Human Evolution: No Easy Fix

Humanity is undeniably complex, and proud of it – no case, we believe, needs to be made for our biological superiority. But we may be doomed as a species precisely because of the way in which our complexity arose.

MADISON –Humans are undeniably complex, and proud of it. No case, we believe, needs to be made for our biological superiority. Our biological functions are exquisitely regulated and resilient to external variations, owing to complicated webs of interactions. Unlike other species, we seem to be endowed with willpower and intellect, hence we are capable of modifying the environment to buffer the effects of our decreasing fitness.

Be that as it may, we may be doomed as a species precisely because of the way in which our complexity arose. Paraphrasing the science writer Philip Ball, nature seems to have activated a time bomb, and our complexity is only a short-term fix.

To grasp the nature of the problem, we need to examine how humans are made at the molecular level, and contrast our constitution with that of other species that we often call “rudimentary,” such as unicellular organisms. This analysis leads us to examine proteins – our cellular building blocks and the executors of biologicalfunctions – across vastly different species. Proteins with common ancestry belonging to different species, termed “orthologs,” offer solid ground for comparison.

It has been generally recognized that the basic “fold,” or shape, of a protein must be conserved across species, because there is a tight correspondence between structure and function. Proteins that retain the same function across very different species – generally the case with orthologs – are expected to keep the same fold.

But the sequence of amino acids that make up the protein chains in these orthologs can vary significantly. Sometimes the extent of sequence identity between two orthologs can be as low as 25-30%, and yet their folds remain strikingly similar, attesting to the robustness of function to evolutionary change.

This conservation of the protein fold across species makes the origin of our complexity even more puzzling, as it is well known that the number of human genes is deceptively small, merely one order of magnitude larger than that of, say, rice. If the structure of the proteins is conserved across species, where is our complexity coming from? Better still, in what sense are we more complex?

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Researchers have recently discovered subtle structural variations occurring in orthologs from species that diverged from each other billions of years ago. In these structures, something subtler than overall topology changes across orthologs. The structure in some seems “looser” than in others – less well packed, with surface regions that enable surrounding water to penetrate and disrupt the structure by interacting favorably with the protein backbone. These structural vulnerabilities are known as dehydrons.

As we examine orthologs, the proteins become more degraded, or richer in dehydrons, in species with a lower effective population – a somewhat elusive indicator inversely related to the size and complexity of the organism and to the complexity of its reproductive pattern. Thus, humans (or mammals) have significantly smaller (ten or more orders of magnitude) populations than bacteria.

The observation that structural degradation is a reflection of decreasing species population resonates in the field of evolution, because natural selection becomes more inefficient as the population gets smaller. Structural degradation is thus an indicator of the species’ exposure to random genetic drift: mildly deleterious mutations that would typically degrade the protein structure are more likely to be selected against in bacteria before they can become fixed in the entire population (estimated in trillions of individuals), whereas such a mutation has a far better chance of prevailing in humans.

A protein that is richer in dehydrons than its ortholog is more vulnerable to becoming disrupted by surrounding water. Precisely for this reason, it becomes more “needy” – that is, more reliant on binding partners to maintain its structural integrity. Furthermore, dehydrons are known to be sticky, so structurally degraded proteins are more likely to promote protein-protein associations than orthologs with lower dehydron content. Thus, protein-protein interactions, a hallmark of complexity, are actually promoted by randomdrift, the evolutionary force behind the protein degradation process.

So, it seems, complexity is not really naturally selected, but instead arises as a short-term fix to the effects of selection inefficiency. At first reading, this assertion seems counterintuitive, but the root of the paradox is simply our dogmatic way of thinking, where complex traits are expected to be an outcome of natural selection.

And where is nature’s gambit taking us? The proteins with the largest accumulation of structural defects are the prions, soluble proteins so poorly wrapped that they relinquish their functionally competent fold and form aberrant aggregates that may cause degenerative neuropathies.

This extreme case of an “aberrantly needy protein” illustrates the high level of genetic risk to which we are exposed as a result of our small population. The prion is a “fitness” catastrophe that gives us clues as to where nature’s gambit might lead humanity. Perhaps the long-term evolutionary cost of our complexity is too high, with our survival as a species ultimately depending on our ability to mitigate its fitness cost through increasingly arduous therapeutic solutions. Let’s hope we pass the test.