Hey Roland! Delta 32 mutation?

[LadyShea]

I watched a show on PBS last night, showing that a genetic mutation called Delta 32 arose during the black plague, and protected people from contracting the plague entirely if they had two copies, and resisting it/recovering from it if they had one copy.

Because most people of European descent descended from plague survivors, the percentage of this mutation is fairly high in that population, and virtually 0 in Asians and Africans.

The really interesting part is that people, today, who have two copies of the mutated gene appear to be totally immune to AIDS, and those with one copy are resistant, as HIV and bubonic plague use similar mechanisms of infection (invade white blood cells via biological trickery and hitch a ride to the lymph nodes to shut down the immune system).

Know anything about this? Is it bullshit or exaggerated or true?

[Roland98]

I swear I'd discussed this on II, but all I could find was this thread where it's only briefly mentioned.

What you've said is kinda true. Let me back up a minute.

CCR5 is a cell-surface protein expressed on a variety of cell types. It acts as a co-receptor for some types of HIV (mainly HIV-1) on some cells where CCR5 is expressed--notably, on T cells. So the virus uses this and another cell surface molecule (CD4) to attach to the host cells. The "delta 32" version of the CCR5 gene is one in which 32 nucleotides are missing (this is in ~20% of Caucasians, and ~2% are homozygous--they have 2 copies of the deleted gene). This deletion causes a stop codon, which means a truncated (shortened) version of the CC5 protein is produced. They have indeed found that those who are homozygous are almost entirely protected from HIV-1 infection (though with a virus like HIV, it probably won't surprise you to learn that there are indeed variants that can use other co-receptors, so it doesn't offer complete protection). Those who have one normal copy and one delta-32 copy have a slower progression of disease generally. So that's mostly true.

The plague part...that's speculation at this point. Some recent papers:

Genes Immun. 2005 Apr 7; [Epub ahead of print]

Detection of the CCR5-Delta32 HIV resistance gene in Bronze Age skeletons.

Hummel S, Schmidt D, Kremeyer B, Herrmann B, Oppermann M.

A mutant allele of the chemokine receptor CCR5 gene (CCR5-Delta32), which confers resistance to HIV-1 infection, is believed to have originated from a single mutation event in historic times, and rapidly expanded in Caucasian populations, owing to an unknown selective advantage. Among other candidates, the plague bacillus Yersinia pestis was implicated as a potential source of strong selective pressure on European populations during medieval times. Here, we report amplifications of the CCR5-Delta32 DNA sequence from up to 2900-year-old skeletal remains from different burial sites in central Germany and southern Italy. Furthermore, the allele frequency of CCR5-Delta32 in victims of the 14th century plague pandemic in Lubeck/northern Germany was not different from a historic control group. Our findings indicate that this mutation was prevalent already among prehistoric Europeans. The results also argue against the possibility of plague representing a major selective force that caused rapid increase in CCR5-Delta32 gene frequencies within these populations.


Nature. 2004 Feb 12;427(6975):606.

Evolutionary genetics: CCR5 mutation and plague protection.

Mecsas J, Franklin G, Kuziel WA, Brubaker RR, Falkow S, Mosier DE.

A recent and prevalent mutation in the chemokine receptor CCR5 in humans of northern European ancestry has been proposed to provide protection against bubonic plague. Here we infect both normal and CCR5-deficient mice with the bacterium Yersinia pestis, the cause of the plague epidemics that wiped out one-third of Europeans in the Middle Ages, and find no difference in either bacterial growth or survival time between the two groups. Unless the pathogenesis of Yersinia infection differs markedly between mice and humans, our results indicate that CCR5 deficiency in people is unlikely to protect against plague.

and a comment on that article:

Nature. 2004 Jul 22;430(6998):417

Evolutionary genetics: Ambiguous role of CCR5 in Y. pestis infection.

Elvin SJ, Williamson ED, Scott JC, Smith JN, Perez De Lema G, Chilla S, Clapham P, Pfeffer K, Schlondorff D, Luckow B.

Mecsas and colleagues suggest that a deficiency in the chemokine receptor CCR5 in humans is unlikely to confer protection against plague, based on their study of Yersinia pestis infection in Ccr5-deficient mice. They were testing the hypothesis that a mutation in the CCR5 gene, frequently found in Caucasians, may have been selected for in the past because it provided protection against (bubonic) plague; the mutation, called CCR5Delta32, is characterized by a 32-base-pair deletion. We have also tested this hypothesis by using Y. pestis infection in mice and, in addition, we have done phagocytosis experiments with macrophages from wild-type and Ccr5-deficient mice. Although, like Mecsas et al., we did not see any difference in the survival of the two groups of mice, we did find that there was a significantly reduced uptake of Y. pestis by Ccr5-deficient macrophages in vitro. Our results indicate that the role of Ccr5 in Y. pestis infection may therefore be more complex than previously thought.

and this article suggests smallpox instead:

Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15276-9.

Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele.

Galvani AP, Slatkin M.

The high frequency, recent origin, and geographic distribution of the CCR5-Delta 32 deletion allele together indicate that it has been intensely selected in Europe. Although the allele confers resistance against HIV-1, HIV has not existed in the human population long enough to account for this selective pressure. The prevailing hypothesis is that the selective rise of CCR5-Delta 32 to its current frequency can be attributed to bubonic plague. By using a population genetic framework that takes into account the temporal pattern and age-dependent nature of specific diseases, we find that smallpox is more consistent with this historical role.

So the jury's still out on why the allele is more common in those of European versus those of African and Asian descent, but the effect on HIV infection and replication is definitely present.

[LadyShea]

Thanks Roland. The researchers on the show went to a small village in England, Eam I think it was called, because they had pretty detailed village records of the plague there, it is fairly isolated, and many people are direct descendents of plague survivors. In the records, one woman buried 6 children and a husband and never became sick, another was very sick and left to die, but recovered, and another man took advantage of the situation by becoming a mortician and burying all the villages plague victims, he also never became sick.

They did DNA tests on some amount of the town's residents and found 14% had it, but I don't remember if it was homozygous.

Anyhoo, interesting stuff, thanks for the additional information. Does this kind of information help with developing vaccines?

[Roland98]

Originally Posted by LadyShea

Thanks Roland. The researchers on the show went to a small village in England, Eam I think it was called, because they had pretty detailed village records of the plague there, it is fairly isolated, and many people are direct descendents of plague survivors. In the records, one woman buried 6 children and a husband and never became sick, another was very sick and left to die, but recovered, and another man took advantage of the situation by becoming a mortician and burying all the villages plague victims, he also never became sick.

They did DNA tests on some amount of the town's residents and found 14% had it, but I don't remember if it was homozygous.

With those numbers it sounds like they looked for one copy, but I guess it's possible if the population had a very high level of those with the mutation that they could have 14% homozygous.

It very well may have protected against the plague (note the rodent studies are inconclusive), and that may have

Anyhoo, interesting stuff, thanks for the additional information. Does this kind of information help with developing vaccines?

In a roundabout way--we can examine more closely how the viral proteins (or bacterial ones, as the case may be) interact with the proteins on the host cell, and try to target vaccines to the particular protein motifs that are responsible for binding. Not sure if they're actually doing this with HIV. I do think they've used this as a target of HIV drugs, however. On my home computer with dial-up or I'd do a search.

[Roland98]

Random. I ran across an old disk today and when I looked to see what was on it, I saw a word document called "AIDS and black death" which contained an article from 2001 at this link. So, some more background.

[Lionel]

Yeah I've done quite a bit of reading and research on the delta 32 mutation. There is alot of information online and even found a place that tests you to see if you have the gene or not. It's called delta32 gene labs. I found out I had one copy which was interesting. Can anyone tell me if there are other genes like this out there that you can test for?