Disease-linked genes bog down evolution

Evolution ultimately refines us into the best fit for our environments and the pressures we face living there. So, intuitively, any versions of genes the spell bad news ought to be weeded out over time, leaving behind healthy, unfettered genetic stock. But, an analysis of the rates of evolution of the human genome shows that deleterious - or disease-linked genes - genes don't just bog down their own evolution: they do the same to non-disease-linked genes that sit nearby on the chromosome. From the University of Arizona, and speaking with Chris Smith, David Enard...

David - The way we framed the study was to compare the evolution that happens at genes that have mutations, that in specific environments can cause disease, with the rest of the genome that is not known to be connected to any kind of disease.

Chris - So would a good example of a disease linked gene be, for example, the genes that are linked to breast cancer, the BRCA genes.

David - Yeah, it's actually a good example because BRCA1, well known in breast cancer, is notorious for the precise reason that it carries mutations that make it more likely for women to have the disease at some point in their life. And unfortunately this happens to be mutations that are found pretty commonly.

Chris - Is the question you're therefore asking, if we look at a gene like BRCA, where there are variants, which are linked to deleterious traits like breast cancer, where did those variants come from and how have they affected evolution of genes like BRCA, but also possibly the genes around them.

David - Yeah. And why would we still observe the frequencies of the disease variant that we observe?

Chris - How can you unpick the past in that way though? What's the approach that enables you to sort of see back in evolutionary time in the genome, to see how we arrive at the position we find ourselves in?

David - There are ways to analyze genomes that can tell us how much past adaptation occurred during human evolution. We can then ask if disease genes in particular had different levels of adaptation, compared to the rest of the genome that is not known to be associated in any way to disease.

Chris - In other words, do the disease genes hang around, because they're changing less quickly or holding up evolution of those particular variants, compared with other genes which are unencumbered.

David - This is what turned out from our analysis. What we found was that the presence of harmful mutations can really slow down potential future adaptation. We saw that, basically by seeing that there is a pretty severe deficit of signals of adaptation, of past adaptation, at genes known to be involved in disease.

Chris - So they slow down the evolution of disease linked genes, but they don't encumber other bits of the genome. That carries on evolving, at the normal pace.

David - Not quite as much. So you have to imagine the closer you are to those disease genes, the harder it's going to be for adaptation to happen rapidly. The further away you get on chromosomes from the disease genes, the easier it becomes for adaptation to happen more rapidly.

Chris - This is getting very interesting. So in other words, you've got the gene that is the disease linked gene. And if it has a particular form that causes a disease, it doesn't just slow down its own evolution. It also spills over and slows down the evolution of the bits of the chromosome that are nearby. Why might that be?

David - It happens because mutations that may be advantageous can happen in the same people on the same chromosomes as the disease variant. So you can imagine, if you have an advantageous variant in the future, that may by chance occur in someone with a chromosome that also carries those disease variants nearby on the same chromosome, what happens is that they cancel out the beneficial effect that new advantageous variants might have.

Chris - It's basically like giving concrete shoes to those other genes that are beneficial, and chucking them in a lake isn't it? They're gonna sink because they're dragged down by the deleterious variant that is nearby.

David - Exactly.

Chris - My question would be then, if you've got deleterious variants in the population, why doesn't evolution just take care of them and get rid of them? Surely their frequency will drop to a low level, if they're being so bad, quite quickly, and they'll just get ditched.

David - I mean, it would be great if that was the case. But what happens is that a lot of the disease variants, we know only cause disease if you carry two copies of the disease variants on both of your chromosomes, that come from both of your parents. So it's a matter of bad luck. If both of your parents happen to carry each one copy of the disease variant, and if you have only one copy, the disease doesn't manifest itself. It's only when you inherit two copies of those disease variants that they cause disease. But that means that a lot of those disease variants can stay for quite a long time during evolution in one copy in many people, and being silent in that one copy state.