HEALTH × GENETICS

Sickle Cell, Malaria's Mark on Our DNA

~7,300 years ago (debated)

Neolithic · Neolithic · Holocene · Northgrippian

Sickle cell disease follows from a single letter changed in HBB, one of the genes for haemoglobin, the protein that carries oxygen in red blood cells. Two copies of the altered gene bring the disease; one copy brings higher protection against severe malaria, so the variant is held in place by two opposing pressures at once. The geography supports that reading: a map of allele frequencies assembled worldwide, set against the pattern of malaria before control campaigns, matches closely across Africa, although the relationship cannot be resolved in the Americas or in Asia. The age of the variant is read from the stretch of chromosome it sits on. Twenty-seven markers inherited with it, in 156 carriers, put its origin at 259 generations, about 7,300 years ago, and make the five classical sickle haplotypes descend from one mutation rather than from five separate ones.

Why it matters

Malaria acts here as a force strong enough to keep a lethal allele in circulation, which is what makes the variant the standing illustration of balancing selection in humans. Modelling puts the advantage of carriers at 15.2 per cent and the equilibrium frequency at 12 per cent, reached in 87 generations: a disease that kills children can still spread, provided the carriers it protects leave more descendants than it costs. The same arithmetic accounts for a present-day burden, since an inherited disease otherwise hard to explain turns out to be the price of a defence against an infection.

Dating & uncertaintyDisputed

Two published ages disagree by a factor of three, and both claim a single origin. A genealogy reconstructed from whole genomes puts the mutation at 259 generations, about 7,300 years. An approximate Bayesian analysis of 479 individuals from thirteen African populations, correcting for population subdivision, past demography and balancing selection, puts it near 22,000 years, and adds that rainforest hunter-gatherers received the variant from farming populations only within the last 6,000 years. The choice decides the cause: at 7,300 years the mutation follows the spread of farming, at 22,000 years it comes first, and the pressure of malaria is then older than the villages usually credited with creating it.

Sources

1. Shriner et al. (2018), The American Journal of Human Genetics · Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle Allele during the Holocene Wet Phasedoi:10.1016/j.ajhg.2018.02.003
2. Laval et al. (2019), The American Journal of Human Genetics · Recent Adaptive Acquisition by African Rainforest Hunter-Gatherers of the Late Pleistocene Sickle-Cell Mutation Suggests Past Differences in Malaria Exposuredoi:10.1016/j.ajhg.2019.02.007
3. Piel et al. (2010), Nature Communications · Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesisdoi:10.1038/ncomms1104
4. Allison (1954), BMJ · Protection Afforded by Sickle-cell Trait Against Subtertian Malarial Infectiondoi:10.1136/bmj.1.4857.290

Our species’ history as one day

23:26:3733 min 22 s before midnight

if the 315,000 years of Homo sapiens were compressed into a single day