Wednesday, May 18, 2011

The Achilles' heel of biological complexity

Here’s the pre-edited version of my latest news story for Nature. This is such an interesting issue that I plan to write a more detailed piece on it for Chemistry World soon.
The complex web of protein interactions in our cells may be masking an ever-worsening problem.

Why are we so complicated? You might imagine that we’ve evolved that way because it conveys adaptive benefits. But a new study in Nature [1] suggests that the complexity in the molecular ‘wiring’ of our genome – the way our proteins talk to each other – may be simply a side effect of a desperate attempt to stave off problematic random mutations in the proteins’ structure.

Ariel Fernández, working at Chicago University 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 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 – now a crucial component of how information is transmitted in our cells – compensates for the reduction in protein stability wrought by drift. But this response comes at a cost.

It might mask the accumulation of structural weaknesses in proteins to a point where the problem can no longer be contained. Then, say Fernández and Lynch, proteins might be liable to misfold spontaneously – as they do in so-called diseases such as Alzheimer’s, Parkinson’s and prion diseases, caused by misfolded proteins in the brain.

If so, this means we may be fighting a losing race. 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 necessary benign in the long run. By finding a short-term solution to drift, it might merely be creating a time-bomb. “Species with low population are ultimately doomed by nature’s strategy of evolving complexity”, says Fernández.

The work provides “interesting and important news”, according to William Martin, a specialist in molecular evolution at the University of Düsseldorf in Germany. Martin says it shows that evolution of eukaryotes – relatively complex organisms like us, with a cellular ‘nucleus’ that houses the chromosomes – “can be substantially affected by drift.”

Drift is a bigger problem for small populations – those of multicelled eukaryotic organisms – than for large ones, because survival by chance rather than by fitness is statistically more likely for small numbers. Many random mutations in a gene, and thus in the protein made from it, will harm the protein’s resistance to unfolding: the protein’s folded-up shape becomes more apt to loosen as water molecules intrude into it. 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 regions vulnerable to water. Fernández and Lynch say that these associations between proteins – a key feature of the cell biology of eukaryotes – may have therefore initially been a passive response to genetic drift. Over time, certain protein-protein interactions may be selected by evolution for useful functions, such as sending molecular signals across cell membranes.

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 [full disclosure: these are actually parts of the chain that hydrogen-bond to one another; exposure to water enables the water molecules to compete for the hydrogen bonding. Ariel Fernández has previously explored how such regions may be ‘wrapped’ in hydrophobic chain segments to keep water away], 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.

On this view, genome complexity doesn’t offer intrinsic evolutionary advantages, but is a kind of knee-jerk response to the chance appearance of ‘needy proteins’ – which ends up exposing us to serious risks.

“I believe prions are indicators of this gambit gone too far”, says Fernandez. “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”. Prions 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”, Fernandez adds. “Perhaps the evolutionary cost of our complexity is too high a price to pay in the long run.”

However, Martin doubts that drift alone can account for the difference in complexity between prokaryotes (single-celled organisms without a cell nucleus) and eukaryotes. His previous work has indicated that bioenergetics also plays a strong role [2]. For example, says Martin, prokaryotes with small population sizes are symbiotic, which tend to degenerate, not to become complex. “Population genetics is just one aspect of the complexity issue”, he says.

1. Fernandez, A. & Lynch, M. Nature doi:10.1038/nature09992 (2011).
2. Lane, N. & Martin, W. Nature 467, 929-934 (2010).

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