Are women to blame for gene-based male sterility?

Women may be harboring genetic mutations that prevent men from fathering children, Israeli scientists say

Men and women may be each other's worst genetic enemies. (photo credit: Couple image)
Men and women may be each other's worst genetic enemies. (photo credit: Couple image)

It sounds like just another case of “blame the wife, not the husband,” but researchers believe they’ve figured out why some men are unable to father children – and it traces directly to women and their defective genes.

The cross-sectional study – published in the journal Nature Communications in July – provides the first proof for a sex-based explanation of the prevalence of male sterility.

Mutations that may cause the condition are twice as common as other mutations that are harmful to both sexes, the study determined after an examination of genes of thousands of people. The finding suggests that the mutations are avoiding natural selection in women, on whom they have no effect – making it more likely that they will show up in men and dash their hopes of fatherhood.

“Because some genes are expressed differently in men than in women, natural selection works differently on each sex,” said Dr. Moran Gershoni, a postdoctoral fellow in Prof. Shmuel Pietrokovski’s molecular genetics research group at Israel’s Weizmann Institute of Science. “We showed for the first time how these differences allow harmful mutations to propagate in the population.”

If all things were equal, sterility should have been eliminated long ago by natural selection, the evolutionary force that ensures survival of the fittest. After all, how can you pass along mutated genes that prevent you from passing along genes?

Yet about 2 percent of American men between the ages of 15 and 44 cannot father children for reasons that are not correctable by surgery, according to the Centers for Disease Control.

There are several theories about how harmful mutations survive. Mutations that contribute to obesity may have helped our ancestors through lean times. Mutations that cause sickle cell anemia when inherited from both parents give immunity from malaria when inherited from just one parent. And mutations that cause Tay-Sachs disease occur at high frequencies and were given a boost by the original small size and insularity Ashkenazi Jewish community.

‘This ‘sex-difference’ hypothesis is 20 years old, but until recently there wasn’t enough genetic data available to test it.’

None of these theories helps explain the prevalence of male sterility and infertility, its less severe relative. The evolutionary effect of not being able to have children is too devastating to be outweighed by other factors, the researchers say.

Failing to find an answer with men, the researchers turned to women for an explanation. Women have almost all the same genetic material as men, but some of it is expressed differently.

To see if women are inadvertently perpetuating harmful mutations in male fertility genes, the researchers first created a mathematical model for how much more common a mutation should be if it affects just one sex than if it harms both men and women. The model showed that such a mutation should occur twice as often as its selectively harmful counterparts.

Using a computer program they developed, the researchers then screened publicly available data on human genes to find 95 that are active exclusively in men, though also carried in women. Expressed in the testes, many of the genes are vital to male procreation, and damage to them in many cases leads to sterility.

Finally, the researchers checked the prevalence of harmful mutations in the genes expressed only in men, using data from the 1,000 Genomes Project, an effort to sequence the genes of thousands of people from around the world. They found that the genes have twice as many harmful mutations as do those that affect both sexes – just as predicted by their model. The results suggest the mutations would be much less common if they were harmful to women as well, they say.

“This ‘sex-difference’ hypothesis is 20 years old, but until recently there wasn’t enough genetic data available to test it,” said Gershoni.

The researchers are doing follow-up experiments to confirm that the mutations they found on the genes expressed only in men contribute to infertility and are propagated by women.

Before men get too indignant, the researchers caution that the effect probably works both ways: Men might genetically contribute to infertility in women by passing on damaged versions of genes that are crucial only to female reproduction.

In fact, they say, differences in gene activity between the sexes may underlie the sex discrepancies seen in many disorders. Diseases that affect one sex more than the other are particularly likely to have different genetic causes, they say. For example, schizophrenia and Parkinson’s disease are more common in men, while depression and autoimmune diseases are more common in women.

The researchers say that understanding these differences in gene expression and how they evolved could guide the development of more effective, sex-specific diagnoses and treatments.

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