Persistence of Detrimental Mutations in Population: A Paradox

According to Charles Darwin, theory of ‘Natural Selection’ is the basic mechanism of evolution. The theory refers to the selective removal of the variations produced by deleterious mutations to select the fit and get rid of the unfit, while ignoring neutral changes.

However, sometimes completely opposite picture is observed in population. 15% of adults suffer from fertility problems, many of these are due to genetic factors. This is something of a paradox: Genes responsible for reduced fertility and or infertility should disappear from the population. A study at the Weizmann Institute of Science recently appeared in Nature Communications may now have solved this riddle.

Previously, various theories explained the survival of harmful mutations. They used to say that, today a obesity causing gene, may have once gained an evolutionary advantage, or disease-causing gene persisted because it is passed on in a small, relatively isolated population.

Dr. Moran Gershoni, and Prof. Shmuel Pietrokovski of the Molecular Genetics Department, developed a new theory to explain this. They stated that, ‘Genes that affect only half the population will have double the mutation rate’ based on the fact that though both males and females carry nearly identical sets of genes, yet many of them are activated differently in each sex. Thus natural selection works differently on the same genes in males and females.

For example, a mutation that impairs breast milk will undergo negative selection only in women. On the other hand, a gene variant that benefits women but is damaging to men could spread in a population, as it undergoes positive selection in half population. Gershoni and Pietrokovski created a mathematical model to explain these facts. Their model demonstrated that these mutations should occur twice as often as those that affect males and females equally.

To test this model, the researchers identified 95 testis specific genes, by computational analysis in public databases. Most of these genes are vital for reproduction and damage to them leads, in many cases, to male sterility. They then looked at these 95 genes in people whose genomes are available through the 1000 Genomes Project, to get a broad cross-section of human populations. Their analysis revealed that genes that are active only in the testes have double the harmful mutation rate compared to those that are active in both sexes — confirming the mathematical model.

Pietrokovski and his team are now conducting follow-up experiments to see whether the mutations they identified play a role in these problems and whether the “sex-difference” approach can explain their survival.

This new understanding of the persistence of genetic mutations could yield insights into other diseases with genetic components, especially those that affect the sexes asymmetrically, including schizophrenia and Parkinson’s, which are more likely to affect men, and depression and autoimmune diseases, which affect more women.



Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men. Moran Gershoni, Shmuel Pietrokovski.  Nature Communications, 2014; 5 DOI: 10.1038/ncomms5438

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Arunima Maiti

Arunima Maiti

Biomedical scientist with special interest in reproductive biology.

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