SLC24A5: A Zebrafish Clue to Skin Colour
A pale zebrafish mutant led to rs1426654, the one common variant that explains more of the skin-colour difference between Europeans and West Africans than any other. Its discovery, its surprisingly recent spread, and what it does and does not say about you.
Zebrafish normally carry dark stripes. A laboratory strain called golden has pale, thin ones, and for years it was a curiosity kept for its looks. In 2005 Keith Cheng’s group at Penn State found the gene behind it and reported something unexpected: the fish’s pigment cells were not fewer, but their melanosomes - the packets that hold melanin - were smaller, sparser and less dense. The broken gene was slc24a5. Humans have the same gene, and in the human version there is one common coding change, rs1426654, that turned out to be the single most important known variant in the pigmentation of European skin.
What the study found
Lamason and colleagues showed that the human SLC24A5 protein could rescue the golden fish, then looked at the human variant. At rs1426654 the ancestral allele, G, encodes alanine at position 111 of the protein; the derived allele, A, encodes threonine. In their European-American samples the derived A allele made up 98.7 to 100 percent of chromosomes. In African, East Asian and Indigenous American samples the ancestral G allele made up 93 to 100 percent. In people of mixed West African and European ancestry, this one letter accounted for an estimated 25 to 38 percent of the difference in skin melanin index between the two parental populations.
No other single common variant in human pigmentation comes close. Skin colour is polygenic, but it is polygenic with one very large term in the sum.
Reading it in your file
rs1426654 is on every major consumer chip and files report it on the forward strand: G is ancestral, A is derived. Genespiral’s appearance analysis reads GG as darker, AG as intermediate and AA as lighter skin tone. For most people of European ancestry the answer is AA and tells them nothing they did not know from a mirror. The marker is more interesting for people with South Asian, Middle Eastern, North or East African, or mixed ancestry, where AG is common and the letter is doing visible work.
Two related markers in the same analysis round out the picture. rs16891982 in SLC45A2 is the second large-effect European lightening variant, and rs12913832 in HERC2 controls most of the blue-versus-brown split in eye colour.
How recent this is
The derived allele is old but its dominance in Europe is not. Haplotype analysis by Basu Mallick and colleagues dated the origin of the A allele to roughly 22,000 to 28,000 years ago and showed that South Asians and Europeans carry the same copy, inherited from a shared ancestor rather than arising twice. Beleza and colleagues estimated that the sweeps that carried SLC24A5 and SLC45A2 toward fixation in Europe began between about 11,000 and 19,000 years ago. The oldest genome yet found carrying the allele is a roughly 13,000-year-old individual from Satsurblia Cave in Georgia.
Ancient DNA then delivered the surprise. The Mesolithic hunter-gatherers of western Europe sequenced so far were GG. La Braña 1, a 7,000-year-old man from northern Spain, had the ancestral alleles at both SLC24A5 and SLC45A2 together with the derived HERC2 allele, giving the now-famous combination of dark skin and blue eyes. Cheddar Man, who lived in Britain around 10,000 years ago, was predicted in 2018 to have had dark to very dark skin, dark hair and blue-green eyes, though the authors noted that skin predictions from ancient DNA carry real uncertainty. The 230-genome survey by Mathieson and colleagues showed that the derived SLC24A5 allele was already near fixation in the first farmers of Anatolia and arrived in Europe with them around 8,000 years ago, after which it was among the strongest selection signals anywhere in the genome. Light skin as it exists in Europe today is, across much of the continent, younger than agriculture.
Why it was favoured so strongly is still argued. The usual explanation is vitamin D: less ultraviolet at high latitude, and a farming diet poorer in vitamin D than a hunter-gatherer one, would have made lighter skin advantageous. The timing fits. The intensity of the selection is harder to account for with vitamin D alone, and the question remains open.
Two roads to the same place
East Asians have light skin and mostly carry the ancestral G at rs1426654. Their lightening happened through different variants, including a change in OCA2 (rs1800414) that is common in East Asia and essentially absent elsewhere. The same outcome evolved independently on the two ends of Eurasia within the last 30,000 years, which is a tidy demonstration that a trait and a gene are not the same thing - a distinction our article on genotype and phenotype takes further.
The derived A allele also appears at meaningful frequency in parts of East Africa, where it was carried back from Eurasia by later migrations. The 2017 study by Crawford and colleagues of African populations found further pigmentation variants, some lightening and some darkening, several of which are far older than modern humans’ departure from Africa. Human skin colour has been varying, in both directions, for a very long time.
Keeping it in proportion
One letter explaining a quarter to a third of a difference between populations still leaves most of the variation among individuals unexplained, and within any population rs1426654 explains almost none, because nearly everyone shares the same genotype. Genespiral shows the marker as one line among many in the appearance analysis for exactly that reason. It is a remarkable piece of history to find in your own file. It is not a measure of anything about you that a photograph would not show better.
This article is educational only.
References
- Lamason RL, et al. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science. 2005. PubMed 16357253
- Basu Mallick C, et al. The light skin allele of SLC24A5 in South Asians and Europeans shares identity by descent. PLoS Genetics. 2013. PubMed 24244186
- Beleza S, et al. The timing of pigmentation lightening in Europeans. Molecular Biology and Evolution. 2013. PubMed 22923467
- Olalde I, et al. Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European. Nature. 2014. PubMed 24463515
- Mathieson I, et al. Genome-wide patterns of selection in 230 ancient Eurasians. Nature. 2015. PubMed 26595274
- Brace S, et al. Ancient genomes indicate population replacement in Early Neolithic Britain. Nature Ecology and Evolution. 2019. PubMed 30988490
- Edwards M, et al. Association of the OCA2 polymorphism His615Arg with melanin content in East Asian populations: further evidence of convergent evolution of skin pigmentation. PLoS Genetics. 2010. PubMed 20221248
- Crawford NG, et al. Loci associated with skin pigmentation identified in African populations. Science. 2017. PubMed 29025994
- dbSNP entry for rs1426654, NCBI.