11 January 2006

Applications of Evolution 3 - tradeoffs in resistance.

Someone just emailed me a copy of an interesting press release. Some time back, a particular mutation known as CCR5delta32 was identified as conferring greatly increased resistance to HIV in individuals who had two copies of that particular gene (in geek terms, those are individuals homozygous for that particular allele). According to the press release, a group of researchers have discovered that this resistance to HIV comes with a price. The individuals who are homozygous for the CCR5delta32 allele do have greatly increased resistance to HIV, but they also have greatly decreased resistance to the West Nile Virus.

This is interesting (to me, anyway) for a number of different reasons.

First, it shows that whether or not a particular mutation is beneficial, neutral, or harmful doesn't just depend on what the mutation does. It also depends on the conditions that the organism lives in. If this mutation is found in someone who lives in an area where West Nile is absent but HIV is common, then this is a beneficial mutation. If the same exact set of genes are found in someone living in an area where West Nile is common and HIV rare or absent, then the mutation is harmful. The environment is almost always important in determining the net effect that a particular mutation is likely to have on the organism.

I should probably stop for a second to make clear what I mean when I use the word "environment." In this case, I'm not just talking about the climate, or pollution, or the effects that humans are having on the natural world. In evolutionary biology (and ecology and other contexts), the "environment" that a particular organism lives in includes everything outside of the organism that has an effect on it. This includes the climate, of course, but it also includes things like predators, competition with other members of the same species, the presence or absence of alternative food sources, and a host of other such things.

In our case, as a species, our environment includes the various disease-causing agents that we are exposed to. As is the case with other environmental factors, like average temperature and rainfall, this factor can vary widely from one geographical location to another. This is true at both large and small scales. On a large scale, for example, leptospirosis is relatively common in Hawaii, but it is pretty much absent in the Northeastern US. On a smaller scale, strains of bacteria that are resistant to multiple antibiotics are more common in hospitals than they are in most homes.

If you want to look into this further, it gets more complex and more interesting, because pathogens are organisms too (that's arguable with viruses, but for these purposes they act like organisms so we'll treat them as such). Anyway, pathogens are organisms, and whether or not a particular mutation in a pathogen is beneficial will depend on the pathogen's environment. For pathogens that impact humans, humans are an environmental factor. Let's say that a strain of HIV mutates in a way that lets it attack people who have the CCR5delta32 resistance. Is that mutation beneficial? Maybe, but maybe not. It's going to depend on whether or not this gain comes with a corresponding cost, and whether the cost is worth the gain. That's going to depend in part on how common people expressing CCR5delta32 resistance are in that area.

Situations like this are things to keep in mind when you hear creationists and ID proponents making arguments like, "almost all mutations are harmful." Life is complex, environments are complex, and the relationships between organisms and environments are extrordinarily complex. The effects of a mutation will depend on an enormous range of factors, and a change in just one external factor can make a harmful mutation beneficial, or a beneficial mutation harmful.

In this case, this mutation was pretty clearly beneficial in North America just a few years back. Anyone who had two copies of the gene with this mutation was resistant to HIV, and until fairly recently West Nile wasn't present here, so the lack of resistance to West Nile wasn't a big problem. Now, it is entirely possible that the mutation is more harmful than helpful. Both HIV and West Nile are relatively uncommon in the US, but HIV transmission can largely be prevented as long as care and common sense are used, while West Nile transmission takes place through an insect vector, and is much harder to prevent. With West Nile now present in almost the entire country, we may well have seen this mutation change from being beneficial to harmful within just a couple of years.

Whether or not a particular mutation is helpful or harmful is very important to evolutionary studies, because it helps determine whether or not that particular mutant form (allele) of the gene is likely to spread, and whether it is likely to spread through the entire population or just certain geographic areas. If the allele is helpful in some locations and harmful in others, it can actually lead to a situation in which you get genetic differences in different areas of the population. That's cool, because it is one of the many scenarios that can lead to one species dividing into two.

This is a pretty cool finding, even if it isn't good news for the HIV research and treatment community. It has definitely taught us some things that are going to be really important to infectious disease specialists - not least, that the CCR5-inhibitors that are currently being tested in clinical trials may have a really big down-side - but also because it can give us some insight into the complex nature of the interactions between our genes and the environment, and how that impacts evolution.


Karl Haro von Mogel said...

Interesting post, and a very interesting find on the ol' CCR5 receptor. I ran into it a few years back when doing some curiosity searches for a class paper on Pubmed, and the prevailing wisdom of the time (yes, only 4 years ago) suggested that the delta 25 mutation in the CCR5 receptor may have given resistence to a bacterial pathogen, yersinia pestis, the bubonic plague. Now, I think there's another likely culprit, rheumatic fever, which I believe is a virus. In either case, its rather interesting how just a little selective pressure from a disease can have such measurable effect on the human gene pool.

But of course, the thing we must always keep in mind, and chuckle about, is how the creationists run around contradicting basic facts of biology in their relentless crusade. I almost feel like going Duane Gish on their butts and bringing up esoteric examples they've never heard of. (But unlike Duane Gish, REAL examples that they've never heard of.)

JM O'Donnell said...

I'm not surprised that lacking CCR5 has a disadvantage, because it's normally involved in sensing chemokine gradients. Without the receptor cells like macrophages, which normally process and transport antigens to effector cells of the immune system would get a little 'confused'. They still function but their function is still somewhat reduced.

There are probably other organisms that this mutation effects as well, such as plague (beneficially) and other organisms in a detrimental manner.

Timothy Chase said...

"If the allele is helpful in some locations and harmful in others, it can actually lead to a situation in which you get genetic differences in different areas of the population. That's cool, because it is one of the many scenarios that can lead to one species dividing into two."

Aha! I thought that might be the case. I had posted a question a while back for someone who had studied speciation on whether something along these lines may be a factor. (Not sure if they ever responded -- I tend to lose track sometimes.) Similarly, as coevolution occurs between host and virus, one should expect a virus to become relatively asymptomatic (that is, in what eventually becomes the "natural host"), but oftentimes it will remain highly pathogenic in closely related populations. This would seem a potential cause of allopatric speciation.

Anonymous said...

I remember this principle from Biology II when we talked about the C allele in the sickle-cell anemia gene. Genes ALWAYS act in the context of the environment; biology is never as simple as the IDers want to pretend it to be.

Anonymous said...

"If the allele is helpful in some locations and harmful in others, it can actually lead to a situation in which you get genetic differences in different areas of the population. That's cool, because it is one of the many scenarios that can lead to one species dividing into two."

This won't work, as Joe Felsenstein pointed, um, out 25 years ago:
Felsenstein, J. (1981). Skepticism towards Santa Rosalia, or why are there so few kinds of animals? Evolution 35: 124-138.

In a nutshell, ou need assortative mating as well if you are going to get speciation. Thanks to Mayr's pronouncements, sympatric speciation has been seen as contraversial, the up side of which is that the conditions that lead to it have been well studied.


Stephen said...

OK, i had to look up assortative mating. The argument still doesn't follow. If you have a geographically isolated population, then some local environment change, like malaria, could easily push for changes in that population. Sure, it will take many such changes to create a new species, but that doesn't mean it won't happen. Assortative mating is impossible for asexual microbes, and it can hardly be argued that there is only one kind. It takes more time, and generations, but speciation happens.

For humans, there is no isolated place. By the time we colonize the stars, we'll be able to transmit DNA information and incorporate handy changes to keep the species in sync.

Anonymous said...

Speciation is complex. In the documentary The Wild Parrots of Telegraph Hill, two species of South American conures are able to hybridize and produce fertile offspring. Because these species are normally geographically isolated, the chance to mate doesn't normally happen. But for escaped parrots in San Francisco, the geographical barriers no longer exist. Give them a few hundred years, and a new species of conure "native" to San Francisco might come into being from this mixed population.
--David Lewin

TQA said...


I'm actually somewhat familiar with the Santa Rosalia paper. My advisor has assured me that it will feature prominently in my oral comps down the line.

I did try to cheat just a little there, and slide by without mentioning assortative mating, purely in the interests of keeping things simple. (One of the problems I'm finding as I study speciation is that it's such a massively complex process that it's difficult to explain clearly to someone who doesn't have a great deal of background knowledge.)

To get speciation from the scenario above would require assortative mating, but I think that in this case it is actually a simpler scenario than the one used by Felsenstein. Felsenstein's model involves three loci, two involved in selection, and one in assortative mating.

In a case such as this, with the two diseases and corresponding alleles distributed geographically, the only form of assortative mating required is mating that is nonrandom with respect to birthplace - essentially, a parapatric speciation model rather than a sympatric one. In fact, if there is a central zone where both diseases are present and both populations strongly selected against, it could even move to something more like an allopatric speciation model.

Sympatric speciation is difficult, and Joe Felsenstein is about the last person I'd want to try to contradict, but I don't think that a situation similar to the one I outlined would fit into the model from the 1981 paper.

I should add, though, that fixation of a single allele wouldn't be enough to constitute speciation (at least for most species concepts). It would just be an early step along the path.

Anonymous said...

Interesting post. I hadn't heard of the West Nile connection. If historically there have been other pathogens affected by this polymorphism, then the reason both variants are floating around at notable frequencies in our species could be due to balancing selection. Even "in North America just a few years back," the effects of this variant could have been a complex equation involving many germ species. It just shows that it's hard to infer a definite fitness advantage even with a known beneficial effect. Still, I think it's safe to say that most mutations (with a phenotypic effect) are pretty universally harmful.