Why dangerous genes stick around: The heterozygote advantage

You’d think that by now natural selection would have gotten rid of trouble-making genes, right? Unless, of course, the trouble-makers aren’t all that bad after all.

August 27, 2013 04:51 pm | Updated 04:52 pm IST

How autosomal recessive disorders like sickle cell anaemia and cystic fibrosis are inherited.

How autosomal recessive disorders like sickle cell anaemia and cystic fibrosis are inherited.

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For female sheep, size matters. It has long been known that rams with big horns father twice as many lambs as those with small or no horns. Two years back, a team of scientists identified the gene in sheep that determines horn size. This gene was called RXFP2.

RXFP2 has two variants or alleles – Ho+ and HoP. Ho+ is responsible for large horns while HoP for short ones. Now sheep, like almost all mammals, are diploid organisms. This means they contain two copies of each gene – one inherited from each parent.

So whether or not a ram grows big horns will depend on if it inherits the Ho+ or the HoP allele of the RXFP2 gene. If it inherits at least one Ho+ allele, it will grow big horns; if both copies are HoP then it will have short horns.

A ‘HoP’, skip, and a jump to a long life

Natural selection holds that traits which have a reproductive advantage – as clearly does the Ho+ allele – are more likely to be passed on to the next generation. By this logic, scientists wondered why the short-horned allele HoP has not been wiped out in the course of evolution. Since it was established that big-horned rams produce more lambs, shouldn’t the Ho+ allele have gradually come to dominate the sheep population?

This mystery seems to have now been solved thanks to a >new study by the same group of researchers who discovered the RXFP2 gene two years ago. This new study attempted to see the effect RXFP2 had on one more parameter – lifespan.

Indeed, they were intrigued to discover that big-horned rams, though more fertile, had shorter lifespans than rams with short or no horns. The allele for large horns Ho+ seemed to be somehow shortening the lifespans of the rams. Because of this homozygous large-horned rams (with two copies of Ho+) were shortest lived, and homozygous short-horned rams (with two copies of HoP) lived the longest.

This meant that heterozygous rams with the Ho+/HoP combination had the best deal – they were big-horned, fertile and long lived. This offered an elegant explanation about why the HoP allele has not been obliterated over time: it wasn’t all bad after all!

This phenomenon is called the ‘heterozygote advantage’. It occurs when an allele which is undesirable in its homozygous form, gives the organism an advantage in its heterozygous form.

Heterozygote advantages are particularly fascinating because they can explain why seemingly harmful mutations like those causing fatal diseases still exist in populations today. A classic example of heterozygote advantage in human beings is the sickle cell anaemia case.

How one disease saves you from another

Sickle cell anaemia was the first inherited disorder to be attributed to a specific genetic mutation – a single letter (base) substitution in the DNA of a gene responsible for producing a part of haemoglobin. This one molecule difference results in the production of sickle-shaped red blood cells which are not able to transport oxygen well. As a result, sickle cell anaemia can cause serious complications and very often death.

However, like sheep humans too are diploid organisms. Therefore we all have two copies of the haemoglobin gene, one from each parent. If only one of our two copies are faulty, then we carry the sickle cell trait, but do not show symptoms of the disease.

But if we are unlucky enough to inherit two copies of the faulty gene (HbS), we inherit the disease in all its viciousness. The life expectancy of those with sickle cell anaemia is greatly reduced (though medical advances have greatly helped). If people with HbS/HbS kept dying young without having the opportunity to pass on the HbS allele to the younger generation, eventually populations would have run out of the HbS allele, right?

However, epidemiologists found out that in some populations – especially in places where malaria was predominant, like Africa – the HbS gene is very common. >On probing , scientists were amazed to find out that the faulty HbS gene was giving people resistance to malaria, a disease with very high mortality in these areas.

In this way, a person inheriting HbS/HbS (homozygote) would be resistant to malaria but would die early from sickle cell anaemia. A person inheriting normal Hb/Hb (homozygote) is born with healthy haemoglobin, but is at high risk of malaria which could very likely kill them. The most fit category of people in this population end up being the ones with HbS/Hb combination (heterozygote) because though they are sickle cell carriers, they do not exhibit symptoms of the disease, at the same time the presence of HbS gives them resistance to malaria.

The case of cystic fibrosis

Another possible example of heterozygote advantage in humans is the link between cystic fibrosis and cholera. Cystic fibrosis, like sickle cell anaemia, occurs when a person has inherited two copies of a faulty gene. Until very recently, cystic fibrosis sufferers usually died very young. Most are sterile, so even if they did live long enough, the chances that they can reproduce and pass on the faulty gene to offspring are very low.

Again the question is: why hasn’t the frequency of the faulty gene dwindled over the years as you would expect it to? >Studies have indicated that people who are carriers or heterozygous for the CF gene (having one normal, and one faulty copy) do not suffer from CF, but show some resistance to cholera. This heterozygote advantage would explain why the CF gene has not been eliminated from the gene pool.

The CF-cholera theory has been thrown to question by some conflicting studies, but whether or not it is true, something is keeping these genes we perceive to be dangerous in our population. There may yet be hundreds of heterozygote advantages waiting to be discovered – just one more piece fitted in the jigsaw puzzle of evolution.

( Nandita Jayaraj writes about her encounters with the strange and interesting and science. You can send her feedback at nandita.j@thehindu.co.in. You can also tweet her >@nandita_j )

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