Many people have skin problems. Though luckily I’ve never had an issue with acne, most people who know me personally are aware that I suffered from extreme eczema as a child. Most of the major issues occurred when I was under five years of age, and in my first few years, so I have only minimal first hand recollection. The problem runs in my family, though I was the most extreme sufferer. Eczema also correlates with asthma, something I also suffer from.
Naturally I was curious about this new paper in Genome Biology, Atopic Dermatitis Susceptibility Variants In Filaggrin Hitchhike Hornerin Selective Sweep:
Human skin has evolved rapidly, leaving evolutionary signatures in the genome. The filaggrin (FLG) gene is widely studied for its skin-barrier function in humans. The extensive genetic variation in this gene, especially common loss-of-function (LoF) mutations, has been established as primary risk factors for atopic dermatitis. To investigate the evolution of this gene, we analyzed 2,504 human genomes and genotyped the copy number variation of filaggrin repeats within FLG in 126 individuals from diverse ancestral backgrounds. We were unable to replicate a recent study claiming that LoF of FLG is adaptive in northern latitudes with lower ultraviolet light exposure. Instead, we present multiple lines of evidence suggesting that FLG genetic variation, including LoF variants, have little or no effect on fitness in modern humans. Haplotype-level scrutinization of the locus revealed signatures of a recent selective sweep in Asia, which increased the allele frequency of a haplotype group (Huxian haplogroup) in Asian populations. Functionally, we found that the Huxian haplogroup carries dozens of functional variants in FLG and hornerin (HRNR) genes, including those that are associated with atopic dermatitis susceptibility, HRNR expression levels and microbiome diversity on the skin. Our results suggest that the target of the adaptive sweep is HRNR gene function, and the functional FLG variants that involve susceptibility to atopic dermatitis, seem to hitchhike the selective sweep on HRNR. Our study presents a novel case of a locus that harbors clinically relevant common genetic variation with complex evolutionary trajectories.
This shows the importance of whole genomes, as the earlier result correlation variation to climate seems to be due to ascertainment bias in terms of SNP discovery. Additionally, it’s intriguing that the haplotype which eczema-like diseases are associated with is very ancient. It’s found in Africans, and ancient genomes. So it’s been segregating in human populations for a while. That indicates some sort of balancing selection going on, so that it’s never purified.
What they found is that in Chinese samples there has been a recent positive sweep. I don’t really buy their conclusion that the haplotype wasn’t found in European hunter-gatherers, they don’t have a large enough sample. But it does seem to be a case where there is balancing selection maintaining standing genetic variation, which purified may be selected for or purified in some populations.
This may be a more common dynamic than we might realize. Many complex diseases may exhibit risk profiles due to being dragged up in frequency because of associations with a nearby region, or, a genetic-correlation where the positive benefit is greater than the negative.