Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

May 21st, 2008

Microevolution and bottlenecks: HIV transmission

HIV (Wellcome Images)“All politics is local” may be a cliche; but “All evolution is local” is at least equally true, and is a more interesting concept to geeks like me. A mutated virus may spread through a population, but it starts somewhere. What are the bottlenecks, what are the resources that evolution can draw on, what are the checks or drivers of transmission and spread?

It’s only relatively recently, though, that the techniques to properly measure microevolution of viruses have become generally available; genomic sequencing of reasonably large chunks of virus has become fast and cheap enough that very small changes in virus sequence can be used to track evolution over short times and distance. I talked about using this to track the foot and mouth disease outbreak in England in 2007. Two recent studies look at microevolution to analyze bottlenecks and transmission, in quite different contexts: Dengue virus circulation in schools, and HIV transmission between individuals. I’ll talk about the dengue study some other time; here I only have room for the Keele et al paper.1

I’ve talked a fair bit (like here and here) about the evolution in situ that HIV undergoes in each of its hosts, evolving rapidly in response to local conditions such as immune responses. Much of the variation in the infected individual is selected, of course; selected in response to local conditions — those local conditions being the genetics of the host, and to a large extent the host’s immune system. The immune system puts tremendous pressure on the virus, and the only way it can escape from the prison is to cripple itself. HIV immune escape variants are usually relatively defective viruses, because the mutations that allow them to become invisible to the immune system, damage the virus’s ability to replicate and spread.

HIV assembling in a macrophage
HIV infecting a macrophage2

Immune systems are idiosyncratic; yours is different than mine. When HIV is transmitted from one person to another the virus moves from one selection immune landscape to a very different one. The mutations that saved it in the first person are now probably no longer protective, yet the damage that those mutations were doing is still very much present – a double whammy. Fortunately for HIV (less so for humanity) it is still able to mutate its way back to a functional virus. If you examine HIV in one individual and then in the next step in the transmission chain, the new host’s virus will probably have started to revert back to the platonic essence of HIV; less, of course, the mutations that the new host’s immune system imposes on it.

A question is: What does the virus have to work with in this process? We speak of HIV as a quasi-species, traveling around as a cloud of related but different viruses. Within that cloud is variation that can be immediately selected. But is that true in transmission? How many viruses actually take that gigantic leap from one host to the next?

This is important for a couple of reasons. The big one is vaccination. One of the huge obstacles to HIV vaccination is variation; not only within a population, but within an individual. Let’s say you are vaccinated and protected against the most common HIV variant. If you are infected only with a handful of viruses, you will probably shut them down. But if you’re infected with a cloud of many different viruses, somewhere in that cloud will be a resistant virus; the chance of protection have gone way down. Which of those is actually what happens?

Keele et al 2008 Fig 2That’s the question that Keele1 (and a cast of thousands, or at any rate another 36 authors; particle phsyics authorship on a biology paper) asked, examining thousands of virus samples (just one gene, not the whole genome; but based on single virus genomes, not pooled genomes from the virus cloud) from over 100 patients shortly after they were newly infected with HIV. They used a mathematical model (which I am for now going to accept on faith; with two grants due in the next two weeks, I don’t have time to sit down and work through the math) to consider three different possibilities:

  1. A cloud of viruses is transmitted;
  2. A limited number of viruses is transmitted out of the cloud;
  3. A cloud of viruses is transmitted, but is rapidly thinned down to become a limited number of viruses, due to selection within the new host.

They concluded that in fact the second possibility was true: Only a very small number of viruses manage to establish a foothold in the hostile new terrain:

we found that 78 (76%) had evidence of infection by a single virus or virus-infected cell and that 24 others (24%) had evidence of infection by at least two to five viruses. Aside from early selection of CTL escape variants found in several subjects, there was no suggestion of virus adaptation to a more replicative variant or bottlenecking in virus diversity preceding peak viremia. … we interpret the findings of low multiplicity infection and limited viral evolution preceding peak viremia to suggest a crucial but finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses.1

(My emphasis)

They also noted particular characteristics of the successful viruses, though I think their study, not being specifically designed for this, wasn’t able to come up with any surprises. But of course this opens the door to this further question: What’s special about these tiny few viruses that are successful transmitters, compared to the thousands or millions of other variants circulating in the original host? Are they just lucky little viruses, or are these the only ones that have some unique qualification for spread? And if so, can we take advantage of that quality to block spread?


  1. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H et al. (2008) Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A doi:10.1073/pnas.0802203105[][][]
  2. Gross, L., 2006. Reconfirming the Traditional Model of HIV Particle Assembly. PLoS Biology, 4(12), p.e445 EP []
May 14th, 2008

Autoimmunity and CD1 (Part I)

Dr. Kilmer's Swamp Root Kidney Liver & Bladder CureWe walk a fine line between death due to immune deficiency, smothered under the weight of pathogens and parasites, and death by hyperimmunity, eaten alive by our own defenses. It’s amazing that our immune system can be tuned so precisely as to recognize anything foreign, yet ignore the vast antigenic universe of our own normal self.

Of course, sometimes the immune system fails, in both directions. We often hear about deaths from pathogens, and autoimmune diseases in general are pretty common. There are many ways by which (it’s believed) the immune system can become self-reactive, but a very common observation is that there are both genetic and environmental predisposing causes to autoimmunity. That is, you may have the genetic makeup to be autoimmune, but until you’re exposed to some environmental trigger, autoimmunity never develops. So, for example, if your identical twin has an autoimmune disease, you are much more likely than someone in the general population to develop the disease; but you still have a good to excellent chance of never getting the disease.

Liver blood vesselsIn many cases the neither the environmental triggers nor the genetic factors are well understood. The most likely environmental trigger, though, is some kind of microbe. In some cases, this may be because of “molecular mimicry” — the microbe has an antigen that looks like self antigen; the self antigen is normally ignored, because the immune system needs some kind of “danger” signal before it becomes activated; the microbial antigen is seen in the context of microbial “danger” signals; an immune response forms against the microbial antigen; the immune response cross-reacts with the self antigen; self cells are damaged by this immune response; the dead cells release more danger signals along with self antigen; and a positive feedback loop drives a full-fledged autoimmune disease.

That’s the model, but there aren’t many, if any, diseases where the whole process has been tracked through step by step; in fact, I think that there has been so much difficulty getting clear molecular connections between microbes and autoimmunity that there’s a robust search for other mechanisms. However, in the latest issue of Cell Host and Microbe, Albert Bendelac’s group shows a series of links between bacterial infection and the autoimmune disease human primary biliary cirrhosis (PBC).1 (There’s also a helpful, if rather dry, commentary2 by Sebastian Joyce and Luc van Kaer in the same issue.) Rather than trying to cover everything today I’m going to give background here, and then talk about the specific findings in a few days.

CD1 - top view with ligandOne interesting thing about Bendelac’s paper is that they link CD1 to the disease, through NKT cells. CD1 is an MHC class I family member; I talked about it back here, and that’s its mug shot to the left here (click for a larger version). CD1, like many members of the MHC class I family, has a “groove” in its “top” side. MHC class I proper binds peptides in that groove, but CD1 has a much more hydrophobic groove that binds to greasy things like lipids, glycolipids, and lipopeptides. These kinds of molecules are typically found in some kinds of bacteria — especially mycobacteria, like tuberculosis and leprosy, but also other kinds of bacteria such as the commensal microbe Sphingomonas.

MHC class I molecules, with their peptides, are recognized by cytotoxic T lymphocytes (CTL),3 but CD1 molecules and their lipids are recognized by a specialized subset of T cells, “natural killer-like” T cells (NKT cells). The function of this CD1/NKT system really isn’t all that clear. The early guesses that this was a branch of the immune system specialized for dealing with mycobacteria has been weakened as NKT cells have been linked to resistance to various viruses, and also as various viruses have been shown to block CD1 — suggesting that CD1 and NKT cells would otherwise eliminate them.

OK, enough for now. In my next post I’ll talk more about the disease itself, and then try to spell out the process by which, according to Bendelac, NKT are central to the autoimmune reaction; as well as how this abnormal reaction suggests some of the normal functions of NKT and CD1.


  1. Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J et al. (2008) Liver Autoimmunity Triggered by Microbial Activation of Natural Killer T Cells. Cell Host & Microbe 3:304-315.[]
  2. Joyce S, Van K, Luc (2008) Invariant Natural Killer T Cells Trigger Adaptive Lymphocytes to Churn Up Bile. Cell Host & Microbe 3:275-277.[]
  3. And natural killer cells, but let’s not go into that now[]
April 13th, 2008

MHC isn’t sexy after all

Mickey and Minnie Mouse Inbreeding is a bad thing, genetically, and almost all species have ways of avoiding it. One way of avoiding inbreeding is to recognize individuals who are related to you, and not mate with them. That’s not so difficult when you’re a big-brained, highly social animal like a wolf, or a human, who have lots of brain devoted to issues of who is who and where they stand in a group. It’s a little more challenging for mice, though.

How do mice distinguish individuals? How do they determine relatedness? For the past 30 years1, the answer has been MHC: Mice select mates that differ at the major histocompatibility complex.

When I talked about this last fall, in the context of MHC diversity, I was rather skeptical that mating preference was the major driver of MHC diversity, quoting Piertney and Oliver:2

A lack of repeatability of several studies, and an apparent plasticity in response across experiments, questioned the robustness of the data, and the general relevance of mate choice as a primary driver of MHC diversity.

It didn’t occur to me to question the fundamental observation that MHC is even involved in distinguishing relatedness.

MHC seemed like a logical candidate for distinguishing individuals and determining relatedness because of its great polymorphism: in an outbred population, the MHC is so variable that few individuals are identical across the region, and individuals with similar MHC are most likely related to some extent. 3 And in fact, mice clearly can distinguish differences in MHC type by smell. 4 However, that doesn’t mean that mice recognize different individuals, or determine relatedness, by the differences in MHC. A couple of papers from Jane Hurst’s group in the past year suggest that in fact they do not. 5,6

Hurst’s group tried to move away from the artificial situation of highly-inbred lab mice, using instead wild mice breeding in semi-natural conditions. They find that under these conditions, mice do (as expected) avoid breeding with close relatives. But this incest avoidance doesn’t correlate with MHC type. Instead, there was a strong correlation with MUP type.

What, you cry, is MUP? These are “major urinary proteins”, which are known to be highly polymorphic in wild mouse populations — though not in lab mice — and which are also known to be very important in scent marking. Indeed, the only known function of MUPs is in scent marking. The lack of variability of MUPs in lab mice might have led to the use of MHC as markers instead in those studies, but in Hurst’s study MHC didn’t contribute to incest avoidance:

By contrast, MUP sharing had a strong and highly significant effect on the likelihood of successful mating (Table 1: model 3, p = 0.005; Figure S1). Specifically, there was no deficit when only one MUP haplotype was shared, but there were many fewer matings between mice that shared both MUP haplotypes (complete match) than expected under random mating conditions (Table 1: model 4, p < 0.002). … Mice thus avoid mating when shared MUP type reliably indicates very close relatedness.

Rodentia:Johnson's household book of nature, containing full & interesting descriptions of the animal kingdom. (New York : Johnson, c1880) Craig, Hugh, Editor.Incidentally, this is consistent with a recent paper from Peter Overath and Hans-Georg Rammensee.7 They looked for influences on urine odor in mice (try writing to your Mom and tell her that’s what you’re doing for your living, by the way, and see how long it takes before she starts talking about your cousin the investment banker) and didn’t find any influence of MHC:

… within the limits of the ensemble of components analysed, the results do not support the notion that functional MHC class I molecules influence the urinary volatile composition.

(However, there are non-volatile as well as volatile components to urine odor, so this isn’t definitive.)

MUPs are highly polymorphic in wild domestic mice, but are non-polymorphic (actually, basically non-existent) in humans. (In fact, MUPs are non-polymorphic even in Mus macedonicus, a mouse species closely related to M. musculus domesticus, but a species that doesn’t need as careful management of increeding because individuals normally disperse more. ) That means that MUPs can’t be a universal mechanism for inbreeding avoidance, so the work on MHC-linked mate choice in other species might still be valid. However, I still think the work on MHC and mate selection in humans is mostly pretty crappy unconvincing. Since the work in humans leans heavily on the assumption that MHC is important in mate selection in mice, that work can be looked at with an even more jaundiced eye now, I think.


  1. Yamazaki, K., Boyse, E. A., Mike, V., Thaler, H. T., Mathieson, B. J., Abbott, J., Boyse, J., Zayas, Z. A., and Thomas, L. (1976). Control of mating preferences in mice by genes in the major histocompatibility complex. J Exp Med 144, 1324-1335[]
  2. Piertney, S. B., and Oliver, M. K. (2006). The evolutionary ecology of the major histocompatibility complex. Heredity 96, 7-21.[]
  3. A review is here: Adv Genet. 2007;59:129-45. Genetic basis for MHC-dependent mate choice. Yamazaki K, Beauchamp GK.[]
  4. For example, Carroll, L.S., Penn, D.J., and Potts, W.K. (2002). Discrimination of MHC-derived odors by untrained mice is consistent with divergence in peptide-binding region residues. Proc. Natl. Acad. Sci. USA 99, 2187–2192.[]
  5. Sherborne, A., Thom, M., Paterson, S., Jury, F., Ollier, W., Stockley, P., Beynon, R., Hurst, J. (2007). The Genetic Basis of Inbreeding Avoidance in House Mice. Current Biology, 17(23), 2061-2066. DOI: 10.1016/j.cub.2007.10.041[]
  6. The Genetic Basis of Inbreeding Avoidance in House Mice
    Amy L. Sherborne, Michael D. Thom, Steve Paterson, Francine Jury, William E.R.
    Ollier, Paula Stockley, Robert J. Beynon, and Jane L. Hurst. Curr Biol. 2007 December 04; 17(23): 2061–2066. doi: 10.1016/j.cub.2007.10.041 []
  7. Röck F, Hadeler K-P, Rammensee H-G, Overath P (2007) Quantitative Analysis of Mouse Urine Volatiles: In Search of MHC-Dependent Differences. PLoS ONE 2(5): e429. doi:10.1371/journal.pone.0000429.[]
December 26th, 2007

Any excuse to say “axolotl”

Axolotl My last post talked about various species that have limited MHC diversity in their population. I got carried away and forgot to mention the paper that actually prompted that long ramble.

Axolotls are a fairly popular laboratory animal; they are salamanders, famous for their ability to regenerate limbs and for neotony — at least, they’re famous in the limited social circles where neotony can be a claim to fame. They’re also known (in even more limited circles) to be immunodeficient: While they do have all the components of an adaptive immune system, their antibody and T cell responses are remarkably slow and ineffective:1

Indeed, urodele amphibians do not react to soluble antigens. Their humoral immune responses are mediated by one unique class, the IgM, and are not anamnestic. A cellular co-operation has not been demonstrated during this humoral immune response; on the contrary, thymectomy, X-ray irradiation or corticosteroid treatment enhances the humoral immune response. Their MLR are usually very poor, and their transplantation reactions are chronic (21 days median survival time) …

(It may be worth noting that in the limited number of amphibians that have been studied to date — i.e. Xenopus — the larval form and the adult form have rather different immune systems; since the axolotl is permanently in a “larval” state, perhaps its immune system is also “immature”? However, the Xenopus larval immune system is apparently more effective than the axolotls’, so who knows.)

At any rate, it had been suggested that axolotl immune responses were defective because they have limited MHC diversity. Aside from the graft rejection, the logic of this link is not at all clear to me. Why would lack of diversity cause a slow antibody response in a single individual? The original paper says

The result of this non-diverse antigenic presentation could be a poor T-helper stimulation (considering the numher of different T clones stimulated), resulting in an extremely low cytokine synthesis and the absence of any cellular co-operation.

–which makes little sense to me; the authors seem to have confused population diversity with individual diversity.

Blogging on Peer-Reviewed ResearchAnyway, it’s all moot, because (and here after two posts I finally reach my original point) the limited diversity seems to be mainly because the original authors sampled laboratory axolotls, which are of course mostly derived from a handful of founders. A recent paper shows that wild axolotls — even though they are a small, critically-endangered population that went through a population bottleneck — have reasonably normal diversity.2 This paper is itself based on a small number of individuals — just nine — and although the sample size makes it hard to be sure I’d guess there is less diversity than “normal” species, but it’s clearly more than was originally claimed back in 1998:

Our results clearly overturn the supposition regarding lack of DAB polymorphism in A. mexicanum. Evidence for balancing selection summarized above also casts doubt on the more general proposition that this species is immunodeficient, although the small sample size limits the strength of this conclusion.


  1. Tournefier, A., Laurens, V., Chapusot, C., Ducoroy, P., Padros, M. R., Salvadori, F. et al. (1998). Structure of MHC class I and class II cDNAs and possible immunodeficiency linked to class II expression in the Mexican axolotl. Immunol Rev, 166, 259-277.[]
  2. Richman, A.D., Herrera, G., Reynoso, V.H., Mendez, G., Zambrano, L. (2007). Evidence for balancing selection at the DAB locus in the axolotl, Ambystoma mexicanum. International Journal of Immunogenetics, 34(6), 475-478. DOI: 10.1111/j.1744-313X.2007.00721.x[]
December 24th, 2007

MHC is diverse, except when it’s not

CheetahThe major histocompatibility complex is by far the most diverse region of vertebrate genomes; except when it isn’t. Since on the one hand it’s generally accepted that MHC genes are diverse in order to protect against pathogens, and on the other hand the precise mechanism driving diversity is controversial,1 it’s interesting to look at the species in which MHC is not particularly diverse. Are they particularly susceptible to pathogens? And is there an explanation for the lack of diversity?

I’ve mentioned a number of cases previously. Tasmanian Devils apparently have quite limited MHC diversity ,2 as do a number of other species including giant pandas,3 European beavers,4 Spanish ibex,5 and, perhaps most famously, cheetahs.

Most of these species are, as you can see, endangered. There are likely two important reasons for that: (1) Population bottlenecks lead to reduced genetic diversity, so endangered species (which have presumably been through a bottleneck relatively recently) are likely to have limited diversity; and (2) It’s easier to get funding to sequence the MHC from charismatic endangered species than from dirt-common starlings or what-not.

However, bottlenecks don’t entirely address the issue. I’ve previously mentioned the San Nicolas Island fox (Urocyon littoralis dickeyi), which has rather impressive MHC diversity despite undergoing drastic population bottlenecks within the past few hundred years.6

Although I believe the diversity at the MHC of these fox populations is still relatively low, it’s probably greater than some of the other populations I’ve mentioned here, such as the Tasmanian Devil, which have larger populations now and historically had more distant and less severe bottlenecks.

Cheetahs are the most famous example of an inbred population following a drastic population bottleneck; many people know that putatively-unrelated cheetahs can mutually tolerate skin grafts (a function of MHC similarity, of course),7 and lots of people also know that cheetahs are more susceptible to disease because of this limited diversity.

The problem with the latter “knowledge” is that as far I can find it’s not true — or at least, not demonstrated. It seems to be one of those circular things where the conclusion seems so obvious that it’s accepted with ridiculously inadequate evidence — whenever a cheetah gets sick, people nod wisely and point to the MHC, while when canine distemper wipes out half the lions in the Serengeti (leaving the cheetahs untouched)8 no one takes that as evidence for lion immunodeficiency. 9

Cottontop tamarinIn fact there’s ample evidence that populations with limited MHC diversity can do just fine out there. North American and European moose, 10 cotton-top tamarins, 11 and marmosets 12 have been claimed to have little MHC diversity. These species, like the cheetah, may indeed reflect limited populations a long time ago — moose apparently underwent a bottleneck around 10,000 years ago, about the same time as cheetahs; I don’t know about the other species — but the point is that no one is pointing to every sick moose and claiming that’s because of limited MHC diversity. What’s more, as the San Nicolas Island fox demonstrates, it’s possible to regenerate MHC diversity very fast — in hundreds rather than thousands of years; why didn’t cheetahs and moose do so? Probably because they didn’t need to, rather than couldn’t.

Limited MHC diversity is not an absolute barrier to species success. This should be pretty obvious, thinking about introduced species. There are over 100 million starlings in North America now, which arose from the 160 birds released just over 100 years ago in New York — how much MHC diversity could they possibly have? 13 Yet it was North American crows, not starlings, that were devastated by West Nile virus . Similarly, Australian rabbits, and rats around the world, have had huge populations arise from tiny numbers of founders, yet are not notorious for epidemics (except for artificially-introduced epidemics, in the case of Australian rabbits, and these are as remarkable for the rabbits’ resistance more than for their susceptibility).

So what’s the explanation? If pathogen pressure drives MHC diversity in almost all vertebrates, why do these vertebrates seem to do just fine with their limited diversity? Are these the exceptions that prove the rule, with hundreds of other introduced species disappearing because they didn’t have the right diversity? Are these species just the lucky ones, or just temporarily lucky and awaiting the right virus? I don’t know the answer, but if anyone has any ideas, let me know.


  1. Frequency-dependent selection or overdominant selection being the major two contenders; see here and links therein for more[]
  2. Siddle, H. V., Kreiss, A., Eldridge, M. D., Noonan, E., Clarke, C. J., Pyecroft, S. et al. (2007). Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. Proc Natl Acad Sci U S A. []
  3. Zhu, L., Ruan, X. D., Ge, Y. F., Wan, Q. H., & Fang, S. G. (2007). Low major histocompatibility complex class II DQA diversity in the Giant Panda (Ailuropoda melanoleuca). BMC Genet, 8, 29.[]
  4. Babik, W., Durka, W., & Radwan, J. (2005). Sequence diversity of the MHC DRB gene in the Eurasian beaver (Castor fiber). Mol Ecol, 14(14), 4249-4257.[]
  5. Amills, M., Jimenez, N., Jordana, J., Riccardi, A., Fernandez-Arias, A., Guiral, J. et al. (2004). Low diversity in the major histocompatibility complex class II DRB1 gene of the Spanish ibex, Capra pyrenaica. Heredity, 93(3), 266-272.[]
  6. Aguilar, A., Roemer, G., Debenham, S., Binns, M., Garcelon, D., and Wayne, R. K. (2004). High MHC diversity maintained by balancing selection in an otherwise genetically monomorphic mammal. Proc Natl Acad Sci U S A 101, 3490-3494. []
  7. O’Brien, S. J., Roelke, M. E., Marker, L., Newman, A., Winkler, C. A., Meltzer, D. et al. (1985). Genetic basis for species vulnerability in the cheetah. Science, 227(4693), 1428-1434.[]
  8. Guiserix, Micheline, Narges Bahi-Jaber, David Fouchet, Frank Sauvage, and Dominique Pontier. 2007. The canine distemper epidemic in Serengeti: are lions victims of a new highly virulent canine distemper virus strain, or is pathogen circulation stochasticity to blame? Journal of the Royal Society 4, no. 17 (December 22): 1127-34.[]
  9. I should say that I’m not saying wild-animal veterinarians or zoo vets do this — these are relatively lay people who I have talked with over the years. However, I’ve also seen papers that blithely talk about cheetahs being “unusually susceptible” — and what does “unusually susceptible” mean, anyway? Compared to some other species? What would be “usual”? — to diseases, citing single cases in zoo cheetahs as evidence — which is utterly ridiculous. E.g. Munson, Linda, Laurie Marker, Edward Dubovi, Jennifer A. Spencer, James F. Evermann, Stephen J. O’Brien, et al. 2004. SEROSURVEY OF VIRAL INFECTIONS IN FREE-RANGING NAMIBIAN CHEETAHS (ACINONYX JUBATUS). J Wildl Dis 40, no. 1 (January 1): 23-31. []
  10. Mikko, S. & Andersson, L. (1995). Low major histocompatibility complex class II diversity in European and North American moose. Proc Natl Acad Sci U S A, 92(10), 4259-4263.[]
  11. Gyllensten, U., Bergstrom, T., Josefsson, A., Sundvall, M., Savage, A., Blumer, E. S. et al. (1994). The cotton-top tamarin revisited: Mhc class I polymorphism of wild tamarins, and polymorphism and allelic diversity of the class II DQA1, DQB1, and DRB loci. Immunogenetics, 40(3), 167-176.[]
  12. Antunes, S. G., de Groot, N. G., Brok, H., Doxiadis, G., Menezes, A. A., Otting, N. et al. (1998). The common marmoset: a new world primate species with limited Mhc class II variability. Proc Natl Acad Sci U S A, 95(20), 11745-11750.[]
  13. No one seems to have looked, actually, and it would be interesting to have some numbers on this.[]
December 21st, 2007

Chicken MHC: Sloppy binding and evolutionary questions

13 day chick embryo
13 day chick embryo

There are a bunch of really interesting articles I want to talk about, but most will have to wait until after the holidays; with one sister and a brother visiting along with their assorted families, and my own Christmas responsibilities (including a three-year-old who confidently expects a motorcycle for Christmas: “But Santa SAID!”), I don’t have much time for detailed commentary.

One paper I do want to comment on, though, is
Koch, M., Camp, S., Collen, T., Avila, D., Salomonsen, J., Wallny, H.-J. et al. (2007). Structures of an MHC Class I Molecule from B21 Chickens Illustrate Promiscuous Peptide Binding. Immunity, 27(6), 885-899.

I may be mistaken, but I believe this is the first non-mammalian MHC class I molecule for which a crystal structure is available. (Actually, it’s not available, because the information they deposited in the Protein Data Bank is not yet released, even though the paper is out.) There are a number of interesting aspects about this molecule, but one is that it apparently violates one of the aspects of MHC that I considered (without thinking very much about it) to be a fairly fundamental characteristic. As such, it raises a question about MHC evolution that hadn’t previously occurred to me.

MHC class I binds to peptides, so that cytotoxic T lymphocytes can examine them. Mammalian MHC class I alleles (that have been tested) all bind to peptides with a broadly similar mechanism — much of the strength of the interaction comes from generic features that any peptide would have (the main chain) but there are also features that confer a certain amount of specificity to the interaction. Typically, a mammalian MHC class I molecule will bind to peptides that are about 9 amino acids long; two or three of those amino acids will snap, Lego-like, into an appropriate notch in the MHC. (See this post for more detail.) As a result, each MHC class I molecule can bind to many different peptide sequences, but only a limited subset of the large universe of 9-amino-acid long peptides. It’s this specificity that makes CTL epitope prediction possible. (However, it’s unusual but not extraordinary to identify peptides that bind, but don’t match the defined motif. For example, the exhaustive study of LCMV by Kotturi et al1 picked up two non-canonical peptides, out of the the 27 total known peptides for LCMV.)

Blogging on Peer-Reviewed ResearchThe interesting thing about this particular chicken MHC class I allele2 is that it seems to be much sloppier (“promiscuous”) than the mammalian alleles that have been looked at so far: “This molecule has a novel mode of peptide binding that allows peptides with completely different sequences to be presented to T lymphocytes.” Several other chicken alleles seem to also show promiscuous peptide binding, though other alleles probably are more conventional (or at least mammal-like) and have clear motifs.3

As a side note, this MHC class I allele is strongly associated with resistance to Marek’s Disease (a herpesvirus of chickens),4 and the authors here suggest that the promiscuous peptide-binding of B21 allows this allele to present more peptides from Marek’s disease, conferring greater resistance:

.. it is clear that many more peptides from representative Marek’s disease virus (MDV) genes are predicted to bind the BF2*2101 molecule than the MHC class I molecules from haplotypes such as B4, B12, and B15 that do not confer strong resistance to Marek’s disease. On this basis, it is likely that the promiscuous BF2*2101 molecule would have a greater chance of binding key protective peptide(s) than the fastidious MHC class I molecules from the other haplotypes.

Koch et al Fig 2
Chicken MHC BF2*2101

I am rather skeptical about this as the cause of resistance to Marek’s Disease. In the case of rapidly-mutating viruses like HIV, having a broad CTL response may well be correlated with resistance, but for herpesviruses, which are very stable genomically, even a single peptide epitope response can certainly confer protection (at least in mice); and it would be really surprising (even for a very “fastidious” allele) that there would be nothing at all (herpesviruses are big viruses, with lots of proteins) that binds. It’s possible, but I would look at other things first. 5

Back to my original issue. I’ve talked (ad nauseum!) about the evolution of MHC diversity. Very briefly6 MHC genes have by far the most alleles of any genes, and that is true for virtually every species that’s been examined — fish, birds, reptiles, mammals. There are two widely-accepted explanations for this diversity: Overdominance, or frequency-dependent selection. (Frequency-dependent selection seems to have a little more evidence on its side.) Both explanations depend on different MHC alleles presenting different peptide subsets from pathogens.

Now here’s my question, and in light of the chicken BF2*2101 data I don’t have an obvious answer for it. (This may be because of my tinsel-addled state, and maybe once the holidays are over the explanation will be obvious to me.) Why do MHC alleles bind to peptide subsets? What is the advantage of binding to subsets, compared to binding to all peptides? If MHC can bind promiscuously to many different peptides, then pathogens would not be able to escape from the MHC. For example, we would have much greater resistance to HIV, because there would be no escape mutants.

The explanation I used to have is that if MHC binds to all peptides, then there would be too many self peptides presented, and the process of negative selection in the thymus would eliminate too many T cells during their maturation. In other words, MHC alleles have to trade off the ability to present many pathogen peptides, in order to leave gaps in the self-reactive repertoire for T cells to actually develop.

But these B21 chickens can apparently get away with promiscuous peptide binding. How does that work? I am suddenly very curious about thymic selection in these chickens. What kind of TcR repertoire do they have? I wonder if they’ve looked.


  1. Kotturi, M. F., Peters, B., Buendia-Laysa, F. J., Sidney, J., Oseroff, C., Botten, J. et al. (2007). The CD8+ T-cell response to lymphocytic choriomeningitis virus involves the L antigen: uncovering new tricks for an old virus. J Virol, 81(10), 4928-4940. []
  2. BF2*2101[]
  3. Wallny H, Avila D, Hunt LG, Powell TJ, Riegert P, Salomonsen J, et al. Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens. Proceedings of the National Academy of Sciences of the United States of America. 2006 31;103(5):1434-9.
    and
    Kaufman J, Milne S, Gobel TWF, Walker BA, Jacob JP, Auffray C, et al. The chicken B locus is a minimal essential major histocompatibility complex. Nature. 1999 Oct 28;401(6756):923-925.[]
  4. Briles WE, Stone HA, Cole RK. Marek’s disease: effects of B histocompatibility alloalleles in resistant and susceptible chicken lines. Science (New York, N.Y.). 1977 14;195(4274):193-5.[]
  5. There is a little precedent for the suggestion, in that it’s been proposed that Epstein-Barr virus, a human herpesvirus, evolved to escape binding by a prevalent MHC class I allele in a particular population: de Campos-Lima, P. O., Gavioli, R., Zhang, Q. J., Wallace, L. E., Dolcetti, R., Rowe, M. et al. (1993). HLA-A11 epitope loss isolates of Epstein-Barr virus from a highly A11+ population. Science, 260(5104), 98-100 and several more recent studies. I am not overwhelmed by those studies either, although the latest (Midgley, R. S., Bell, A. I., McGeoch, D. J., & Rickinson, A. B. (2003). Latent gene sequencing reveals familial relationships among Chinese Epstein-Barr virus strains and evidence for positive selection of A11 epitope changes. J Virol, 77(21), 11517-11530. ) is the most convincing.[]
  6. See here, here, here, and here for more detail, if you care[]
November 5th, 2007

Testing overdominance in MHC: Can it be done?

Plasmodium in mosquito midgut
Malaria parasites in mosquito midgut

Why is it so hard to come up with a disproof (or a proof) of overdominant selection in MHC?

I’m starting kind of in mid-sentence here, because this is a continuation of a series of posts on MHC diversity. Briefly: The major histocompatibility complex region in vertebrates is extraordinarily diverse — a hundred times more variable (more alleles) than the average genomic chunk. Even populations that are otherwise inbred and lack diversity throughout their genome, rapidly evolve, or maintain, MHC diversity. There is clearly powerful evolutionary selection for this diversity, and there are several different explanations as to what this driver might be. The two most plausible explanations are frequency-dependent selection (in which rare alleles are selected simply because they are rare, and pathogens haven’t adapted to them) and overdominance, or heterozygote advantage (where individuals with diverse MHC regions, containing many alleles, are selected because they are more resistant to pathogens).

Overdominance was (as far as I know) the first mechanism put forward to explain MHC diversity. 1 The concept is a simple one: If one MHC allele protects against disease by binding a certain set of peptides, then two alleles should protect against more diseases by cumulatively binding a larger set of peptides. A heterozygous individual should be more resistant to pathogens than individuals that are homozygous for either single allele.

This simple concept, though, turns out to be very difficult to test rigorously. Most importantly, several of the different predictions between overdominance and frequency-dependent selection depend on how the population evolves, over time; but when trying to test predictions, we are usually looking, more or less, at a static snapshot of evolution. In the static state, it’s much harder to differentiate between the two possibilities: Is the allele diversity we see a stable diversity (consistent with overdominance) or is it a dynamic diversity, with different alleles gaining and losing advantage as they become more or less frequent (consistent with frequency-dependent selection)?

True overdominance is explicitly not dependent on allele frequency. 2 There are conditions (that are not true overdominance) in which heterozygotes will have a selective advantage over homozygotes, where the advantage is strictly dependent on allele frequency. Therefore … 3

overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote.

Blogging on Peer-Reviewed ResearchThere are a fair number of studies on more or less wild populations that have claimed to show evidence for overdominance, but few (if any) deal with the frequency problem. For that reason, most of the claims in the literature are at best consistent with overdominance, but are not proof of it.

A second complication is that individuals heterozygous at the MHC are quite likely to be heterozygous generally. How can specific effects of MHC heterozygosity be distinguished from a general heterozygote advantage? Again, this makes studies on wild populations hard to interpret cleanly.

There’s a third complication: Overdominance is most likely to be a factor in infections with more than one pathogen. 4

MHC-mediated resistance to a single pathogen is inherited as a dominant trait. This means that there will be no differences in susceptibility between a homozygote MHC allele or haplotype and a heterozygote carrying the focal allele plus a different one. Therefore, heterozygote advantage is difficult to detect in single pathogen challenges.

An exception to this might be when there’s technically a single pathogen, but it’s highly antigenically diverse — the obvious example being HIV, which mutates rapidly and regularly throws out antigenic variants during the course of infection. It’s interesting, then, that HIV infection is one of the situations where heterozygote advantage has been observed, 5 though I don’t think population allele frequency was taken into account in these studies. On the other hand, malaria is antigenically diverse as well, but experiments have not shown overdominance in that case.6

So we’re left with the difficult situation where you need to have fairly large numbers and multiple generations, in order to detect selection; yet you probably can’t use most natural populations to strictly the test the theory. Setting up a large and relatively diverse, yet well-controlled, lab animal population, and then infecting with multiple pathogens; or following a reasonably well-controlled field population; is a daunting task.

In the next post in this series I’ll mention a few cases where this has been done.


  1. Doherty, P. C., and Zinkernagel, R. M. (1975). A biological role for the major histocompatibility antigens. Lancet 1, 1406-1409.[]
  2. At least, that’s how I understand it; and I repeat that I’m not an expert. Anyone knowledgeable about this, feel free to jump in.[]
  3. Lipsitch, M., C. T. Bergstrom, and R. Antia. 2003. Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures. BMC Med Genet 4: 2. []
  4. Wegner, K. M., M. Kalbe, H. Schaschl, and T. B. Reusch. 2004. Parasites and individual major histocompatibility complex diversity–an optimal choice? Microbes Infect 6: 1110-1116. []
  5. For example, Carrington, M., G. W. Nelson, M. P. Martin, T. Kissner, D. Vlahov, J. J. Goedert, R. Kaslow, S. Buchbinder, K. Hoots, and S. J. O’Brien. 1999. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 283: 1748-1752. []
  6. Wedekind, C., Walker, M., and Little, T. J. (2005). The course of malaria in mice: major histocompatibility complex (MHC) effects, but no general MHC heterozygote advantage in single-strain infections. Genetics 170, 1427-1430.[]
October 15th, 2007

MHC molecules: The sitcom

I talk a lot about MHC molecules, especially MHC class I. Something I haven’t mentioned much is that MHC class I is just one member of a huge extended family of structurally-related molecules. MHC class I and class II are the “classical” MHCs (the Archie Bunker and Edith of histocompatibility complexes); but there’s a long list of spin-off “non-classical” MHCs as well. 1 Many of them are solid citizens that conscientiously perform immune-related tasks, but there are also some whacky neighbours that run around doing zany stuff.

Last week I covered the structure of MHC class I (the Bjorkman structure of HLA-A2). For comparison, here’s a superficial glance at the comparative anatomy of a number of classical and non-classical MHCs. The structural similarity is often pretty remarkable, considering the variety of things they do — iron-regulatory molecules, odor detection, and antigen presentation, for a start! In general, the two things I look at structurally are whether they bind to β2-microglobulin, and what their equivalent of a peptide-binding groove looks like. (Because I’m mostly emphasizing the peptide-binding groove in these images, β2-m is often hard to see, hidden as it is underneath the floor of the groove. If you squint, you can see it — it’s colored blue in the ribbon structures — except for ZAG and MHC class II, which don’t have it at all.)

The molecules (along with their Protein Database accessions, and the Pubmed ID of the article describing their structure) I’ve chosen are as follows:

MHC Family Role Groove binds β2-m PDB PMID
HLA-A2 (MHC class I) Classical Antigen presentation Peptide Yes 2GTW 10843695
HLA-DR (MHC class II) Classical Antigen presentation Peptide No 1DLH 8145819
HLA-E Non-classical NK cells recognition Peptide Yes 1MHE 9660937
CD1d Non-classical Non-classical T cell recognition Lipglycans Yes 2GAZ 16982895
FcRn (Neonatal Fc receptor) Non-classical Neonatal Fc receptor Nothing Yes 1EXU 10933786
ZAG (Zinc-α-2-Glycoprotein) Non-classical Lipid catabolism Something (what?) No 1ZAG 10206894
HFE Non-classical Iron regulation Nothing Yes 1A6Z 10638746
Qa2 Non-classical Immune regulation? Peptide Yes 1k8d 11738047
M10.5 Non-classical Odor receptor chaperone? Nothing? Yes 1ZS8 16089503

First of all, let’s look at some of the guys who bind stuff in their groove (click on each image for a larger version). Here we are, looking “down” from the top of the molecule (as the T cell would looks at HLA-A2, for example) — a surface representation of the MHC molecule with its ligand shown in green. In the lower row, I show the ligand all by itself, as it sits in the groove.

HLA-A2 HLA-DR HLA-E Qa-2 CD1d
HLA-A2 peptide HLA-DR peptide HLA-E peptide Qa-2 peptide CD1d Ligand
MHC class I MHC class II HLA-E Qa-2 CD1d

The odd one out is CD1d, which binds non-peptides — here, a Mycobacterium tuberculosis phosphatidylinositol mannoside. The CD1 binding groove is much deeper and more hydrophobic than that of the peptide-binders’: a tunnel, in places, rather than a groove. Another difference is between MHC class II (HLA-DR in this picture) and most of the other peptide binders; MHC class II peptides can flop out over the edges of the groove (whereas the other guys bury the ends of the peptide) — so MHC class II peptides can be quite a bit longer than the 9 or so amino acids that other MHCs can handle.

Next let’s look at the rest of the crew — the ones that don’t bind peptides, or perhaps anything, in their grooves. For ease of comparison I’m including MHC class I (HLA-A2) again, at the left. In the lower row, I’m showing the same views as ribbon diagrams.

HLA-A2 FcRn ZAG HFE M10.5
HLA-A2 FcRn ZAG HFE M10.5
MHC class I FcRn ZAG HFE M10.5

(Notice that ZAG doesn’t have any β2-m associated with it, but nevertheless forms a very nice binding groove.) You can see very easily for FcRn that the groove is completely screwed up: it’s collapsed and filled in, so there’s nowhere for a peptide, or even a much smaller molecule, to fit in. It’s harder to see for HFE, but the groove there is still too narrow to bind peptides (though it’s not completely collapsed). ZAG and M10.5 are much more interesting. Both have grooves that could actually hold something, but we don’t know what (if anything) they bind.

ZAG binding With ZAG, something actually co-crystallized with the molecule! –but they don’t know what it is. ” … Instead of a peptide, the ZAG groove contains an as yet unidentified ligand that cocrystallizes with the protein.”2 (The figure at right clearly shows something undefined in the ZAG binding groove.)

M10.5 was equally interesting (in the “incident of the dog in the night” sense) — because, even though the groove could actually potentially hold a peptide3 nothing at all was in the crystallized groove. This never happens with classical MHC molecules, which always find something to bind there. But the groove seems (biochemically as well as structurally) to be a complete blank.

M10.5 has an open groove more similar to the peptide-binding classical class I MHC molecules than the non-peptide-binding homologs. … M10.5 electron-density maps show no ordered density corresponding to a peptide … We conclude that the M10.5 groove does not contain a single defined peptidic or non-peptidic occupant or a mixture of compounds with a similar conformation.4

Given that M10.5 seems to be involved in odor recognition — Could it be a pheremone binder? Sadly (because that would be a great story), probably not: “The hydrophobic nature of most pheromones is not complementary to the charged character of the groove, which is much larger than a single pheromone molecule.”

Their final guess is that maybe M10.5 chaperones a V2R — a different receptor:

In this hypothesized scenario, newly synthesized M10 and V2R proteins would be stabilized through mutual interactions with a V2R loop in the M10 groove, enabling the M10 to escort the V2R to the cell surface, rationalizing the observation that M10 proteins are required for cell surface expression of V2Rs. 4

Anyway, there’s a field guide to some of the MHC family. There are many, many more, each with its own beautiful plumage and habitat, but these cover most of the general variations in structure you’ll see.


  1. Actually, many of the “non-classicals” are just about as ancient as the “classical” MHCs, so it’s not really clear which is the spin-off. But I liked the metaphor.[]
  2. Sanchez, L. M., A. J. Chirino, and P. Bjorkman. 1999. Crystal structure of human ZAG, a fat-depleting factor related to MHC molecules. Science 283: 1914-1919. []
  3. “We conclude that the M10.5 groove can accommodate a peptide that adopts a class I MHC-binding conformation, but that differences between the A and F pocket regions of M10.5 and classical class I MHC molecules would require a peptide bound in the M10.5 groove to be anchored differently than a class I MHC-binding peptide”[]
  4. Olson, R., K. E. Huey-Tubman, C. Dulac, and P. J. Bjorkman. 2005. Structure of a pheromone receptor-associated MHC molecule with an open and empty groove. PLoS Biol 3: e257.[][]
October 14th, 2007

T cell skewing?

HLA-A
HLA-A
HLA-B
HLA-B

As a scientist, I’m comfortable with being wrong most of the time. I’m used to it. But when I make a throwaway comment in a blog and get smacked down in PNAS the following week … well, it seems like overkill, you know?

It’s not quite that bad. A couple weeks ago I was talking about the possibility that tuberculosis-specific T cells were mainly restricted by HLA-B as proposed by Lewinsohn et al.1 I wasn’t very enthusiastic about the idea, suggesting that the skewing they saw was probably just chance. I did admit that there was some biological plausibility to the possibility, but I was mainly thinking about some kind of allele-specific immune evasion. Now, Harari et al argue in the latest PNAS that there is a fundamental difference between CTL restricted by HLA-B, and those restricted by HLA-A.

HLA-A and HLA-B are two distinct major histocompatibility class I genes. There are three classical class I genes in humans (and many other species), with A and B being the most important for T cell recognition. (Here is a map of the human MHC region — HLA-A is way over to the left, in among a bunch of non-classical MHC class I genes, while HLA-B and C are closer to the middle, to the right of the pinkish-shaded Class I region.) Each of HLA-A, B, and C has many different alleles among the human population (HLA-A, B, and C are not alleles of each other, a mistake a lot of people make — they are independent, if linked, genes.) HLA-A and B are typically around 80% identical at the protein sequence level (different alleles within A or B are around 90-95% identical), they look pretty much identical structurally2, and in general they’re hard to tell apart. The only things that I can think of where HLA-A and B differ is that (1) HLA-B has been evolving faster, and (2) HIV is more likely to be controlled by HLA-B than A alleles — something that I, and I think just about everyone, put down to the allelic differences (i.e. different viral peptides being bound) rather than any general HLA-A vs. B distinction. So far as I can remember, no one has ever suggested that they have functional differences as far as T cells go.

Recently it’s been suggested that CTL fall into two broad categories, “polyfunctional” and “only effector”, and that the former category is more important for controlling viruses3. Harari et al4 are now suggesting that these different categories are more associated with HLA-B or -A, respectively:

Polyfunctional CD8 T cell responses, also including IL-2 production and Ag-specific proliferation, are predominantly driven by virus epitopes restricted by HLA-B alleles. … Conversely, HLA-A-restricted epitopes are mostly associated with “only effector” IFN–secreting, with cytotoxicity, and with the lack of IL-2 production and Ag-specific proliferation. … Thus, the functional profile of the CD8 T cell response is strongly influenced by the extent to which there is stimulation of polyfunctional (predominantly restricted by HLA-B) versus only effector (restricted by HLA-A) T cell responses.

It’s an interesting idea. However, their data are not really striking — to me at least. The differences they show in polyfunctional CTL have HLA-A restricting, for example, 0.1% to HLA-B’s 0.25% of the population — not so exciting. The stats they show have P values that are officially statistically significant but aren’t really overwhelming — 0.03, 0.02 — and I question whether the stats are done correctly in all cases (e.g. in one part of Figure 3 where there are overlapping error bars and an N of 5, but they show a P value of 0.005, which just doesn’t look right, unless I’m missing something). They do call the effect “skewing”, which is a conservative claim, so I’ll tentatively accept that far. But I’d really like to see this replicated by a different group, and extended in a larger dataset, before I am completely convinced.


  1. Immunodominant Tuberculosis CD8 Antigens Preferentially Restricted by HLA-B. Lewinsohn, D. A., Winata, E., Swarbrick, G. M., Tanner, K. E., Cook, M. S., Null, M. D., Cansler, M. E., Sette, A., Sidney, J., and Lewinsohn, D. M. (2007). PLoS Pathog 3, e127. []
  2. The ribbon diagrams here are of HLA-A*1101 and HLA-B*2709 []
  3. Reviews: Harari, A., Dutoit, V., Cellerai, C., Bart, P. A., Du Pasquier, R. A., and Pantaleo, G. (2006). Functional signatures of protective antiviral T-cell immunity in human virus infections. Immunol Rev 211, 236-254. and Harari, A., Dutoit, V., Cellerai, C., Bart, P. A., Du Pasquier, R. A., and Pantaleo, G. (2006). Functional signatures of protective antiviral T-cell immunity in human virus infections. Immunol Rev 211, 236-254. []
  4. Harari, A., Cellerai, C., Bellutti Enders, F., Kostler, J., Codarri, L., Tapia, G., Boyman, O., Castro, E., Gaudieri, S., James, I., John, M., Wagner, R., Mallal, S., and Pantaleo, G. (2007). Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype. Proc Natl Acad Sci U S A 104:16233-1623 []
October 11th, 2007

Creepy cancer post of the month

Tasmanian DevilThere’s been some buzz about the recent paper on the contagious tumor of Tasmanian devils.1 Clearly the thing is a ghastly disease that’s threatening the Devils with extinction — but from a technical viewpoint, the paper last year on a different transmissible tumor was much more interesting.

The other tumor I’m talking about is canine transmissible venereal tumor (CTVT), and the paper is:
Murgia, C., Pritchard, J. K., Kim, S. Y., Fassati, A., and Weiss, R. A. (2006). Clonal origin and evolution of a transmissible cancer. Cell 126, 477-487 .

Most people haven’t heard of CTVT. (I had, but then I’m a veterinarian originally.) It’s just what it sounds like from the name: A sexually-transmitted cancer that spreads between dogs. (And it does seem to be a pure cancer, not a virus that causes cancer.) Until the Tasmanian Devil contagious tumor, that made CTVT essentially unique; no other tumors are known to be transmissible. (Actually, the Tasmanian Devil paper cites a tumor of Syrian hamsters2 that is apparently transmissible — but I’d never heard of that before, and I’m not clear that it still exists or if it has died out in the past 40 years.)

It turns out that the Tasmanian Devil tumor apparently can spread because it is essentially a self graft. Apparently Devils are highly inbred, and show very little polymorphism at the major histocompatibility complex (MHC) region. As I’ve been pointing out (ad nauseum) lately (see here and the links therein) this is really unusual, as in most vertebrates the MHC region is normally by far the most diverse region of the genome. The MHC region is important in graft rejection — duh, that’s what “histocompatibility” means. Essentially, then, it seems that the Devil tumor can “take” on virtually any other Devil, because it’s recognized as “self” MHC. 3 This is interesting, of course, but there’s nothing surprising about it. Endangered species are commonly inbred — inbred animals lack variation at the MHC4 — and matching MHC allows grafts to take. This is all known.

The canine tumor story is very different. This tumor does not match the recipient dogs’ MHC. The same tumor can infect unrelated dogs, with virtually any MHC; Murgia et al looked at tumor-bearing dogs from around the world (“None of the host dogs showed close relatedness to any of the others, consistent with the fact that they came from three locations in Europe, Asia, and Africa and were mongrels”), and they all carried the same tumor. So why is CTVT not rejected as an allograft?

CTVT phhylogeny Most, if not all, tumors in humans show evidence of having been edited by the immune system. That is, the tumors have altered their MHC expression in some way that probably allows them to evade the immune system. That’s one reason that tumors themselves are not rejected. (Presumably, there are many more proto-tumors that arise during our lifetime, that fail to alter their MHC and are destroyed by our immune systems before there are more than a half-dozen abnormal cells. We only see the successful ones.) CTVT has done this, as well, and expresses very low (but detectable) levels of MHC. Also, again like many other tumors, CTVT expresses an immune modulator, TGFβ. 5 Murgia et al suggest that these are enough to make the tumor invisible to the immune system and allow it to engraft.

But I’m not at all convinced. These changes — low MHC expression, high TGFβ — are very common, if not universal, tumor adaptations, yet CVTV is unique — extraordinarily, spectacularly, unique — in its ability to spread and persist within a highly outbred species. CVTV has persisted for hundreds, if not thousands or even tens of thousands of years:

The precise date when CTVT first occurred is difficult to determine. From its indistinguishable histopathology and its ability to grow as an allograft, it is likely that Novinski (1876) studied the same clone, and CTVT could have become established centuries before this date. Our analysis of divergence of microsatellites indicates that the tumor arose between 200 and 2500 years ago. Whether this time period represents the time the tumor first arose or whether it represents a later bottleneck in the tumor’s dispersion as a parasite cannot be resolved. While this estimated date indicates a relatively recent evolutionary origin, CTVT represents the oldest known mammalian somatic cell in continuous propagation, having undergone countless mitoses and host-to-host transfers.

In fact, the tumor may even predate dogs. The figure to the right from Murgia et al shows the relationship between the tumor and dogs and wolves (click for a larger version)– the thing is even closer to wolves than it is to dogs.

Frankly, the thing is damn creepy, and I kind of hope I’m right and there’s much more to its ability to persist than the really very common changes that have been pointed at so far, because I wouldn’t want to think that every tumor was capable of this kind of behaviour. Whatever it is, though, is more novel and scientifically interesting than the Tasmanian Devil tumor. Hopefully the Devil tumor is easier to deal with than the canine one.


  1. Siddle, H. V., Kreiss, A., Eldridge, M. D., Noonan, E., Clarke, C. J., Pyecroft, S., Woods, G. M., and Belov, K. (2007). Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. Proc Natl Acad Sci U S A 104:16221-16226 []
  2. Copper, H. L., Mackay, C. M., And Banfield, W. G. (1964). Chromosome Studies Of A Contagious Reticulum Cell Sarcoma Of The Syrian Hamster. J Natl Cancer Inst 33, 691-706.[]
  3. This is apparently the same mechanism as with the Syrian hamster transmissible tumor; hamsters are highly inbred as well. Streilein, J. W., and Duncan, W. R. (1983). On the anomalous nature of the major histocompatibility complex in Syrian hamsters, Hm-1. Transplant Proc 15, 1540-1545.[]
  4. Though not inevitably. The San Nicolas Island foxes I used as an example were inbred, yet had significant MHC diversity.[]
  5. The Devil paper states that CTVT also “up-regulates nonclassical class I expression to avoid the natural killer cell response” — but I don’t know where they get this from. It’s not in the reference they cite, and I can’t find evidence for it anywhere (but that doesn’t mean it’s not correct) []