A study carried out in yeast suggests that eukaryotes, including humans, have the ability to suppress potentially harmful genetic variants by initiating ‘rescue’ mutations that effectively correct the initial genetic fault.
While this work is still at an early stage and needs to be confirmed in humans, the researchers think it could shed light on the origins of genetic diseases and perhaps help researchers design better treatments for these conditions.
This international study, led by the University of Lausanne in Switzerland and the Wellcome Sanger Institute in the U.K., used genes and mutations linked to temperature sensitivity in yeast to explore whether unfavorable mutations could be corrected naturally.
As reported in the journal Molecular Systems Biology, 1,106 temperature-sensitive alleles from 580 essential genes in 10 wild yeast strains were analyzed by the research team to see if mutations that decreased the yeast’s chance of survival at hot temperatures would be corrected by natural genetic variation.
During experiments the researchers found that loss of function mutations in around a quarter of the essential genes could be overcome by natural genetic variation in at least one wild yeast strain.
“The proportion of harmful mutations in essential genes that could be suppressed was unexpected,” said Jolanda van Leeuwen, Ph.D., a senior author of the paper and a professor at the University of Lausanne.
“Because we only sampled a small fraction of wild yeast strains the percentage of mutations that can be suppressed by natural variants is likely to be much higher. The frequency of suppression suggests it could make an important contribution in other contexts as well – including, potentially, for human disease.”
Notably, a single strong rescue allele could overcome temperature sensitivity in the yeast in almost all of these cases. “In biology, explanations tend to be complex, so it’s unusual to find a single ‘smoking gun’,” said Leopold Parts, Ph.D., a senior author of the paper from the Wellcome Sanger Institute.
“We might have expected a number of genes to combine to overcome a serious genetic defect like the temperature-sensitive allele, so for this to be the result of a single mutation is very surprising.”
It is a known phenomenon in genetic disease that some patients have more severe disease than others, but reasons behind this are not always clear. While humans are undoubtedly more complex organisms with more complex genetics than yeast, it may be that similar rescue mutations to those seen in the yeast grown for this study are present in humans. For example, patients with less severe disease, or those with potentially pathogenic mutations who don’t show symptoms.
“Given the high frequency at which we observed suppression via complementing natural variants, we expect it to have an important contribution to other phenotypes, species and contexts, including human disease,” conclude the authors.
“The large overlap between natural suppressor variants and those identified in a laboratory setting suggests that suppressor screening in human cell lines will help understand variable penetrance of human disease mutations as well.”
