[inthebox]

Understanding Genetics: Human Health and the Genome

Many people who are resistant to HIV have a mutation in the CCR5 gene called CCR5-delta32.

A "beneficial mutation"

Well, the HIV epidemic is too new to have caused so many people to have the mutation. Also, a high frequency of a resistance gene would be expected in the region where infection rates are high. However, it's virtually absent in African and Asian populations.

Unexpected to be explained by natural selection.

Also this mutation seems to be a deletion - not adding new genetic information

Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele — PNAS



This also contradicts natural selective pressures

The Black Death and AIDS: CCR5-{Delta}32 in genetics and history -- Cohn and Weaver 99 (8): 497 -- QJM


There is another theory that small pox was the agent selecting for this mutation.



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1] The evidence / facts at this moment contradict evolution.


Any thoughts?



2] Is there any relation between smallpox eradication in 1979 and the start of the aids epidemic in 1981 [cdc] ?


3] Does yersinia pestis or smallpox require the coreceptor ccr5 to infect cd4 cells?

Links if so.










G&P

[ebaines]

You haven't shown any "evidence/facts" that contradict evolution. The existence of mutations in genes is a natural occurrence - happens all the time - and if it turns out that one such mutation is beneficial to the survival and procreation of the species then natural selection will favor that mutation being passed on to more offspring in subsequent generations. So please explain - how do you draw the conclusion that the existence of a mutation that prevents infection of individuals by AIDS somehow contradicts evolution?

[asking]

Hi Inthebox.

Happy Darwin's Birthday! Thanks for posting.
Especially, thank you for posting in the biology section. I really appreciate that.

I want to make two general comments about this story. First of all it was not written as an argument for evolution--the researcher (clearly) takes evolution as a given. Her focus is primarily on drug development. Second, it's rather clumsily written, particularly in terms of what's known about evolution. This is typical of molecular biologists who work in biomedicine.

Understanding Genetics: Human Health and the Genome

Okay. First off, she keeps calling the version of the gene that is protective against AIDS infection a "mutation." This is misleading because it's not "a mutation." It's a version of a particular gene, which should be called an "allele." She's trying to make it easier to understand by leaving out the word allele. But it makes it sound like the rest of the genome is not a mutation. EVERY SINGLE GENE in the genome is the product of changes (mutations). So the CCR5 delta 32 allele and the many other alleles of that gene could all be called "mutations."

But if everything is a mutation, why use the word? (Answer: you shouldn't.) She does for reasons that are historical and a window into how molecular biologists think. They started studying fruit flies and yeast and other simple organisms. They would irradiate them in order to induce mutations and then pick the ones that had weird characteristics that they could play with--like white eyes, deformed wings, or an inability to make a certain enzyme. So they got in the habit of thinking that there are "normal" alleles and "mutations." This dualist and essentialist thinking has not served biology well.

In real life (outside the lab), many of our genes come in different versions, like flavors of ice cream. (The ones that come in only one version are the ones we share in common with chimpanzees and other animals--rabbits and even in a few cases plants and mushrooms.)

So for genes that come in more than one form, there could be just two alleles or 20. It depends on the gene. Since every person has two copies of each gene, they could have two alleles that are the same or two that are different. At a given gene position, I could have alleles a and b and you could have alleles x and y--all for the same gene. Or I could have a and x and you could have b and x. So many possibilities. And then people mate and these alleles recombine again. So the first thing to understand is that the genome is riddled with variability. It is all normal!

Different alleles are useful in different situations. So if you've been exposed to AIDS or another virus that latches onto CD4 and CCR5, then the CCR5 delta 32 allele is extremely useful, especially if you are lucky enough to have two copies. In an environment riddled with AIDS, these 1% of people who have two copies of this allele are going to outbreed other genotypes all other things being equal (which they never are). But even so, on average, they will have a "selective advantage."

In an environment without AIDS, this allele might have no effect. In which case, we'd say it was "selectively neutral." Or it could have negative effects and other combinations of alleles would gradually replace it over time. However, it is nearly impossible for selection to drive a particular allele out of the population entirely. If populations are very small, it could happen by chance. But in large populations like ours (6+ billion), there are always a few examples of rare alleles continuing through some family or other

Another thing to understand is that our genomes do mutate all the time at a very low rate--on the order of 175 mutations per person. That sounds like a lot, but that is out of 3.2 billion base pairs (or 6.4 billion bases/nucleotides). So it's not much. Each of these changes can be useful or not, harmful or not. Some may be harmful in all environments, others may only be harmful or useful only in certain situations. So a population that has significant amounts of the CCR5 dela 32 allele and is exposed to AIDS would tend to build up even higher levels of the delta32 allele, while a population free of AIDS would tend to have low levels of this allele. If the allele is really rare or non existent, as in AFrica, no amount of selection can bring it into existence, let alone increase its frequency in the population.

A "beneficial mutation"

If 20% of the population carries it, it's not a lethal mutation. If this many people carry it, by definition, it had some selective advantage at some time in our past. These researchers have estimated that this happened during an earlier epidemic.

In the context of certain diseases such as AIDS this allele appears to be beneficial.

Unexpected to be explained by natural selection.

If you are saying natural selection can't be invoked here, I couldn't disagree more. Natural selection likely explains the 20% rate of this allele. All the facts are consistent with what we know about mutation (change in genetic information) and natural selection.

There is no alternate scientific theory that would explain all this.

Also this mutation seems to be a deletion - not adding new genetic information

This is a point of interest only to someone trying to disprove evolution. If you are a person chronically exposed to AIDS, you would be happy to have two copies of this allele, which protects against AIDS and would not care if it was caused by a deletion, an insertion, or a substitution. In fact, if it kept you alive, you'd probably accept a chromosomal inversion! If the CCR5 delta 32 allele is newer than the 16 or more* other CCR5 alleles, most people would consider that new information.

*Multiple nonfunctional alleles of CCR5 are frequen...[Blood. 2000] - PubMed Result

I feel that your argument that information is only in the specific nucleotides, not in how the resulting protein operates in a cell or in the overall physiology of the organism is an exceptionally weak argument. The argument that information is only in the letters of the genome and not in the words and sentences is so literal as to be meaningless.

Suppose I wrote:
I pray.
I prey.
I pry.

The second allele represents a base substitution and by your argument, that's new information. The third allele represents a deletion, which by your argument is not new information. But it has a different meaning, so I would say it's very different information--just as different as prey is from pray. If you think of gene mutations in that light, you can see why I think your argument is not a good one.

In the context of an entire book, substituting "pry" for "pray" throughout would result in a book with a very different meaning. Genes are expressed in many different kinds of cells in different contexts, so when the meaning of an allele changes, it doesn't just change one thing, but many, just as substituting Prey or Pry for Pray throughout a book would. Who knows what other effects CCR5-delta32 has on human physiology.

Also, to clarify, when the researchers say that this allele arose during the bubonic plague years, they don't actually mean that the deletion never occurred before. It did not appear as a mutation in response to a disease. It may be quite old. Gene mutations can appear and disappear over time. What they are saying is that it became relatively common among Europeans starting around that time. The exact reason is, apparently, up for discussion. But it had to exist at a frequency that would benefit fairly large numbers of people. If it was just one or two people carrying the allele, they could easily have died from some other cause (fell off a horse, executed for treason, died of pneumonia in childhood) without passing on the allele.

Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele — PNAS

This also contradicts natural selective pressures

The Black Death and AIDS: CCR5-{Delta}32 in genetics and history -- Cohn and Weaver 99 (8): 497 -- QJM


There is another theory that small pox was the agent selecting for this mutation.
1] The evidence / facts at this moment contradict evolution.

Well, whether it was bubonic plague, small pox or something completely different, quibbling over which particular selective event resulted in an increase in the proportion of people carrying this allele is not an argument about natural selection. Nothing you have posted undermines the idea that species have developed through descent with modification. Or that both mutation and selection are, separately, regular events among all organisms.

The last article you cited is by two historians, who may have much to say about plague and smallpox. But I would not expect them to have anything definitive to say about the spread of the CCR5-delta 32 allele.

Based on their summary alone, I would suggest that they do not understand selection. They argue that mortality was greater in other areas besides northern europe, so the CCR5 delta32 allele should be more common in these other areas. But that is not necessarily the case. Selection does not induce new mutations; it can only operate on variants that are already present. If the Mediterranean or Chinese populations did not carry this particular allele to any extent, there's no reason it would have been selected. In particular, if these other populations carried OTHER alleles that were equally or more protective, specifically against bubonic plague (or whatever disease), alleles that were rare or non existent in European populations, then the same disease would select differently on different populations.

The basic mechanisms of evolution by natural selection is extremely simple--the generation of variation through mutation, followed by selection for different types in different places at different times. But the consequences of those two forces are not simple, but instead rather complex.

Yesterday was the 200th anniversary of Charles Darwin's birthday. Happy Darwin Day!

[asking]

PS. inthebox, I've been skimming the historical article. It's very interesting. I am glad you posted it. I definitely agree with the authors that many molecular biologists don't pay much attention to details of history and that they should cooperate with historians when proposing their explanations. In general, I see an arrogance about historical information and fossil record information (a different kind of history) that sometimes leads some of the molecular crowd into absurd pronouncements about what happened in the past, whether historically or in terms of evolutionary history.

[inthebox]

If every gene is the result of a mutation then the cc5r delta 32, is a mutation also.

A deletion.

The links even note the unexpected higher occurrence in Europeans despite the fact that HIV originated and unfortunantly is all to common in Africa. You would think that the greatest selective pressure for a "beneficial" mutaion or allelle to be selected for would be in Africa. At least statistically speaking, and even then the author of the first article states HIV is too "new"

If this silent or neutral allelle/mutation first occurred in Europeans do you think it an amazing coincidence that hundreds of years later HIV, like other viruses, despite its own mutation rate, would be configured as to be unable to infect a new host population?

If it can be shown that yersinia, a bacteria not a virus [ another coincidence] , has the same mechanism of overcoming immune cells via the same cd4 receptor ccr5 delta 32 co coreceptor complex then the theory that the pLague selected for this mutation/allele is plausible.

Same with small pox, which makes the coincidence of small pox eradication and the emergence of HIV fascinating.

Would this be an example of convergence?
Two different selective pressures, if they can be proven, selecting for the same allele/ mutation/ trait?








G&P

Nonetheless this is still microevolution at best.

[inthebox]

As to the nonfunctioning alleles being present in various populations, why is it not selected for in subsaharan Africa?

In light of what we know about mutations and cancer, or sickle cell or downs, or alzheimers, the argument that complex cellular pathways and organ interactions occurred via mutations is also very weak.


Catalogue of Somatic Mutations in Cancer




Okay, so what do you think of a trial of homozygote ccr5 delta 32 people serving as bone marrow donors for those with HIV/AIDS who have undergone chemo?


American AIDS Patient Cured After Leukemia Treatment


Practical science --- YEAH:)




G&P

[asking]

If this silent or neutral allelle/mutation first occurred in Europeans do you think it an amazing coincidence that hundreds of years later HIV, like other viruses, despite its own mutation rate, would be configured as to be unable to infect a new host population?

I wouldn't call it an amazing coincidence. With so many infectious agents and a limited number of ways to latch onto human cells, it doesn't stretch the imagination that two unrelated organisms would latch onto the same receptor. I'm pretty sure there are other examples of that. Do we know that for sure in this case? I haven't read enough of this story.

Would this be an example of convergence?

If true, yes.

Two different selective pressures, if they can be proven, selecting for the same allele/ mutation/ trait?

Are you asking if two different selective pressures could both favor the same allele? Certainly, in principle.

But, just for the record, an allele is not equivalent to or synonymous with a single trait. A single allele might affect many traits and many alleles can affect a single trait.

I thought it was interesting that the CCR5 gene had at least 16 different alleles. Each one might have a subtly different effect on a variety of traits. If the 16 alleles can be combined in, what? 120 different ways, that's a lot of variation at just one gene locus.