Male-harming DNA mutation reinforces ‘mother’s curse’ hypothesis

There is new evidence that the “mother’s curse” – the possibility that moms may transmit genes to their children that harm their sons but not their daughters – holds true in animals.

Such a possibility arises because there are two independent parts of the genome in the eukaryote cells, which are found in plants and animals, and the two are locked in a “conflict-driven molecular arms race” that impacts human health and wellness. The lion’s share of the genome is located in the cell nucleus. But there is also a much smaller secondary portion located in the mitochondria.

According to the generally accepted theory, mitochondria were originally independent bacteria that developed an ability to tap highly toxic oxygen molecules as a powerful energy source. Eukaryotes lacked this capability, so some of them found a way to swallow the mitochondria’s ancestor without digesting it – converting it into an “endosymbiont,” an organism that lives within the body of another organism. Unlike the nuclear genome, which is built from a combination of father’s and mother’s genetic material, the mitochondrial genome is passed down exclusively from the mother. As a result, male offspring are an evolutionary dead end. While natural selection actively suppresses mutations in the mitochondrial DNA (mtDNA) that weaken females, there is no direct mechanism for weeding out those that weaken males: a situation that leads to the mother’s curse.

While natural selection actively suppresses mutations in the mitochondrial DNA (mtDNA) that weaken females, there is no direct mechanism for weeding out those that weaken males: the situation that makes the mother’s curse possible.

Now, a team of biologists from Vanderbilt University and the Fred Hutchinson Cancer Research Center in Seattle have discovered a mtDNA mutant in the fruit fly Drosophila melanogaster that substantiates the mother’s curse hypothesis in animals: It reduces male offspring’s fertility as they age but does not have any observable effect on female siblings.

“In the 20 years since this possibility was recognized, a few mitochondrial mutants have been reported that have deleterious effects on male offspring,” said Maulik Patel, assistant professor of biological sciences at Vanderbilt who headed the study, “but none of them convincingly showed that the mutants did not have any negative effects on the females. Our study is the first to look comprehensively for possible effects of male-harming mtDNA mutants on females and we were fortunate to find one such mutant that has a negative impact on male offspring without having, as far as we can assess, any adverse effects on the female siblings.”

The discovery is described in an article published online Aug. 2 in the journal eLife.

The “mothers curse” is one of the more bizarre consequences of natural selection. According to evolutionary theory, the mitochondrial DNA (mtDNA) and nuclear DNA are locked in an unending competition. As one accumulates beneficial mutations, then the other is forced to adapt. This is known as the “Red Queen hypothesis.” The name is derived from a statement made by the Red Queen in Lewis Carroll’s Through the Looking-Glass: “…it takes all the running you can do, to keep in the same place.”

In plants, which have much larger mitochondrial genomes that contain a larger number of genes, striking instances of male-harming mitochondria have already been discovered. The mitochondrial genome in animals is much smaller, however, making it much harder to detect similar male-harming mutations.

The experiment that ultimately discovered the male-harming mtDNA mutant was something of a tour-de-force that took more than four years to complete. The scientists set up 18 independent lines of fruit flies, each consisting of 300 females and 100 males. In 12 of these lines virgin females were collected every generation and mated with males from the original stock. The researchers did this for 35 generations (about 70 weeks). In the remaining six lines the females were allowed to mate with the sibling males of their choice. Throughout this period the researchers were monitoring fitness of flies to determine whether males were getting harmed.

Ganesh Miriyala, Aimee Littleton and I spent a year and a half ‘flipping flies’ with no idea of whether we would end up with anything meaningful,” said Patel. Miriyala and Littleton were research technicians at the Hutchinson Center.

Fortunately, when they were done, the researchers found that a single-point mtDNA mutant had taken over one of the lines. This produced a single amino-acid change in the chemical structure of a subunit of an enzyme called cytochrome C oxidase. The researchers determined that the mutation causes the sperm production and sperm motility of the males to drop prematurely as they age, but it does not appear to have any other effects on males or females.

“We weren’t looking specifically for mutants that affect fertility,” said Patel, “but, in retrospect, it makes sense. Mutants that affect males but not females must be affecting tissues that are different in males and females.”

Their findings are consistent with a hypothesis that has been advanced to explain an association between a human mtDNA mutant and reduced sperm motility: That mtDNA mutations may be a significant contributor to untreatable male subfertility, known to affect 7-10 percent of men.

The researchers also discovered that the mutant enzyme was temperature sensitive. Turning up the temperature in their cages by four degrees Celsius caused the male carriers to become almost completely sterile. This allowed the scientists to perform an additional experiment to test a second prediction of the mother’s curse hypothesis: that the nuclear genome should evolve mechanisms for restoring male fitness by suppressing the activity of male-harming mtDNA mutants.

They mated females with the mutant mtDNA with males from a number of different fruit fly strains collected from a number of different locations around the world. Then they assayed the male offspring’s fertility and were surprised to discover that the nuclear genomes from many of the strains were capable of completely restoring the males’ fertility.

“The strategy that we used in this study, combined with advances in methods for manipulating mitochondrial genomes, provides us with exciting new opportunities to explore the ‘dark side’ of one of the oldest and most important symbioses on the planet. We hope this will lead to ways to treat mitochondrial diseases, only a few which currently can be treated, and which are inherited by one newborn in every 200 and become manifest in about one adult out of 5,000,” said Patel.

In addition to Patel, Miriyala and Littleton, co-authors of paper include Janet Young from the Fred Hutchinson Cancer Research Center, Hieko Yang and Yukiko Yamashita from the University of Michigan, Kien Trinh, Scott Kennedy and Leo Pallanck from the University of Washington. The research was conducted in the laboratory of evolutionary biologist Harmit Singh Malik at the Fred Hutchinson Cancer Research Center.

The research was supported by grants from the Helen Hay Whitney Foundation, the Mathers Foundation and National Institute of Health grants F30 AG045021, GM104990 and GM074108.

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