Origins of HCM...very interesting information

[Pam Alexson]

http://ukpmc.ac.uk/articlerender.cgi?artid=513720

[gfox42]

This paper tries to address a question that's probably not foremost in the minds of most HCM patients, but since it's not too far from what I do professionally, I've given it some thought.

Namely: since HCM-associated genes tend to cause such severe problems, why is HCM so common? Put differently: HCM makes it less likely that people will survive and pass on their genes -- so why are so many of us able to talk to each other on this board?

A big hint is that there are a LOT of different HCM-associated genes: lots of different mutations lead to HCM.

What these authors did was to examine several different mutations and ask what they could infer about the population history of each one. They present a reasonable case that, in general, the different mutations tend to have occurred independently of one another. What that means is that, at least for their study population, the mutations they observed had different origins. The other thing they observed is what's called a "founder effect." These are particularly well studied in white South Africans -- much of their sample. A founder effect is just what it sounds like: if I go off as part of a small group and start a new population, then for many generations my genes will have an overly large representation in the population. They argue that this is one reason why at least some HCM-associated genes in their study population are still present.

In the short term, this doesn't have any clinical meaning. We'll still need to be treated using the same techniques. But in the very long term, studies like this can prove to be quite important. As more genes are found that predispose people to HCM, understanding how they spread (or don't spread) in populations can become an important issue.

Gordon

[EmilysDad]

Does this point out a large or small impact on reproductive fitness? The fact that it does frequently spontaneously arise and that it is only penetrated into 1:500 indicates that it does have some impact on fitness, or it would be even more widespread. What is the expected frequency of a truly neutral allele that might arise spontaneously at similar rates? Can this lead us to an estimate of the loss of fitness?

Genetics has come a long way since I took it in college and grad school. Back then we understood Mendelian genetics and knew about incomplete dominance and were just starting to learn about regulation. Now we know that regulatory controls are also genetic, and enormously complicated. For example, Emily has a defect in a gene that I share. This gene, the Opa1 gene, can cause optic nerve neuropathy at several known loci, none of which Emily or I have. Our defect is at a locus that is not associated with pathology, and my eyesight is predictably normal. However, because she has another defect in her mitochondrial DNA that alters her energy metabolism, it has led to the expression of optic nerve neuropathy from a defect that is benign in me. Did she inherit bad eyesight from me? Yes and no. In the absence of the mitochondrial defect, which arose in only some cell lineages in her, her eyesight would be normal. This stuff makes my head explode!

[gfox42]

As I understand it, the argument they're making in this paper is that HCM variants mostly have a large negative impact on reproductive fitness -- there are a lot of HCM variants (because mutations occur in many sites in many different genes in the same pathways) but they mostly stay fairly uncommon because of this negative effect on fitness.

If you're still reading this and not trained in biology (as Bob and I are), "fitness" here means, roughly, something related to the average number of offspring you leave behind. People with severely harmful genetic variants have reduced fitness. This has to be understood as an average -- sure, some people with HCM may have a LOT of surviving kids, but averaged over a lot of people, these mutations tend to reduce our fitness.

I think the other point Bob makes is a really important one, and it relates to the most common questions raised about the genetics of HCM on this board. Roughly, the question is "how can you say this is genetic when I have HCM but my parents didn't?" The answer is, as Bob says, really complicated, but the main points are that our phenotypes are determined not only by a particular variant we have, but also by the ways that many of our other genes interact with that variant, and by our environment. Like most people, I have a large number of ways in which I resemble my parents, but there are many things about me that are really quite different from them.

Gordon