Freethought & Rationalism Archive

ps418 · 04-28-2003, 11:41 AM

Recently I've been interested in ancient pandemics (sparked by the AIDS-Myth thread), mainly because compared to some other forces, pathogens can act as very strong selective forces on alleles that confer resistance. A proportion of between-population genetic differences are surely due to the selective forces of viral and bacterial pandemics selecting for resistance-confering alleles. Thus, pathogen-driven selection may be an important force for enhancing genetic differentiation between population (because different populations do battle with different pathogens).

One example I've been reading about is the CCR5Delta 32, a chemokine receptor gene variant that confers nearly complete resistance to HIV infection in homozygotes, and signficantly slows the progression from infection to AIDS and infection to death in heterozygotes (see CCR5 receptor gene and HIV infection). This allele has a frequency of about 5-15% in european populations, but is essentially absent in African and East Asian populations. This allele is currently being selected for by HIV (Sullivan et al, 2001), and there is also strong population genetic evidence that this allele was subject to strong selection in the recent past (Bamshad et al, 2002; Libert et al, 1998; Stephens et al, 1998).

Since HIV is thought to be less than a century old, HIV itself was not the selective force. However, Lalani et al (1999) suggests that CCR5 delta 32 may confer resistance to various Poxviruses, such as variola (smallpox). Stephens et al (1998) estimate a very recent, European origin of the CCR5 delta 32 allele, ~700 years. This suggests a possible association with the Black Plague, which fits with what is known about the distribution of the allele. However, the Black Plague is thought to have been caused by a bacterium (Yersinia Pestis) rather than a poxvirus, and as far as I know there is no evidene linking CCR5 delta 32 with resistance to Yersinia Pestis infection. On the other hand, other researchers have suggested that the Black Death was not caused by Yersinia Pestis, but instead by some other, airborne pathogen (a virus?). Stephens et al write:

Quote:

. . . the cumulative results point to a selective sweep and to one with enormous selective mortality within historic times, perhaps mediated by a widespread epidemic. The bubonic plague, which claimed the lives of 25%�33% of Europeans during the Black Death from 1346 to 1352 (650 years ago) and which has had multiple outbreaks in Europe before and since, is an obvious candidate (Lenski 1988; McEvedy 1988). The plague bacillus, Yersinia pestis, is transmitted by fleas on black rats and carries a 70-kb plasmid (PYV), which encodes an effector protein, Yop1, that enters macrophages, causing diminished immune defenses (Rosqvist et al. 1988; Cornelis and Wolf-Wulz 1997; Mills et al. 1997). If the mechanism of Yersinia-induced macrophage apoptosis (cell death) involved macrophage chemokine receptor 5, the CCR5- D32 mutation would be an attractive candidate for a strong selective pressure 600�700 years ago. Other possibilities are Shigella, Salmonella, and Mycobacterium tuberculosis, which likewise target macrophages. Additional infectious-disease candidates would include
syphilis, small pox, and influenza, which have decimated
millions of individuals during the previous millennium (McNeil 1976; Garrett 1994). Attempts to examine these deadly pathogens of documented mortality during the dawn of Western civilization, in the context of the CCR5 genotype, would be illuminating.

Pretty interesting, I say, that population genetics can potentially tell us something about historical and prehistorical pandemics, and how they have shaped human genetic evolution. I wonder how many 'deleterious' alleles have been maintained because of there conferring resistance, even though the resistance would only become apparent in the midst of an epidemic?

Refs

Akey et al, 2002. Interrogating a High-Density SNP Map for Signatures of Natural Selection. Genome Research 12, 1805-1814.

Bamshad et al, 2002. A strong signature of balancing selection in the 5' cis-regulatory region of CCR5 . PNAS 99, 10539-10544.

Lalani et al, 1999. Use of chemokine receptors by Poxviruses. Science 286, 1968-1971.

Libert et al, 1998. The deltaccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe. Human Molecular Genetics 7, 399-406.

Stephens et al, 1998. Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. American Journal Human Genetics 62(6):1507-15.

Sullivan et al, 2001. The coreceptor mutation CCR5Delta 32 influences the dynamics of HIV epidemics and is selected for by HIV. PNAS 98, 10214-10219.

Godot · 04-29-2003, 01:34 AM

This thread looked lonely all by itself.

I agree that it is something worth looking at. Unfortunately, I'm not equipped to handle the task, but I would be happy to lurk in the background if others around here want to chat it up with you!

AtomSmasher · 04-29-2003, 02:28 AM

Excellent find, this is an intriguing hypothesis I have come across many times. There are quite a few "deleterious" genes that were interesting during my research into eugenic selection against congenital illnesses such as anemia and Cystic Fibrosis. The genes involved in both patholigies confer resistence to other illnesses such as malaria and cholera (respectively). Now I'd like to see counter or corroborative examples from other diseases.

Wounded King · 04-29-2003, 03:39 AM

The recent work on the allelic variation in prion proteins would seem to be another possible example of this, albeit a prehistorical one.

Mead S, Stumpf MP, Whitfield J, Beck JA, Poulter M, Campbell T, Uphill JB, Goldstein D, Alpers M, Fisher EM, Collinge J.
Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics.
Science. 2003 Apr 25;300(5619):640-3.

ps418 · 04-29-2003, 07:34 AM

Another example of a resistance-conferring allele, also a chemokine receptor, that has been subject to very strong pathogen-driven selection is the null allele of Duffy antigen receptor for chemokines (DARC). The DARCs are expressed on erythrocytes (red blood cells). The null allele results an absence of the DARC on erythrocytes, much the same way that the CCR5 delta 32 allele corresponds to a transmembrane chemokine receptor on macrophages and T-cells that is truncated and does not actually protrude from the cell surface. This is caused by a single T->C SNP in a regulatory element that prevents transcription of the DARC (Tournamille et al. 1995). Perhaps surprisingly, there is no evidence of a deleterious effect of the null allele (Hamblin and De Rienzo, 2000, p. 1675).

The DARC null allele shows extreme regional differentiation. The null allele in particular is nearly fixed (present in all individuals) in sub-Saharan Africa, but is almost completely absent in Europe and Asian populations. Hamblin and Di Rienzo (2000) write:

Quote:

The Duffy blood group locus is characterized by three main alleles�FY*A and FY*B, which differ by a single amino acid, and FY*O, which corresponds to the Fy(a2b2) serological phenotype (i.e., the absence of Fy antigen). In Asia and the Pacific the FY*A allele is at high frequency, whereas in Europe and the Americas the FY*A and FY*B alleles are at intermediate frequencies. The FY*O allele is at or near fixation in most sub-Saharan African populations but is very rare outside Africa. As a result, the level of interpopulation differentiation of the FY*O allele, as measured by the FST statistic, is the highest observed for any allele in humans
(Cavalli-Sforza et al. 1994). These findings strongly suggest that the observed pattern of allele frequencies at this locus has been driven by positive natural selection.

Individuals homozygous for null allele have complete resistance to infection by Plasmodium vivax, which infects erythrocytes via the DARC. Thus, it seems very likely that pathogen-driven selection is responsible for the distribution of the allele.

Quote:

Thus, the connection between the Fy(a2b2) serological phenotype and resistance to vivax malaria is direct and well understood, providing a plausible hypothesis for the cause of the selective fixation of the FY*O allele in much of Africa

Hamblin and Di Rienzo (2000, p. 1669).

Like the CCR5 delta 32 allele, however, it is not certain that the selective forces currently acting on the DARC null allele (the malarial vector Plasmodium vivax) are the ones that acted upon it in the past. For instance, there may be many other bugs that exploit the DARC, but which are not around right now.

Quote:

Although our estimates of the time of fixation of FY*O may be consistent with selection by vivax malaria, this explanation may still be questioned. On the basis of both the likely origin of P. vivax in Asia and the present-day distributions of vivax malaria and the FY*O allele, Livingstone (1984) argued that it was the
prior fixation of the FY*O allele that fortuitously prevented the establishment of P. vivax in sub-Saharan Africa, rather than the opposite. This argument suggests a possible parallel between the FY*O allele and the CCR5-D32 deletion (Hill and Motulsky 1999). In the case of CCR5-D32, an unknown selective agent in the past is proposed to have caused an increase in frequency of the mutant allele, which happens, by chance, to confer resistance to HIV-1 today (Stephens et al. 1998). The FY*O mutation could have a similar history �namely, that its frequency increased because of selection by a pathogen other than P. vivax. Receptors that are exposed on the surface of blood cells, such as the Duffy antigen and CCR5, are targets for exploitation by many pathogens (Pease and Murphy 1998) and may be subject to periodic episodes of selection by different agents.

Hamblin and Di Rienzo (2000, p. 1678).

Refs

Hamblin and Di Rienzo, 2000. Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. American Journal of Human Genetics 66:1669�1679.

Pease and Murphy, 1998. Microbial corruption of the chemokine
system: an expanding paradigm. Semiology and Immunology 10:169�178.

Tournamille et al, 1995. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nature Genetics 10:224�228.

Patrick

ps418 · 04-29-2003, 07:46 AM

Also, there is an excellent review by Cooke and Hill:

Genetics of susceptibility to human infectious disease. Nature Reviews Genetics 2, 967-977. Free, PDF file

Patrick

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04-29-2003, 01:34 AM	#2
Godot Veteran Member Join Date: Mar 2003 Location: Calgary Posts: 1,335	This thread looked lonely all by itself. I agree that it is something worth looking at. Unfortunately, I'm not equipped to handle the task, but I would be happy to lurk in the background if others around here want to chat it up with you!

04-29-2003, 02:28 AM	#3
AtomSmasher Junior Member Join Date: Dec 2002 Location: Tampa, Florida, U.S. Posts: 95	Excellent find, this is an intriguing hypothesis I have come across many times. There are quite a few "deleterious" genes that were interesting during my research into eugenic selection against congenital illnesses such as anemia and Cystic Fibrosis. The genes involved in both patholigies confer resistence to other illnesses such as malaria and cholera (respectively). Now I'd like to see counter or corroborative examples from other diseases.

04-29-2003, 03:39 AM	#4
Wounded King Veteran Member Join Date: Mar 2003 Location: Edinburgh Posts: 1,211	The recent work on the allelic variation in prion proteins would seem to be another possible example of this, albeit a prehistorical one. Mead S, Stumpf MP, Whitfield J, Beck JA, Poulter M, Campbell T, Uphill JB, Goldstein D, Alpers M, Fisher EM, Collinge J. Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science. 2003 Apr 25;300(5619):640-3.

04-29-2003, 07:46 AM	#6
ps418 Veteran Member Join Date: Mar 2001 Location: Louisville, KY, USA Posts: 1,840	Also, there is an excellent review by Cooke and Hill: Genetics of susceptibility to human infectious disease. Nature Reviews Genetics 2, 967-977. Free, PDF file Patrick

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