Mudança de gene em canibais revela evolução em ação diante de nossos olhos

NEJM Volume 361:2056-2065 November 19, 2009 Number 21

A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure

Simon Mead, M.R.C.P., Jerome Whitfield, M.A., Mark Poulter, B.Sc., Paresh Shah, Ph.D., James Uphill, B.Sc., Tracy Campbell, B.Sc., Huda Al-Dujaily, B.Sc., Holger Hummerich, Ph.D., Jon Beck, B.Sc., Charles A. Mein, Ph.D., Claudio Verzilli, Ph.D., John Whittaker, Ph.D., Michael P. Alpers, F.R.S., and John Collinge, F.R.S.

ABSTRACT

Background Kuru is a devastating epidemic prion disease that affected a highly restricted geographic area of the Papua New Guinea highlands; at its peak, it predominantly affected adult women and children of both sexes. Its incidence has steadily declined since the cessation of its route of transmission, endocannibalism.

Methods We performed genetic and selected clinical and genealogic assessments of more than 3000 persons from Eastern Highland populations, including 709 who participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru.

Results Persons who were exposed to kuru and survived the epidemic in Papua New Guinea are predominantly heterozygotes at the known resistance factor at codon 129 of the prion protein gene (PRNP). We now report a novel PRNP variant — G127V — that was found exclusively in people who lived in the region in which kuru was prevalent and that was present in half of the otherwise susceptible women from the region of highest exposure who were homozygous for methionine at PRNP codon 129. Although this allele is common in the area with the highest incidence of kuru, it is not found in patients with kuru and in unexposed population groups worldwide. Genealogic analysis reveals a significantly lower incidence of kuru in pedigrees that harbor the protective allele than in geographically matched control families.

Conclusions The 127V polymorphism is an acquired prion disease resistance factor selected during the kuru epidemic, rather than a pathogenic mutation that could have triggered the kuru epidemic. Variants at codons 127 and 129 of PRNP demonstrate the population genetic response to an epidemic of prion disease and represent a powerful episode of recent selection in humans.



Source Information

From the Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology (S.M., J. Whitfield, M.P., P.S., J.U., T.C., H.A.-D., H.H., J.B., M.P.A., J.C.); the Genome Centre, Barts and the London Queen Mary's School of Medicine and Dentistry, John Vane Science Centre (C.A.M.); and the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine (C.V., J. Whittaker) — all in London; Papua New Guinea Institute of Medical Research, Goroka, Eastern Highlands Province, Papua New Guinea (J. Whitfield, M.P.A.); and the Centre for International Health, Curtin University, Perth, WA, Australia (M.P.A.).

Address reprint requests to Dr. Collinge at the Department of Neurodegenerative Disease, Institute of Neurology, Queen Sq., London WC1N 3BG, United Kingdom, or at j.collinge@prion.ucl.ac.uk.

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