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No cannibalism signature in human gene

New analysis rejects earlier claim that balancing selection protected prehistoric people from prion disease after cannibalistic feasts

By | January 9, 2006

A new population genetics analysis of human prion gene evolution contradicts a 2003 Science paper that claimed commonplace cannibalism among prehistoric humans shaped evolution of the prion gene. In the February issue of Genome Research, Marta Soldevila and her colleagues at Pompeu Fabra University in Barcelona, Spain, say they have corrected a data collection bias in the original paper, and their results show no evidence that either prion disease or cannibalism significantly shaped human evolution.

"This is a definitive analysis," said Martin Kreitman of the University of Chicago, who was not an author of the new study. Authors of the Science paper "didn't have support for balancing selection that they claimed," Kreitman said.

A common methionine/valine polymorphism at codon 129 of the human prion protein gene PRNP can influence risk of transmissible spongiform encephalopathies (TSEs). Homozygosity for either amino acid has been linked to increased susceptibility to TSEs, including to Kuru, a prion disease limited to New Guinea. Discovered by anthropologists in the 1950s, Kuru was transmitted during cannibalistic funeral rites among the Fore linguistic group.

In the 2003 paper, Simon Mead at University College London and his colleagues reported that Fore women who likely participated in cannibalistic feasts were signficantly more likely to be heterozygous at codon 129 than expected by chance. The authors then conducted an analysis of PRNP polymorphisms among people from all over the world and found an unexpectedly large number of common haplotypes. Too many common haplotypes is the mark of balancing selection, Kreitman said, because it suggests that multiple gene variants have been selected for simultaneously. (Under positive or purifying selection, most variants are found at low frequencies.)

The Science authors proposed that, throughout human evolution, prion disease transmitted through cannibalism encouraged balancing selection on several PRNP haplotypes, which then conferred heterozygous resistance to disease.

However, in July 2004, Kreitman and Anna Di Rienzo, also of the University of Chicago, published a criticism of the Mead et al. paper in Trends in Genetics, citing an ascertainment bias in haplotype sampling. Mead and colleagues sequenced the full PRNP gene in a few people of European ancestry, and then used the single nucleotide polymorphisms (SNPs) they discovered to genotype a larger, global population. But without resequencing every individual included in the final study, the authors likely biased their results toward common polymorphisms, the signature of balancing selection, Kreitman told The Scientist. "They had in fact excluded the low-frequency variants and only looked at the common ones?and then came to the conclusion that there are too many common ones," Kreitman said.

In the new study, Soldevila and her colleagues completely sequenced the prion protein-coding region in 174 humans from various geographic regions. They ran multiple statistical tests and found no evidence of balancing selection either overall or among people from any continental region, said senior author Jaume Bertranpetit. The values of their statistical results suggest that positive selection may have acted upon the gene, Bertranpetit said, although complex scenarios, including episodes of both positive and purifying selection, may also explain the data.

"This new study is very insightful," Christopher Seabury of Texas A&M University in College Station, who was not involved in the study, told The Scientist. However, "there's still a significant overabundance of PRNP codon 129 heterozygotes in the Fore women who engaged in cannibalistic feasts," he said. It's possible that balancing selection on the prion locus has taken place locally among the Fore or other small groups, Bertranpetit agreed, "but it has not been important in human history."

According to Bertranpetit and Kreitman, ascertainment biases in human population genetics studies have become more common since the introduction of SNP databases like HapMap. Many SNPs available in such databases "are from relatively small samples and they tend to be biased towards being more intermediate or common, rather than rare," Kreitman said. "If you then run some kind of statistical analysis against a model which assumes you've actually found all the polymorphisms, including the rare ones, there's a problem."
mlp@nasw.org

Links within this article:

analysis
M. Soldevila et al., "The prion protein gene in humans revisited: Lessons from a worldwide resequencing study," Genome Research, Epub 20 Dec 2005.
PMID: 16369046.

paper
S. Mead et al., "Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics," Science 300:640-643, 25 Apr 2003.
PMID: 12690204.

Marta Soldevila
http://www.upf.es/cexs/recerca/bioevo/CV-MartaSoldevila.htm

Martin Kreitman
http://pondside.uchicago.edu/ecol-evol/faculty/kreitman_m.html

susceptibility
M.S. Palmer et al., "Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease," Nature 352:340-342, 25 July 1991.
PMID: 1677164.

Kuru
L. Cervenakova et al., "Phenotype-genotype studies in kuru: implications for new variant Creutzfeldt-Jakob disease," PNAS 95:13239-13241, 27 Oct 1998.
PMID: 9789072.

Anna Di Rienzo
http://www.genes.uchicago.edu/fri/drnzores.html

criticism
M. Kreitman, A. Di Rienzo, "Balancing claims for balancing selection," Trends Genet. 20:300-304, July 2004.
PMID: 15219394.

Jaume Bertranpetit
http://www.upf.edu/cexs/recerca/bioevo/CV-Bertranpetit.htm

HapMap
http://www.hapmap.org/

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Mettler Toledo
BD Biosciences
BD Biosciences