You may have seen the various press snippets (link 1, 2, 3, 4) surrounding the advanced online publication of a paper in the journal Nature this week (also comment in John Hawks’ Blog). This work is part of a field where bioinformaticians (those who study the large sets of data generated by projects such as the Human Genome Project and the HapMap Project) study the evolutionary footprints that are to be found in the DNA sequence of our chromosomes.
Since the Human Genome Project was completed five years ago, it has been joined by genome projects from a wide variety of inhabitants of the evolutionary tree so that it is possible to dissect the genetic differences between them. In the most part, this has been used to identify similarities between species. These ‘conserved’ regions have arisen because they have been subject to strong selective pressure not to accrue random mutations. Conserved regions usually indicate the presence of genes (which have to be kept intact in order to make functional protein) or regulatory regions (which control the use of particular genes). You can think of these conserved regions as being responsible for the core properties of a protein, and on a larger scale, responsible for the general features of an organism - head, limbs, organs, metabolism, muscle etc. It also stands to reason that mutations in these conserved regions are likely to have the most serious consequences……that of causing genetic disorders.
However, some researchers have looked at the flipside of this coin - hunting out the regions of the genome which show the greatest differences between species. These, it is hypothesized, represent the sites where natural selection and speciation events have occurred - they are responsible for what makes us different from our evolutionary ancestors.
This Nature paper details the application of this latter approach: the assumption that genes showing fast evolution between the homininae lineage (human, chimpanzee, gorilla and orang-utan) and hominina lineage (humans and their ancestors since the split with chimpanzees circa 6 million years ago) are responsible for our defining and distinguishing evolutionary features, in particular, increased brain size/cognitive power.
So, in brief, the reasoning goes like this: fast-evolved human genes > used in brain > they made us what we are today.
It’s not the first time that such an approach has been tried. Indeed, genes such as ASPM and Microcephalin have shown fast evolution and appear to play a role in brain development (lots of nice reviews here: link 1, link 2, link 3, link 4). There are even genes which are entirely specific to humans - for example the SIGLEC11 gene is expressed in brain microglial cells.
The first author of the paper, Katherine Pollard, carried out a systematic screen of the human genome, comparing it with chimp, in order to identify what she calls ‘Human Accelerated Regions’ (HARs) - the fast-evolved regions. The most significant finding was called HAR1 and shows 66 times more sequence changes than would be expected of an average stretch of DNA. The HAR1 region seems to be correlated with two overlapping genes, HAR1F and HAR1R. The genes themselves are odd in that they don’t make proteins - their function must be carried out in their mRNA form. Most RNA genes are regulatory in that they control the actions of other genes, but no such role has yet been shown for HAR1F/R. Again, the authors show that this humanised gene acts in the brain, and more specifically, the developing foetal brain. It is found in the precursor cells that will go on to produce the cerebral cortex - the higher functioning, business end of the brain.
How does schizophrenia fit into this story? A related hypothesis follows directly on from the ‘fast-evolved human gene’ argument. This states that schizophrenia is a uniquely human disease caused by dysfunction of uniquely human cognitive faculties and is, therefore, likely to have genetic causation in those brain genes that have driven human speciation. In other words, genes like the HARs are possible candidates for schizophrenia genes. Here are three papers that originally stated this idea.
Brune, M. (2004) Schizophrenia-an evolutionary enigma? Neurosci Biobehav Rev 28 (1), 41-53
Randall, P.L. (1998) Schizophrenia as a consequence of brain evolution. Schizophr Res 30 (2), 143-148
Crow, T.J. (1995) A theory of the evolutionary origins of psychosis. Eur Neuropsychopharmacol 5 Suppl, 59-63
It has to be said that this idea has been in the wilderness for a while, overtaken by more pharmacological thoughts on the genes involved in schizophrenia. Does it deserve another shot at glory? It’s hard to say just yet, but there are a few intriguing clues:-
- HAR1F/R is found in the same cortex precursor cells as Reelin, itself a reasonably well-established schizophrenia candidate gene.
- Another brain capacity gene, like ASPM and Microcephalin, is Nde1 (’Nude 1‘) which is a direct interactor with the DISC1 schizophrenia candidate gene.
- A previous paper on fast-evolving brain genes identified GRIK4 (a glutamate responsive neurotransmitter receptor in the brain). We have just described its involvement in the genetics of schizophrenia and bipolar disorder.
- Similarly, the NPAS3 gene was identified as ‘HAR21′ (also incorrectly labeled HAR30 in table S8) by Pollard et al. We have shown that this gene is involved in schizophrenia too - and described a region of the gene/protein that is human-specific (although this is not the same region flagged up in HAR21).
Circumstantial at best maybe, but certainly the basis for future study.
What an chillingly emotive idea, though. The genetic forces that boosted our cognitive faculties in Africa’s Rift Valley may contribute to the debilitating characteristics of psychiatric illness.