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I ran a Schol Bio tutorial out at the uni yesterday & the last exercise we did involved going over a question from last year’s paper. This question looked at sickle-cell disease (SCD), which is seen in individuals who are homozygous for a recessive mutation - on chromosome 11 - that affects the haemoglobin molecule. The mutant molecule differs in just one amino acid from the normal one, but this is enough for it to have significant health effects. When red blood cells containing the mutant form of haemoglobin are placed in a low oxygen environment, then they collapse into a rigid, jagged, sickle shape that clogs capillaries. This in turn has a range of physical effects on organ systems throughout the body – this is an example of pleiotropy. Individuals affected by SCD usually die early, before they reach reproductive age. (People who are heterozygous have the less-severe sickle-cell trait.) Overall, sickle-cell is a Bad Thing for those who have it, so you’d expect that its frequency in a population would decline rather quickly. And yet – that’s not the case, & in parts of the world (notably equatorial Africa, India, Asia & around the Mediterranean the frequency of the Hbs allele can reach 70%. (In comparison, its frequency is around 1% in the NZ population.) So what’s going on?

Cue malaria. (The name literally means ‘bad air’ – in earlier times people believed that the fever & shaking typical of malarial ‘crises’ were due to bad air.) This is a disease that affects millions of people world-wide. It’s due to infection by Plasmodium, a unicellular organism that lives & reproduces within its hosts red blood cells and is spread by Anopheles mosquitoes. If you look at a map showing the distribution of malaria, and compare that with one showing the frequency of the sickle-cell allele in various populations, you’ll see a considerable degree of overlap: the highest frequencies of Hbs coincide with areas where malaria is endemic. It turns out that having a copy of the mutant allele gives a certain degree of protection against malaria, because Plasmodium can’t reproduce inside affected blood cells.

map of high frequency sickle-cell anemia areas of the Old World showing that it is most common in West Central Africa and India

map of endemic falciparum malarial regions of the Old World showing high frequencies around the Mediterranean Basin, in Central Africa, and South Asia

Both images from the excellent ‘natural selection’ page at Palomar.

Anyway, the actual question in last year’s paper was: Discuss the genetics, inheritance and frequency of the Hbs allele and evaluate whether modern biotechnological applications could, in the future, provide a cure for sickle cell disease.

Genetics: because normal & mutant haemoglobin differ by just a single amino acid, this tells us that we’re looking at a point mutation – more specifically, a substitution mutation. (It can’t be an insertion or a deletion mutation because that would have a fairly major impact on the expressed protein & we wouldn’t still get a form of haemoglobin.) This mutation isn’t sex-linked: we know this because the context material noted that the mutation is found on chromosome 11. In other words, it’s an autosomal mutation. (You’d be wrong to describe it as ‘somatic’, because this refers to cells & not chromosomes.) And the mutation must have occurred in an individual’s gametes, as otherwise it couldn’t be passed on to offspring.

What about patterns of inheritance? It’s obviously not a straight dominant/recessive relationship because people who are heterozygous have at least some sickling of their red blood cells. So the best model is co-dominance. And someone with the Hbs allele would most likely have had at least one parent heterozygous for this allele. Why? Because individuals with full-blown SCD (ie homozygous recessive) are very unlikely to survive to reproduce. (Some do, with fairly intensive treatment, but not all.) And similarly, because people who are homozygous dominant, & produce only normal red blood cells, are reasonably likely to catch & die from malaria if left untreated.

The frequency of the allele in different populations is thus explained by the presence of both Plasmodium & its mosquito vector. For example, frequency of Hbs in some African gene pools is around 20%. Where malaria is endemic, people who are heterozygotes for Hbs have a certain degree of protection against the parasite, because Plasmodium can’t get into their sickled red blood cells. This heterozygote advantage maintains the Hbs allele in those populations. However, in countries like NZ there is no selective advantage in carrying the mutant allele, & in fact that 1% frequency here is probably due (at least in part) to immigration. In addition, modern medical care can reduce the health impacts for carriers and can also allow individuals with full SCD to survive, and this will also help to maintain the sickle-cell allele in the population. (Sickle-cell disease & the heterozygous ‘sickle-cell trait’ do incur significant social & economic costs in a population. This is an issue in the US, for example, where while the overall frequency of the allele in the population is around 1%, it reaches 10% in African-Americans.)

The prospects of a cure… Well, we threw around a number of possibilites. But in the end the group decided that biotechnological applications don’t offer any prospect of a cure at present. Treatment, yes, but not cure. For example, while it’s perfectly possible to test adults, embryos or zygotes for the allele, and this gives choices about reproduction & so may reduce the number of affected individuals in the future, this is not a cure. And you could potentially  use bone marrow (stem cell) treatments for affected individuals, but this would not stop the allele being passed on to any offspring – you’d have to do the treatment all over again. Genetic engineering – fiddling in this case with the germ line – isn’t yet an option either as we can’t control where the ‘good’ Hb allele would be inserted in the genome, & it could well be in a place that interfered with the normal functioning of other genes, thus causing more problems than it cured.

And as more than one person pointed out yesterday, curing SCD without also getting rid of malaria doesn’t really solve anything for the great majority of those living in regions where malaria is endemic.

That really was a good tutorial – well done, everyone!