The Mother’s Curse and Mitochondrial DNA

By: Jenny Lam


Image Credit: Flickr @ Darryl Leja, NHGRI

For a long time, biologists believed that our DNA was only found in one place in the cell: the nucleus. However, a small portion of a eukaryote’s total DNA resides in the mitochondria, sites of cellular respiration and the generators of chemical energy to power the cell’s biochemical pathways. Because sperm have no mitochondria, mitochondrial DNA (mtDNA) is only inherited through the maternal line, leading to the mother’s curse hypothesis, which proposes that mothers can pass down genes through mtDNA that harm male offspring but not female offspring.


Image Credit: Jenny Lam

But first, why do mitochondria have DNA? The well-accepted endosymbiotic theory describes the origins of eukaryotic cells, as well as some of their organelles, such as the mitochondrion and chloroplast (Vanderbilt University, 2016). These organelles were believed to have once been prokaryotes that were engulfed by a larger prokaryotic cell (an ancestor to a eukaryotic cell), but remained undigested and eventually formed a mutualistic relationship with the larger cell as an endosymbiont, an organism that lives inside of another organism. One of these endosymbionts had the ability to utilize toxic oxygen molecules to efficiently extract energy from carbon sources, such as glucose, through cellular respiration, which highly benefited the larger cell. In turn, the larger cell provided protection for the engulfed cell, and over many generations, the engulfed cell lost its ability to survive without the host, becoming the organelle known as the mitochondrion.


Because mitochondria evolved from these ancient prokaryotic cells, they have their own set of DNA separate from nuclear DNA, which is usually only passed down through mothers in mammals. This is due to the fact that mitochondria in the sperm are usually destroyed by the egg cell after fertilization. The mother’s curse stems from the maternal inheritance of mtDNA; mutations in mtDNA that are harmful to males but are beneficial or neutral to females are not selected against, as males’ mtDNA do not get passed on in offspring.


A study from Vanderbilt University and the Fred Hutchinson Cancer Research center discovered a mutation in mtDNA in the fruit fly Drosophila melanogaster that provides evidence for the mother’s curse hypothesis in animals, as it lowers sperm production and motility, causing the fertility of males to decrease with age with no observable effects on their female counterparts. Although the mother’s curse has not been studied extensively in humans, one particular situation may reveal its effects on humans. Leber hereditary optical neuropathy (LHON), a genetic disease caused by the T1448C mutation, was traced back to a single woman and has been passed on ever since through the mother’s DNA, while only harming the sons (Mehta, 2017). Scientists from various Canadian universities assessed the reproductive fitness of over 2,000 carriers of LHON and found that male carriers tend to have lower survival rates in their first year of life (Milot, E., et al, 2017). The study concluded a positive selection through females that may amplify the effects of the mother’s curse.


However, if mutations in mtDNA that were selected against males could not be selected against, this may eventually result in species extinction, as the mutations would accumulate to a dangerously high frequency if natural selection cannot act on them. Because there has not been an observed extinction of a species due to the accumulation of harmful mtDNA mutations, this indicates that species have mechanisms to counter the effects of these mutations. It is also thought that the mitochondrial and nuclear DNA can adapt and evolve in response to one another, meaning that the nuclear genome should evolve mechanisms to counter the harmful effects of the male-harming mtDNA mutations. The researchers who studied the mother’s curse in the fruit flies found that the nuclear genomes of many of the fruit fly strains were able to restore the males’ fertility, strengthening this notion (Vanderbilt University, 2016).


Image Credit: Flickr @ Zappys Technology Solutions

There has also been increased controversy over the validity of the ‘mother’s curse’ and how mtDNA is inherited, as recent studies have suggested that a small part of the father’s mtDNA may be passed onto offspring, called paternal leakage. For instance, although the mitochondria in the sperm get decomposed, the tail of the sperm may contain a small amount of mtDNA, which offspring may be able to inherit. In 2002, a 28-year-old man was discovered to have both maternal and paternal mtDNA in his muscle tissue, whereas every other tissue only contained maternal mtDNA (Ladoukakis, 2004). Two years later, a study even claimed evidence of recombination between the maternal and paternal mtDNA.


Even in the case that fathers never transmit mtDNA to their children, some studies have suggested that natural selection can act indirectly on male-harming mtDNA through kin selection. Kin selection is a type of natural selection that favors the reproductive success of an individual’s relatives, even at the expense of said individual. Because related organisms have more genes in common, an individual can maximize their genetic representation in the next generation by helping their close relatives. Male organisms that are negatively affected by harmful mtDNA most likely are not able to help out their close female relatives to increase their biological fitness, lowering the chances that these female organisms will be able to pass down their male-harming mtDNA to the next generation.


Overall, the effect of the mother’s curse on evolution and natural selection remains largely unknown and debatable due to controversy in the contributions of each parent in passing down mitochondrial DNA. However, learning more about mitochondrial DNA can provide great insight into genetic diseases relating to mitochondria, as well as how males can be affected by the way mtDNA is passed down through generations.


Questions

Why is mitochondrial DNA usually passed on through the maternal line in sexual reproduction?

Mitochondria are usually inherited exclusively from the mother; mitochondria in mammalian sperm are destroyed by the egg cell after fertilization. This results in the offspring receiving no paternal mtDNA. However, there is growing debate on each parent’s mitochondrial contributions, as studies have discovered rare instances of biparental inheritance of mtDNA. The term heteroplasmy refers to the presence of more than one type of mtDNA in an individual.


What are some ways that species can reduce the effects of male-specific mtDNA mutations?

There are several ways that animals can counter the effects of these mutations, such as paternal leakage, kin selection, and the interaction between nuclear and mitochondrial genes. In several mammals, such as mice, there is evidence of paternal inheritance of mtDNA, although paternal mtDNA exists at a much lower frequency. In plants, nuclear restorer genes can counter the harmful effects that mtDNA mutations have on fertility, demonstrating the interactions between nuclear and mitochondrial genes. Additionally, through kin selection, the relatives of organisms whose siblings are affected by these mtDNA mutations can have their inclusive fitness reduced, possibly affecting their reproductive success.


References

Ladoukakis, E. D., & Eyre-Walker, A. (2004). Evolutionary genetics: Direct evidence of recombination in human mitochondrial DNA. Heredity, 93(4), 321. doi:10.1038/sj.hdy.6800572


Milot, E., Moreau, C., Gagnon, A., Cohen, A. A., Brais, B., & Labuda, D. (2017). Mother’s curse neutralizes natural selection against a human genetic disease over three centuries. Nature Ecology & Evolution, 1(9), 1400–1406. https://doi.org/10.1038/s41559-017-0276-6


Mehta, D. (2017, October 24). The Mother’s Curse: how a French king’s legacy revealed a loophole in evolution. Massive Science. https://massivesci.com/articles/dawkins-selfish-gene-mothers-curse-louis-xiv/


Vanderbilt University. (2016, August 2). Discovery of male-harming DNA mutation reinforces 'mother's curse' hypothesis. ScienceDaily. www.sciencedaily.com/releases/2016/08/160802171837.htm


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