The Evolution & Medicine Review

Diseases, human history and co-evolution with pathogens

Peter Gluckman and Tatjana Buklijas

Liggins Institute, The University of Auckland, New Zealand

Leprosy and kuru may at first glance seem to be diseases with little in common, except, perhaps, their large historical significance, declining prevalence and the fact that both affect only humans. Although leprosy is chronic and poorly contagious, in medieval Europe and the Middle East the appearance of the sick and the stigma of the disease provoked so much fear that unprecedented social strategies were invented to exclude them from communities. In the West, leprosy began to disappear by the 1700s-possibly because of the plague’s selective effect against the immunologically weak. Yet long after Hansen’s description of Mycobacterium leprae in 1873 and despite the availability of effective treatment, this obligatory parasite adapted almost exclusively to humans remains prevalent. Kuru, in contrast, probably first appeared in the early twentieth century within the Fore linguistic group in the highlands of New Guinea who consumed their dead relatives at mortuary feasts. As the ritual was mostly performed by women and children of both sexes, men remained mostly unaffected. By the time the physician and anthropologist D. Carleton Gajdusek  first described the disease in the Western medical press (1957), the numbers of affected were falling because of the decline in cannibalism. But the real sensation came a few decades later when kuru was shown to be transmitted through infectious protein particles that were named prions. Prion diseases arise from an interaction between the normal prion protein (PrPc) found on cell membranes and its infectious isoform (PrPsc) which is able to convert PrPc into the diseased form through conformational change and aggregation.

Two recent studies of these diseases provide illuminating insights into human evolution. In the case of leprosy, a comparative genomic and phylogeographic analysis by Marc Monot and colleagues used extant and extinct sources of M. leprae genetic material to build a picture of the spread and evolution of its strains worldwide, as well as to raise the question of how this microbe became a human pathogen (1). Following earlier sequencing of the Tamil Nadu strain of M. leprae, the team sequenced and compared strains from Brazil, Thailand and the U. S., selecting 84 informative SNPs. Then, the informative SNPs were tested in 400 isolates from 28 countries supplemented with ancient M. leprae DNA obtained from European and Middle Eastern medieval bone samples. This comprehensive survey confirmed an earlier proposal that leprosy originated with early humans in East Africa (2), then spread into Europe and Middle East  from where it was introduced into Asia (through the southern coast, and along the Silk Road, in the opposite direction from the plague) as well as into West Africa. The origin of American isolates can be traced back to European immigrants, rather than migrations across the Bering Straits.

A puzzle that remains is the discrepancy between the low genetic diversity of M. leprae (99.995% sequence identity among the four strains sequenced) and the exceptionally large number of pseudogenes. Furthermore, the period at which pseudogene formation – an indicator of radical change in the lifestyle of the organism, such as going from free living to parasitism – is thought to have occurred does not fit with human evolutionary history.  If an ancestor of M. leprae infected an early hominin or primate and then was transmitted vertically, we would expect more genetic diversity. A competing hypothesis suggests that while the genome decay of M. leprae is indeed ancient, human parasitism as a lifestyle for this microbe is not, and that an ancestral form of M. leprae infected an invertebrate host (perhaps an insect) that acted as a vector. The question remains open and addressing it will require combining the tools from genetics, palaeomicrobiology, as well as human and primate evolutionary history.

The leprosy study, thus, complements the study of human evolutionary history, as well as recent large genetic population maps, in providing more information on human migrations and contacts. The work on kuru, in contrast, focuses on recent evolution of resistance to a pathogen.   Mead and colleagues performed genetic, clinical and genealogic assessment of over 3,000 persons from Papua New Guinea:  709 who had participated in cannibalism (of which 152 subsequently died) and healthy individuals from the Eastern Highlands (2,053) and from more distant parts of the country (313) (3).  The study first sequenced PRNP (the prion protein gene) in 112 patients with kuru, 142 women born before 1950 and 282 young persons from affected regions, and then went on to genotype codons 127 and 129 of the gene in the entire patient and control populations. Homozygosity at codon 129 of PRNP was previously known to predict higher susceptibility to kuru, but the new study found that heterozygosity at codon 127 (127V polymorphism) is associated with strong and possibly complete resistance to kuru (as it was not found in a single kuru patient) and confirmed that heterozygosity at 129 entailed a level of resistance (as 129MV was associated with elderly unaffected women from exposed regions and 129MM and 129VV were found in young kuru patients). The resistance may be explained by the changed conformation of the PrP molecule.

Further evidence for the selective effect of kuru was provided by deviation from Hardy-Weinberg equilibrium at codon 129 for the population born before 1960 and especially among elderly women from exposed areas. Among the parents of 127V carriers, just 1 out of 36 was recorded as having died of kuru, compared to 33 out of 218 in the matched 127G pedigrees. Furthermore, it was found that among persons born before 1960, 127V alleles were more likely to be found in otherwise susceptible 129MM homozygotes than in 129MV heterozygotes. As 127V and 129M were in equilibrium in the population born after 1960, it seems that 127V confers resistance on otherwise susceptible 129MM homozygotes.

The authors argue that there has been recent selection for the resistance alleles. Although an alternative explanation may be offered, that 127V is associated not with resistance but with low-penetrance, late-onset or recessive prion disease, which might have triggered the epidemic, other evidence-the poor transmissibility of inherited prion diseases, as well as the lack of correspondence between the ‘127V area’ and the geographic origins of kuru according to oral history-does not support it. The geographic restriction of the 127 polymorphism indicates a recent common ancestor about 10 generations ago, slightly predating the onset of the kuru epidemic. This fits with the thesis that it was the selection pressure of kuru that increased the frequency of the 127V allele, and indeed started a complex selection process of maximizing heterozygosity at 127V against homozygosity at 129. As the authors conclude,‘the relative viability of combined codon 127-129 genotypes of PRNP in elderly persons from the kuru region suggests that there was stronger selection … than that in the classically quoted examples of endemic malaria and haemoglobin S or C alleles’.

(1)    Monot, M et al. Comparative genomics and phylogeographic analysis of Mycobacterium leprae. Nature Genetics 41(2009), 1282-1289.

(2)    Monot, M et al. On the origin of leprosy. Science 308(2005), 1040-1042.

(3)    Mead, S. et al. A novel protective prion protein variant that colocalizes with kuru exposure. The New England Journal of Medicine 361(2009), 2056-2065.