Pie charts show the proportion of chromosomes within different populations worldwide that carry a non-working copy of the FLG gene, a primary risk factor for eczema. Even in East Asia, where the rates are high, the scientists found no evidence that preserving this genetic mutation has an evolutionary benefit to humans. Image credit: Muthukrishnan Eaaswarkhanth et al.
Some human genetic diseases persist for generation after generation because the genes that cause them can benefit health.
Sickle-cell anemia, an inherited form of anemia, is one example. This disorder compels red blood cells to take on a crescent moon shape, leading to anemia. But carrying a copy of the sickle cell gene can guard against malaria.
A new study probes the evolutionary history of eczema, a condition that causes the skin to become itchy, red, dry and cracked, and finds no evidence that a genetic predisposition for this disorder has helped humans.
The study, led by University at Buffalo researcher Omer Gokcumen, examines a genetic variation in the filaggrin (FLG) gene associated with atopic dermatitis, the most common form of eczema.
“The genetic variant studied appears to be a random vestige of evolution. We present a complex evolutionary history of this disease variant, and it seems to be just bad luck that it has endured for so long,” Dr. Gokcumen said.
“Unlike other disease variants, such as those linked to sickle cell anemia or psoriasis, the one we studied is just not that important from the standpoint of evolution. It doesn’t appear to affect what biologists call ‘fitness,’ which is another word for reproductive success.”
In some people, inherited genetic mutations cause the FLG gene to stop working, impairing healthy skin function and creating an increased risk for developing eczema.
To investigate the evolution of this gene, Dr. Gokcumen and co-authors analyzed 2,504 human genomes from 26 global populations.
They found that loss-of-function (LoF) mutations are significantly more common in FLG than in other human genes. However, despite this prevalence, the variants don’t appear to serve an adaptive purpose.
“Based on our results, the most plausible explanation is that despite the negative effects of atopic dermatitis on human well-being, the fitness advantage of not being susceptible to this disease may not be very high,” the researchers explained.
“In fact, extant chimpanzees carry LoF mutations of this gene as well. Therefore, the most likely conclusion is that FLG has been accumulating LoF variants since human chimpanzee ancestor, and the current distribution of these variants is primarily shaped by genetic drift.”
The team’s conclusions held true even when they took a closer look at the genomes of individuals from East Asia, who are more likely to have broken FLG genes than people from other parts of the world.
A genomic analysis showed that this trend may have been an artifact of evolutionary hitchhiking.
In East Asia, many people share a genetic profile that includes a LoF mutation of FLG, paired with a notable mutation in a nearby gene that carries instructions for making hornerin (HRNR), another human protein.
While the FLG mutation did not appear to have importance from the standpoint of evolution and adaptation, the HRNR mutation did.
This leads the researchers to believe that the FLG mutation may have proliferated in East Asia for the sake of preserving the HRNR mutation.
“Large sections of the genome are often lost or inherited together during evolution, so genes like those for HRNR and FLG that are close to each other often share an evolutionary history,” Dr. Gokcumen said.
“While this work did not draw concrete conclusions about why the HRNR mutation was so important, changes in the HRNR gene can affect healthy skin function, influencing microbiome diversity on the skin.”
The team’s findings were published online September 27, 2016 in the journal Genome Biology and Evolution.
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Muthukrishnan Eaaswarkhanth et al. Atopic Dermatitis Susceptibility Variants in Filaggrin Hitchhike Hornerin Selective Sweep. Genome Biol Evol, published online September 27, 2016; doi: 10.1093/gbe/evw242
This article is based on a press-release from the State University of New York at Buffalo.
