The first item on my long list of predictions for 2009 was that this will be the year of rare variants for common disease - the year that we really start tracking down the low-frequency genetic variants (between 0.1 and 5% in frequency) that likely contribute substantially to the risk of common diseases like arthritis and diabetes. It's far too early for me to claim vindication for this prediction, but a paper published online today in Science is at least a step in the right direction.
The paper reports the discovery of four rare variants (all with a frequency of less than 3%) within the IFIH1 gene
that affect the risk of the childhood-onset auto-immune disease type 1
diabetes. This gene has previously been shown to contain relatively
common genetic variants that increase the risk of this disease, but
here's the twist: all four of the rare variants actually decrease disease risk.
Remarkably, all four variants are found in locations in the gene that would be predicted to result in severe functional disruption: one introduces a premature stop signal, two are found in conserved RNA splicing sites, and the fourth alters an evolutionarily conserved site of the gene's encoded protein. While rare, the variants have a larger individual effect on disease risk than the common variants previously identified; one of them almost halves the risk of contracting the disease.
The IFIH1 gene is known to play a role in the response to infection by viruses known as enteroviruses; intriguingly, infection by this same class of viruses is more common in newly diagnosed type 1 diabetes patients than in the general population, suggesting that the disease may be partly due to an over-aggressive immune response to these foreign invaders. The researchers argue that the four rare protective variants may thus reduce type 1 diabetes risk by inhibiting the immune response to enterovirus infection.
That provides the basis for an evolutionary explanation for the low frequency of these variants, despite their protective effects:
In the modern world we are fortunate enough to suddenly find ourselves virtually bereft of nasty infectious invaders; sadly for the sufferers of auto-immune diseases, our genes are yet to figure this out.
(See also: p-ter at Gene Expression.)
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Remarkably, all four variants are found in locations in the gene that would be predicted to result in severe functional disruption: one introduces a premature stop signal, two are found in conserved RNA splicing sites, and the fourth alters an evolutionarily conserved site of the gene's encoded protein. While rare, the variants have a larger individual effect on disease risk than the common variants previously identified; one of them almost halves the risk of contracting the disease.
The IFIH1 gene is known to play a role in the response to infection by viruses known as enteroviruses; intriguingly, infection by this same class of viruses is more common in newly diagnosed type 1 diabetes patients than in the general population, suggesting that the disease may be partly due to an over-aggressive immune response to these foreign invaders. The researchers argue that the four rare protective variants may thus reduce type 1 diabetes risk by inhibiting the immune response to enterovirus infection.
That provides the basis for an evolutionary explanation for the low frequency of these variants, despite their protective effects:
We have found that rare alleles of all associated IFIH1 polymorphisms consistently protect from T1D [type 1 diabetes], while IFIH1 alleles carried by the majority of the population predispose to the disease. This observation suggests that variants that disrupt IFIH1 function in the host antiviral response have been negatively selected, rather than positively selected because they confer protection from T1D.In other words, during the recent evolutionary history of humans the need for protection against nasty little creatures like enteroviruses outweighed the pressure to keep the immune system in check to reduce auto-immunity. This meant that these rare diabetes-protective variants were actually at an evolutionary disadvantage, and have thus been held at low frequencies in the population by natural selection.
In the modern world we are fortunate enough to suddenly find ourselves virtually bereft of nasty infectious invaders; sadly for the sufferers of auto-immune diseases, our genes are yet to figure this out.
(See also: p-ter at Gene Expression.)
Subscribe to Genetic Future.
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