As many as a one in 20 men is infertile, but in many cases the underlying cause for it remains unknown.
Recent research has found that a peculiarity in the way in which the DNA inside our mitochondria (the powerhouses of the cell) is passed from generation to generation, may hold the key to a better understanding of male infertility.
Enter the mitochondrion
Long ago, a precursor to all the animal and plant species on our planet engulfed an ancient bacterium that had the knack for energy production.
What happened next is of monumental importance to the history of life on earth.
Rather than digest the bacterium, the two entities initiated an intimate relationship, which allowed our primitive ancestor to tap into the remarkable energy converting properties of what was to become the mitochondrion.
This symbiosis led to the diversity of complex life as we know it.
And one of the consequences of this ancient merger is that all members of the animal kingdom harbour two sets of genomes.
The vast majority of genes that encode our biological function reside within the nuclei of cells (nuclear DNA). These are the genes that are typically inherited from each parent – one copy from the father and one from the mother.
The mitochondria, on the other hand, have retained their own small genomes (mtDNA), which are pivotal to the task of encoding energy production. Oddly, the mitochondria are inherited only from the mother.
So males are essentially evolutionary dead-ends for mitochondrial genes. And this seemingly trivial fact might have dramatic consequences for males.
What does this mean for male fertility?
In theory, this means that mutations in the mitochondrial DNA (mtDNA) that exert harmful effects on how males function will escape the watch of natural selection if these same mutations are benign, beneficial or only slightly harmful to how females function.
This is because females, who transmit the mtDNA to the next generation, will be oblivious to the information that these mutations are actually harmful in their male counterparts.
If we liken natural selection to a sieve that catches harmful mutations and lets all other genetic variants through to the next generation, then the mitochondrial genome is prone to a sex-specific hole in this sieve – it lets male-specific mutations through and allows them to accumulate over generations.
If true, this theory means that males harbour a load of mutations within their mitochondria that females manage to avoid.
This concept was previously termed Mother’s curse by Neil Gemmell and colleagues from the University of Otago in New Zealand.
These male-harming mtDNA mutations are most likely to affect tissues and traits that are most different across the sexes, such as gonads – testes in males as opposed to ovaries in females – and sperm and ova (gametes).
Since mitochondrial DNA is passed down through women, we proposed that it will have evolved, through natural selection, to work best for female traits – ovaries and ova.
Adaptation of the mitochondria for ovary function will not necessary equip males with the ideal set of mitochondrial genes required for uncompromised testes function.
Together with my colleagues, Paolo Innocenti and Ted Morrow from Sweden’s Uppsala University, I set about examining this idea.
We started by acquiring lines of fruit flies (Drosophila melanogaster) created by Dr David Clancy at Lancaster University in the United Kingdom.
These fruit flies differed only in their mitochondria; each strain of flies harboured a unique and naturally occurring mitochondrial genome sourced from one of five wild populations from around the globe.
So, the flies across each strain were essentially genetic clones in everything but their mitochondrial DNA.
We then looked for changes in the way that more than 12 000 genes, within the nuclear genome, reacted when they were placed alongside the five different mitochondria.
What we found was exceptional – we were dumbstruck by the patterns that emerged and the magnitude of their effects.
First, differences in the mitochondrial DNA sequences, across the fly strains, exerted far-reaching effects on gene expression patterns within the much larger nuclear genome.
These effects were large, and massively-biased towards males (affecting one in ten nuclear genes in males but close to none in females – an amazingly strong pattern), and linked to male, but not female, reproductive success.
Second, a large proportion of the genes that were affected by the mitochondria were linked to male reproductive tissues (expression in the testes and accessory gland).
Together, these results provide a remarkable and powerful validation of the idea that the mitochondria are hotspots for mutations that affect male fertility.
What now for male infertility?
The evolutionary process that we explored should affect all species in which the offspring inherit their mitochondrial DNA exclusively from their mother, including humans.
One of the primary predictions of the evolutionary process that we have uncovered is that all mitochondria will accumulate a load of male-harming mutations over the course of generations.
So there might be no escaping Mother’s curse, and no such thing as a mitochondrion that is benign in its effect on males.
How might males reverse this curse, and why are all males, and ultimately all species with maternal inheritance of mitochondrial DNA, not extinct as a result of the process?
What we suspect is that, rather than sitting idly by, males launch their own evolutionary counter-responses, via adaptations in nuclear genes that restore lost fertility caused by these male-harming mitochondrial mutations.
If this is so, then identifying these nuclear counter-adaptations might ultimately provide medical biologists with valuable insights into clinical solutions for mitochondrial-induced infertility in humans.
Read more about male infertility