Evolution, Huntingtin and Cancer?

A recent manuscript by a Swedish group (Ji et al., The Lancet, 2012) has revealed that the incidence of cancers amongst individuals bearing mutant expanded polyglutamine genes (and particularly Huntingtin expansions) is significantly lower than in the general population, even after adjusting for age. This study is a continuation of previous work done by this group and others, conducted to investigate whether mutations in genes containing expanded polyglutamine regions confer a biological advantage. As for other fatal genetic conditions, people have often wondered why the prevalence of disorders which kill people remains steady in the population. One can assume that if these mutations (with a  high or complete penetrance, and of dominant genetic nature) kill those bearing them, natural selection would slowly operate to eliminate these detrimental mutations, and the incidence should decrease over time. This is clearly not the case in HD – prevalence is steady, and there are no signs that the expanded alleles are under ‘negative selection’. So why is this?

Negative selection refers to the process of natural selection by which changes in the genome which are deleterious, or which decrease ‘fitness’ (the ability of the mutations being passed on to the next generation), will be eliminated (or decrease) as time passes. Some arguments were made initially to explain the lack of negative selection in HD because of the late onset of the disease. After all, most people who start having symptoms of HD develop them after they have had children. If this is the case, then bearing the mutation should not affect the number of offspring, and therefore negative selection would not operate to eliminate these mutations from the population. To a large extent, it is correct that most HD carriers have children prior to the onset of the disease, however other factors might affect the number of children in families at risk for HD. For instance, it is well known that society rejects people with genetic disorders in their family. Marrying into families known or suspected of suffering from a genetic disorder is unwelcome. From this psychological and social perspective, fitness can be affected merely due to the fact that people might not want to marry and have children with people suspected to have HD or to be potential carriers for the gene. This is well known in many cultures, but perhaps the isolated populations of HD in South America (Maracaibo townships in Venezuela perhaps the most poignant example) illustrate this point all too well. Yet even in these populations there is no evidence of negative selection as far as I am aware of (although rigorous genetic epidemiological studies have not been conducted).

If anything, small studies have revealed that the number of offspring of people carrying the HD mutation is increased! This was true when measuring the number of children of people carrying the HD mutationas compared to the general population, but even more informative, the fact that mutation carriers had more children than their siblings which did not carry the mutation! (see Carter and Nguyen, BMC Medical Genetics 2011). This finding, if reproduced in larger population studies, suggests that perhaps the Htt mutation confers an evolutionary advantage to those bearing it (and contributes to maintaining the mutation in the population in spite of its fatal nature). These reports highlight an often overlooked aspect of the genetic contribution of these mutations, that of selective advantage for those carrying them. This phenomenon is called ‘antagonistic pleiotropy’. Pleiotropy is a term used to define the fact that most proteins carry a myriad of functions in the organism – the mutation in HD leads to HD and the death of the individuals, but it might also confer other functional effects distinct from HD, which might be beneficial to those bearing the mutant protein. While Htt function is still rather unclear, we know that it plays multiple roles: it is critical for embryonic development; it modulates transcription, energy production, and other functions still ill-defined in molecular terms. ‘Antagonistic pleiotropy’ refers to the fact that two functions of the same protein might ‘be antagonistic’ with each other in terms of natural selection. This is best illustrated by sickle cell anemia mutations (which can cause death) and resistance to malaria. The mutation leads to disease, but it is maintained (or selected for) because in areas where malaria is endemic, the mutations make people more resistant to being infected by the malaria-causing pathogen. While the story is not so clear-cut in HD, the principle might apply. Something about the expansion might confer a positive effect on those carrying the mutation, which is why it might be maintained in the population. Since most people though history did not live very long (lifespan for most of our time as a species was less than 40 years of age), perhaps dying of HD was not a strong negative pressure since people did not live that long!

The beauty of epidemiological data is that it provides unbiased information: the findings regarding the lower incidence of cancer, and the increased number of offspring amongst HD carriers are descriptive in nature; it highlights that this happens, but it does not tell us how or why. But they are important clues as to what mechanisms Htt and polyglutamine expansions might be modulating. Now these observations open the door widely for the research community to try to investigate how this is taking place. A key mechanism known to modulate cancer susceptibility is a protein called p53, a key ‘gate-keeper’ of cancer progression. p53 mutations account for a large percentage of cancers in the general population, and the biology of p53 has been linked to HD for quite some time. p53 is a critical protein in cell cycle control and the DNA damage response (perhaps the most important cancer-relevant mechanisms known). The Htt-p53 link might be the explanation for the reduced cancer incidence in HD, but how this happens indeed is unknown at this point. With the genome sequencing project, understanding the link between cancer pathways and HD is feasible and should be expanded to the realm of molecular analysis. With the ability to obtain human patient derived cells(and stem cells), researchers can now begin to understand if indeed there is a strong connection between HD expansions and p53 signaling, and what exactly is this interplay. This is important, as we might, through these studies, be able to pinpoint specific molecular pathways which Htt mutations might work in. No doubt, future work will answer the question whether p53 or other cancer pathways are relevant to the function of mutant Htt.

Another interesting point is the fact that HD is caused exclusively by mutations in the polyglutamine tract. However, the ‘normal’ expansion of polyglutamine tracts is a novel development during evolution (see for instance the great and comprehensive work of Elena Cattaneo’s group in this area). That is, the polyQ tract does not appear until late in evolution, and the expansion is larger in mammals that in other species. Therefore, the polyQ tract is not required for the most ancient, evolutionarily conserved functions of Htt! For instance, in insects and other organisms, there is no Htt polyQ region; in rodents, the ‘tract’ if rather small (7-10 glutamines). It is only in large mammals and particularly primates, that the polyQ stretch is large within the ‘normal range’ (for instance, in the human population, the average length is 15-25 glutamines). This begs the question of why the expansion is promoted so late in the molecular evolution of the Htt gene, and why mostly in large mammals. Clearly, the expansion is conferring some advantage to animals with large brains, and it is likely that this function is what underlies the expansion both in the ‘normal’ range but also likely in the ‘pathogenic’ range. Again, molecular evolution is sending us a clear message here: Htt polyQexpansions have been selected for because they do something advantageous to the organism – the question is what, and how can we use this information to our benefit! Making the polyQ tract larger seems like a good idea judging by the genetic data, but going a bit too far is not so good… seems like a common theme in human biology and psychology!

Have a nice weekend!

nacho