Published online 18 May 2011 | Nature | doi:10.1038/news.2011.294

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The complex web of protein interactions in our cells may be masking an ever-worsening problem.

Are your proteins out to get you? This prion certainly is ... LAGUNA DESIGN/SCIENCE PHOTO LIBRARY

Why are we so complicated? You might imagine that we've evolved that way because it conveys adaptive benefits. But a study published by Nature1 today suggests that the complexity in the molecular 'wiring' of our genome — the way our proteins talk to each other — may simply be a side effect of a desperate attempt to stave off problematic random mutations in proteins' structures.

Ariel Fernández, previously at the University of Chicago, Illinois, and now at the Mathematics Institute of Argentina in Buenos Aires, and Michael Lynch of Indiana University in Bloomington argue that complexity in the network of our protein interactions arises because our relatively small population size — compared with that of single-celled organisms — makes us especially vulnerable to 'genetic drift': changes in the gene pool due to the reproductive success of certain individuals by chance rather than by superior fitness.

Whereas natural selection tends to weed out harmful mutations in genes and their related proteins, genetic drift does not. Fernández and Lynch argue that the large number of physical interactions between our proteins — a crucial component of how information is transmitted in our cells — compensates for the reduction in protein stability wrought by drift.

Short-term fix

But this response comes at a cost. It might mask the accumulation of structural weaknesses in proteins to a point at which the problem can no longer be contained. Then, say Fernández and Lynch, proteins might be liable to spontaneously misfold — as they do in disorders such as Alzheimer's disease, Parkinson's disease and prion diseases, all of which are caused by misfolded proteins in the brain.

If so, it may be a losing battle. Genetic drift may eat away at the stability of our proteins until they are overwhelmed, leaving us a sickly species.

This would imply that Darwinian evolution isn't necessarily benign in the long run. By finding a short-term solution to drift, it might merely be creating a time bomb. Or, as Fernández says, "Species with low population are ultimately doomed by nature's strategy of evolving complexity."

The work provides "interesting and important news", according to William Martin, a specialist in molecular evolution at the Heinrich Heine University of Düsseldorf in Germany. Martin says it shows that the evolution of eukaryotes — relatively complex organisms, such as humans, with a cellular nucleus that houses the chromosomes — "can be substantially affected by drift". Drift is a bigger problem for small populations than for large ones, because survival by chance rather than by fitness is statistically more likely among small numbers.

Waterproofing

Many random mutations in a gene, and thus in the protein made from it, lower the protein's resistance to unfolding by exposing it to intruding water molecules. This loss of shape weakens the protein's ability to function.

Such problems can be avoided if proteins stick loosely to one another so as to shelter the water-sensitive regions. Fernández and Lynch say that these associations between proteins — a key feature of the cell biology of eukaryotes — may therefore have started out as a passive response to genetic drift. Some of these protein–protein interactions turned out to have useful functions, such as sending molecular signals across cell membranes, and so were selected by evolution.

Using protein structures reported in the Protein Data Bank, the two researchers verified that disruption of the interface between proteins and water, caused mostly by exposure of 'sticky' parts of the folded peptide chain, leads to a greater propensity for a protein to associate with others. They also showed that drift could account for this poor 'wrapping' of proteins.

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"I believe prions are indicators of this gambit gone too far," says Fernández. "The proteins with the largest accumulation of structural defects are the prions, soluble proteins so poorly wrapped that they relinquish their functional fold and aggregate." These misfolded prions then cause disease by triggering the misfolding of other proteins.

"If genetic variability resulting from random drift keeps increasing, we as a species may end up facing more and more fitness catastrophes of the type that prions represent," Fernández adds. "Perhaps the evolutionary cost of our complexity is too high a price to pay in the long run."