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Cheetah genetic diversity revisited Hilary Miller Feb 04

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ResearchBlogging.org

Another chapter has been added to the story of genetic variation in the cheetah, with a paper out in next month’s Molecular Biology and Evolution journal giving a detailed description of variation at key immune genes in the species.  I first became familiar with the cheetah story as a PhD student when I was studying genetic diversity in the black robin.  At the time the cheetah was something of a poster child for the perils of low genetic variation, but this most recent paper suggests that their immune system is not as genetically invariant as first thought, and they may not be so vulnerable to disease after all.

Back in 1985, Stephen O’Brien and colleagues at the National Cancer Institute in Maryland reported extremely low levels of genetic variation in cheetahs - so low in fact, that skin grafts from one animal were not rejected by another, a sign that their immune systems are genetically identical.  This lack of genetic variation was attributed to a decline in population numbers at end of last ice age, plus more recent declines that have led to inbreeding.  The species appeared to be highly susceptible to feline infectious peritonitis (FIP), a disease which had decimated some captive populations, and attempts to breed cheetahs in captivity were hampered by poor reproductive success and apparently high levels of sperm defects.  O’Brien and colleagues attributed these problems to their extremely low levels of genetic variation, and the species quickly became a classic example of the perils of inbreeding. 

The cheetah (Acinonyx jubatus) is found mainly in southern and eastern Africa

However, in the early 1990’s, field studies questioned whether the cheetah’s survival in the wild was being compromised by their lack of genetic variation.  In a commentary in Science in 1994, Caro and Laurenson pointed out that disease susceptibility and breeding problems only appeared to be an issue for captive cheetahs, and that predation of cubs, habitat destruction and persecution by humans were greater threats to the species.

Still, a lack of variation at immune genes is still an important potential threat to any species, as shown by the case of the Tasmanian devil, where low variation at Major Histocompatibility Complex, or MHC genes, has allowed Devil Facial Tumour Disease to spread unchecked throughout the population.  MHC genes are key part of the immune system in vertebrates as they code for the molecules that distinguish self from non-self, and instruct the immune system to respond when foreign proteins (i.e. from a pathogen) are detected.  High diversity at MHC genes plays an important role in protecting populations from disease epidemics as it allows wide array of foreign pathogens to be resisted, and means that some individuals are likely to be more resistant to new diseases than others (instead of all individuals being equally susceptible).  

The skin graft experiments of the mid-1980s indicated that cheetahs have virtually no MHC variation, because of the absence of an immune response when skin from one cheetah was grafted onto another.  However the disease susceptibility seen in captive cheetahs doesn’t seem to extend to cheetahs in the wild – a recent study on wild cheetahs in Namibia  found that the population was generally in good health, and that many individuals carried antibodies to a range of diseases (suggesting they had been exposed to those diseases) but no clinical symptoms of acute disease.  These results suggest that wild cheetahs may have more MHC diversity than the captive population, and that their immune systems work just fine. 

Somewhat surprisingly, only a couple of studies in the 26 years since the skin-graft study was published have actually attempted to quantify cheetah MHC diversity.  These studies found low diversity and seemed to corroborate the skin-graft results, but either used low resolution methods to measure MHC diversity or had small sample sizes, so weren’t particularly conclusive.

This latest study, by Aines Castro-Prieto, Simone Sommer and colleagues at the Leibniz Institute for Zoo and Wildlife Research in Berlin, takes a much more comprehensive approach to measuring genetic variation.  Castro-Prieto and colleagues determined how many different alleles are present at two types of MHC genes in 149 Namibian cheetahs.  They found more variation than was previously described for the first type (Class I MHC), but not for the second type of gene (Class II MHC).  The number of different MHC alleles counted in the Namibian cheetahs is still quite low compared with what is seen in other big cat populations, so it appears that cheetahs have lost a fair amount of variation as their numbers have declined.  However, the amount of DNA sequence variation among the alleles is fairly high – that is the different alleles code for proteins that are quite different from one another in their sequence, so overall they can probably recognise a wide array of foreign proteins. 

Castro-Prieto and colleagues also found hallmarks of selection on the MHC sequences, and speculate that selection, driven by exposure to a range of pathogens over thousands of generations, has led to highly divergent alleles being retained.  However, they point out that although wild cheetahs appear to have enough MHC variation to respond to common infectious diseases, they may still be at risk from new emerging diseases, as the few remaining alleles might not be sufficient to be able to recognise and ward off an entirely new pathogen.   

This study provides some much-needed data on immune variation in cheetahs, and it seems that the idea of the cheetah being a classic case of disease vulnerability associated with low genetic diversity is looking a little shaky.  As Castro-Prieto et al point out, “the long term survival of free-ranging cheetahs in Namibia seems more likely to depend on human-induced rather than genetic factors”.

Reference: Castro-Prieto A, Wachter B, & Sommer S (2010). Cheetah paradigm revisited: MHC diversity in the world’s largest free-ranging population. Molecular biology and evolution PMID: 21183613

Further reading:

For an excellent write-up on why genetic diversity is important (and more stuff about cheetahs), see this (fairly old) post on Mauka to Makai .

O’Brien SJ, Roelke ME, Marker L, Newman A, Winkler CA, Meltzer D, Colly L, Evermann JF, Bush M, Wildt DE (1985) Genetic basis for species vulnerability in the cheetah. Science 227: 1428-1434

Caro TM, Laurenson MK (1994) Ecological and genetic factors in conservation: a cautionary tale. Science 263: 485-486.

Thalwitzer S, Wachter B, Robert N, Wibbelt G, Muller T, Lonzer J, Meli ML, Bay G, Hofer H, Lutz H (2010) Seroprevalences to Viral Pathogens in Free-Ranging and Captive Cheetahs (Acinonyx jubatus) on Namibian Farmland. Clin. Vaccine Immunol. 17: 232-238.

Tasmanian devil facial tumour disease: too good a match for the immune system Hilary Miller Apr 13

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ResearchBlogging.org
A central premise in conservation genetics is that high genetic diversity is good for a species’ continued survival, and low genetic diversity is bad. This seems intuitively obvious (after all, we all know that you shouldn’t marry your cousin) but actually finding examples in nature where we can say for sure that low genetic diversity has contributed to a population’s demise is difficult.   

However, the recent decline of tasmanian devil populations due to disease provides an excellent example of the perils of low genetic diversity.  Wild devil populations in eastern Tasmania have been decimated in recent years by devil facial tumour disease (DFTD).  This nasty disease is a transmissible cancer spread by biting, and causes large tumours to form around the mouth, interferring with feeding and eventually causing death.  Kathy Belov’s group at the University of Sydney has been studying the genetic basis of DFTD susceptibility in devils and has found that a lack of variation in immune system genes is responsible for the spread of the cancer in some populations.    

Tasmanian devil with facial tumour disease (photo: Menna Jones)

Belov’s group has been studying the genes of the Major Histocompatibility Complex, or MHC.  MHC molecules are a crucial part of the immune system in vertebrates, as they are responsible for recognising foreign invaders and mounting an immune response.  MHC molecules are also an important part of the process of self/non-self recognition that prevents the immune system attacking the body’s own cells.  MHC genes are normally highly variable in populations, with a large number of different alleles (or variants) for each gene.  This variability allows for a wide array of foreign pathogens to be resisted and accounts for differences in disease resistance among individuals.  Thus, populations with low or no variation at MHC genes are potentially susceptible to disease epidemics, as all individuals in the population will be equally susceptible to novel diseases.   

Devil populations in eastern Tasmania have low levels of genetic diversity due to reductions in population size over the last 150 years.  DFTD is so virulent in these populations because the tumours have the same MHC type as healthy devil cells.  Being an infectious cancer, transmission of DFTD between individuals is a bit like a skin graft or organ transplant. If the tissue’s MHC type matches, the transplant is accepted, if not it is rejected.  Because the MHC types of the tumour and the devil match, DFTD cells are not recognised as foreign so no immune response is mounted.  And because of the low genetic diversity, all devils in the population have similar MHC types meaning the disease can easily spread from one individual to another. 

DFTD has spread rapidly throughout eastern Tasmanian populations, causing a 90% decline in total devil numbers.  However, a population at West Pencil Pine in northwestern Tasmania has much lower prevalence of DFTD, suggesting this population harbours animals that are resistant to the disease.  New research by Belov’s lab published in Proceedings of the Royal Society of London last month shows that these populations have differences in their MHC makeup that appear to allow them to resist the disease. 

Here the story gets a little (more) complicated: Tasmanian devils have multiple MHC genes (up to 7 genes each), which fall into two groups on the basis of their DNA sequence.  The tumour cells have both group 1 and group 2 variants, as do the individuals from the susceptible eastern populations.  However the northwestern populations harbour a greater diversity of MHC types, and many individuals from these populations have MHC types which have only either group 1 or group 2 sequences.  None of these individuals have succumbed to DFTD, suggesting they are resistant to the disease.  Belov’s group proposes that in individuals with only group 1 sequences, the immune system will recognise the group 2 sequences on the tumour as foreign and resist it (and vice versa for individuals with only group 2 sequences).   This has yet to be tested in practice, as it is obviously difficult to get permission to infect an endangered species with a deadly disease.  However, these findings are promising for the continued survival of the species and may have a significant impact on their conservation management.

Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ, Pyecroft S, Woods GM, & Belov K (2007). Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. Proceedings of the National Academy of Sciences of the United States of America, 104 (41), 16221-6 PMID: 17911263

Siddle, H., Marzec, J., Cheng, Y., Jones, M., & Belov, K. (2010). MHC gene copy number variation in Tasmanian devils: implications for the spread of a contagious cancer Proceedings of the Royal Society B: Biological Sciences DOI: 10.1098/rspb.2009.2362

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