic diversity and affects critical biological processes like aging [5].

What is the biological process behind heteroplasmy?

Here’s a step-by-step breakdown and explanation of how mutations in mitochondrial DNA (mtDNA) occur and propagate within cells. 

1. Mutation occurrence

The first step towards heteroplasmy is the occurrence of a mutation in mtDNA. Because mitochondria are the energy-producing factories of cells, they generate reactive oxygen species as byproducts. These molecules can damage mtDNA, leading to mutations.

2. Cell division and mtDNA replication

When a cell divides, its mitochondria divide and distribute into the new cells. Mitochondria replicate their DNA independently of the cell cycle, which means at the time of cell division, each mitochondrion could have a different mixture of normal and mutated mtDNA.

3. Mitochondrial segregation

During cell division, the mitochondria, each potentially holding a unique mix of normal and mutant mtDNA, are randomly segregated into the daughter cells. This random distribution can lead to different levels of heteroplasmy in each cell. Some cells might receive more mitochondria with the mutated mtDNA, while others might receive more with the normal mtDNA.

4. Bottleneck effect

A critical aspect of heteroplasmy is the mitochondrial “bottleneck.” This term refers to the significant reduction in the number of segregating units of mtDNA (either mitochondria or nucleoids, which are clusters of mtDNA) during the formation of eggs. 

This reduction increases the chance of significant fluctuations in the proportion of mutant mtDNA transmitted to the next generation, leading to variable expression of disease in individuals carrying the mutation.

5. Effect on health

The level of heteroplasmy can greatly influence health outcomes. If a mutation is harmful, cells with a higher proportion of the mutated mtDNA may become dysfunctional and contribute to disease. 

The degree to which a cell, tissue, or individual is affected by a mtDNA mutation depends on the threshold level, which is the proportion of mutated mtDNA needed to cause cellular dysfunction or disease.

The biological process behind heteroplasmy involves a complex interplay of mtDNA mutation, replication, segregation, and the bottleneck effect, all of which contribute to the varying degrees of heteroplasmy across cells, tissues, and individuals, ultimately influencing health and disease outcomes.

Key mechanisms in heteroplasmy explained

Heteroplasmy involves a series of biological events including replication, segregation, and the bottleneck effect. Let’s look into each of these crucial mechanisms.


Replication refers to the process of duplicating DNA. In the context of heteroplasmy, we’re interested in replicating mitochondrial DNA (mtDNA).

Unlike nuclear DNA, which is replicated once per cell cycle, mtDNA replication can occur continuously, independent of the cell cycle. 

This means that mtDNA can be replicated whenever new mitochondria are needed, leading to varying copy numbers of mtDNA within each mitochondrion.

When a mutation occurs in mtDNA, replication leads to the duplication of both the mutated and normal mtDNA, contributing to heteroplasmy.


Segregation occurs during cell division when cellular components, including mitochondria, are divided between the two new cells.

Since each mitochondrion can contain a different mix of normal and mutated mtDNA, this segregation process can lead to daughter cells with varying heteroplasmy levels. 

For instance, one daughter cell may have more mitochondria carrying the mutated mtDNA, while the other may receive more mitochondria with the normal mtDNA.

This random segregation of mitochondria contributes to the variation in heteroplasmy levels across cells and tissues.

Bottleneck effect

The bottleneck effect refers to a sharp reduction in mtDNA copies passed on to the next generation.

This happens during egg cell formation when the number of mtDNA molecules is drastically reduced, increasing the chance of substantial fluctuations in the proportion of mutant mtDNA.

Imagine a scenario where the mother’s cells have a 50% mix of normal and mutated mtDNA. Due to the bottleneck effect, one egg cell might end up with 70% mutated mtDNA, while another might receive only 30%. 

This can result in significant variations in heteroplasmy levels among offspring and between siblings, leading to different health outcomes, even within the same family.

What is the role of heteroplasmy in human diseases?

The impact of heteroplasmy extends beyond genetic diversity and plays a crucial role in human health and diseases.

This is primarily because mitochondrial DNA (mtDNA), the site of heteroplasmy, encodes vital proteins for the proper functioning of mitochondria, our cellular powerhouses.

Mitochondrial dysfunction, often resulting from harmful mtDNA mutations, can disrupt energy production and other mitochondrial roles, affecting tissues with high-energy demands like the brain, heart, and muscles. 

What is the role of heteroplasmy in human diseases?
Photograph: ktsimage/Envato

Consequently, depending on the proportion of mutated mtDNA, heteroplasmy can lead to various mitochondrial diseases. Here are some examples:

1. Leber’s Hereditary Optic Neuropathy (LHON)

As mentioned earlier, LHON is a mitochondrial disease characterized by rapid, painless vision loss. It’s associated with several mtDNA mutations, and heteroplasmy plays a significant role in the disease manifestation.

2. Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS)

MELAS is a complex mitochondrial disorder caused by mutations in mtDNA. Symptoms can include muscle weakness, seizures, and stroke-like episodes [6]. The level of heteroplasmy can impact the severity and onset of the disease.

3. Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

MERRF is a mitochondrial disease associated with a specific mtDNA mutation. It leads to issues with muscle coordination, seizures, and other problems [7]. Here too, heteroplasmy influences disease severity.

Apart from these classic mitochondrial diseases, heteroplasmy may also play a role in more common conditions like diabetes, neurodegenerative diseases, cancer, and aging. 

For instance, researchers have found elevated levels of mtDNA mutations (and hence potentially higher heteroplasmy) in individuals with type 2 diabetes and Alzheimer’s disease.

It’s worth noting that the relationship between heteroplasmy and disease is not straightforward. A certain threshold level of mutated mtDNA is often needed to cause disease symptoms. 

Other factors like nuclear DNA, environmental influences, and chance also contribute to disease expression. 

Studies linking heteroplasmy to aging and diseases

The link between heteroplasmy, aging, and diseases has been a significant focus of scientific research.

Several studies have investigated these associations, providing intriguing insights into the role of heteroplasmy in human health. Here, we’ll examine a couple of these studies:

1. Heteroplasmy, aging, and longevity

A 2017 study published in “Aging” used a novel sequencing technique to examine the relationship between heteroplasmy and aging. Researchers observed that heteroplasmy levels in blood cells increased with age in a human population [8]. 

Furthermore, individuals who lived past 100, often referred to as centenarians, had higher heteroplasmy levels than younger individuals. However, the harmful effects of these mutations seemed to be neutralized by compensatory mechanisms in these centenarians. 

This study suggested a complex relationship between heteroplasmy, aging, and longevity, highlighting the role of compensatory mechanisms in moderating the potential negative effects of heteroplasmy.

2. Heteroplasmy and neurodegenerative diseases

A 2016 study published in “Cell Systems” explored the link between heteroplasmy and neurodegenerative diseases like Alzheimer’s and Parkinson’s. Researchers found an increased load of mtDNA mutations in the brain tissues of individuals with these diseases compared to healthy controls [9]. 

They concluded that elevated heteroplasmy levels might contribute to the pathogenesis of neurodegenerative diseases. However, they also noted that more research is needed to understand the cause-and-effect relationship fully.

3. Heteroplasmy and diabetes

A 2019 study published in “BMC Genomics” investigated the link between heteroplasmy and type 2 diabetes. The study found that certain mtDNA mutations associated with diabetes showed a significant increase in heteroplasmy levels in diabetic individuals compared to controls [10]. 

This suggested that heteroplasmy might play a role in developing or progressing type 2 diabetes.

These studies, along with many others, underscore the potential role of heteroplasmy in aging and disease processes. However, heteroplasmy’s role is complex, and more research is needed to unravel these complexities. 

What techniques are used for detecting and quantifying heteroplasmy?

Detecting and quantifying heteroplasmy is a complex task due to the need to discern minor differences in mtDNA sequences within a single cell or individual. However, technological advancements have led to the development of several techniques that can effectively detect and quantify heteroplasmy. Here are some of these methods:

1. Next-Generation Sequencing (NGS)

Next-generation sequencing (NGS) is a powerful tool for identifying and quantifying heteroplasmy [11]. It allows for high-throughput sequencing of mtDNA, which means it can sequence millions of fragments simultaneously. 

This makes it possible to detect even low levels of heteroplasmy that other methods might miss. However, it requires complex bioinformatic analysis and is subject to errors that can lead to the false identification of heteroplasmy.

2. Polymerase Chain Reaction (PCR) and Sanger Sequencing

PCR amplification of mtDNA followed by Sanger sequencing has been a traditional method of detecting mtDNA mutations [12]. However, it’s less sensitive than NGS and typically fails to detect heteroplasmy below a certain threshold (usually around 10-20%).

3. Digital PCR (dPCR)

Digital PCR is a more recent technique that has proven helpful in quantifying heteroplasmy. In dPCR, the DNA sample is partitioned into thousands or millions of separate reactions, allowing for the absolute quantification of nucleic acids [13]. 

Compared to other methods, this can provide a more accurate measure of heteroplasmy levels.

4. Single Molecule Real-Time (SMRT) Sequencing

SMRT sequencing is another recent advancement in sequencing technology. It allows for real-time sequencing of single DNA molecules, providing highly accurate and long-read sequencing data [14]. 

This makes it particularly useful for detecting and quantifying heteroplasmy, including low-level heteroplasmy.

5. Single-cell Sequencing

Given that heteroplasmy can vary from cell to cell, single-cell sequencing can provide a powerful tool for studying heteroplasmy. It allows researchers to determine the level of heteroplasmy in individual cells, helping to map the cellular landscape of heteroplasmy [15].

It’s worth noting that each method has its strengths and weaknesses, and the choice of method can depend on the specific research question and available resources. 

Furthermore, the rapidly advancing field of sequencing technology promises to deliver even more accurate and efficient methods for detecting and quantifying heteroplasmy in the future.

How understanding heteroplasmy can aid in personalized medicine
Photograph: wayhomestudioo/Envato

How understanding heteroplasmy can aid in personalized medicine

Heteroplasmy, with its role in genetic diversity and disease susceptibility, can be a critical component of this personalized approach, particularly in the following ways:

1. Disease prediction and prevention

Understanding an individual’s heteroplasmy profile can provide insights into their risk of developing certain diseases. 

For instance, specific mtDNA mutations associated with diseases like Leber’s Hereditary Optic Neuropathy (LHON) or Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) can be identified and quantified. 

This could allow for early interventions or lifestyle adjustments to mitigate disease risk or delay disease onset.

2. Tailored treatment approaches

The level of heteroplasmy can influence the severity and progression of mitochondrial diseases. By understanding an individual’s heteroplasmy levels, healthcare providers can personalize treatment plans. 

For example, patients with high levels of harmful mtDNA mutations might require more aggressive treatment than those with lower levels.

3. Patient monitoring

Heteroplasmy levels can change over time, and tracking these changes can provide valuable information about disease progression or response to treatment. 

Regular monitoring of heteroplasmy levels could help adjust treatment plans as needed, providing truly personalized care.

4. Potential therapeutic interventions

As our understanding of heteroplasmy improves, it opens the door for potential therapeutic interventions targeting the mitochondrial genome. Such treatments could be tailored to individuals based on their specific heteroplasmic mutations.

5. Family planning

Understanding heteroplasmy can inform family planning decisions for families with a history of mitochondrial diseases. 

Techniques like preimplantation genetic diagnosis (PGD) can be used to assess the level of heteroplasmy in embryos, potentially preventing the transmission of harmful mtDNA mutations to future generations.

While we are just beginning to scratch the surface of the potential role of heteroplasmy in personalized medicine, it’s clear that understanding an individual’s unique heteroplasmy profile can contribute to more precise and effective healthcare. 

As research progresses, we can expect to see more heteroplasmy applications in personalized medicine.

Closing thoughts

Heteroplasmy plays a pivotal role in genetic diversity and human health. It influences the onset and severity of numerous diseases, contributes to our understanding of aging, and holds substantial promise for the future of personalized medicine.

Although the exploration of heteroplasmy presents challenges, technological advancements in sequencing and detection methods have paved the way for more extensive and detailed research. 

In personalized medicine, the study of heteroplasmy offers immense potential. It enables us to appreciate the unique genetic makeup of individuals, guiding tailored healthcare decisions and improving health outcomes. 

Furthermore, it provides invaluable information for informed family planning decisions, particularly for families affected by mitochondrial diseases.


What is the importance of heteroplasmy?

Heteroplasmy is the presence of multiple types of mitochondrial DNA in a person’s cells. It affects disease susceptibility and can help with personalized medicine.

What are two likely sources of such heteroplasmy?

Heteroplasmy is caused by mutations during mtDNA replication and differences in inherited mtDNA variants from the mother. This leads to genetic diversity within individuals or cells.

[1] https://en.wikipedia.org/wiki/Heteroplasmy 
[2] https://biobeat.nigms.nih.gov/2020/05/the-maternal-magic-of-mitochondria/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809581/ 
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615366/
[5] https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-4287-0
[6] https://www.ncbi.nlm.nih.gov/books/NBK532959/
[7] https://rarediseases.org/rare-diseases/merrf-syndrome/ 
[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697406/ 
[9] https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00495-8
[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9523097/ 
[11] https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1002737
[12] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017848/
[13] https://www.jbc.org/article/S0021-9258(22)01018-3/
[14] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586377/
[15] https://academic.oup.com/nar/article/51/8/e48/7097663

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