Genes 2 Brains 2 Mind 2 Me

The human brain is renown for its complexity.  Indeed, while we often marvel at the mature brain in its splendid form and capability, its even more staggering to consider how to build such a powerful computing machine.  Admittedly, mother nature has been working on this for a long time – perhaps since the first neuronal cells and cell networks appeared on the scene hundreds of millions of years ago.  In that case, shouldn’t things be pretty well figured out by now?  Consider the example of Down syndrome, a developmental disability that affects about 1 in 800 children.  In this disability, a mere 50% increase in a relative handful of genes is enough to alter the development of the human brain.  To me, its somehow surprising that the development of such a complex organ can be so sensitive to minor disruptions – but perhaps that’s the main attribute of the design – to factor-in aspects of the early environment whilst building.  Perhaps?

So what are these genes that, in the case of Down syndrome, can alter the course of brain development?  Well, it is widely known that individuals with Down syndrome have an extra copy of chromosome 21.  However, the disorder does not necessarily depend on having an extra copy of each and every gene on chromosome 21.   Rare partial trisomies of only 5.4 million base-pairs on 21q22 can produce the same developmental outcomes as the full chromosome trisomy.  Also, it turns out that mice have a large chunk of mouse chromosome 16 that has the very same linear array of genes (synteny) found on human chromosome 21 (see the figure here).  In mice that have an extra copy of about 104 genes, (the Ts65Dn segment above) many of the developmental traits related to brain structure and physiology are observed.  In mice that have an extra copy of about 81 genes, this is also the case (the Ts1Cje segment).

To focus this line of research even further, the recent paper by Belichenko et al., “The “Down Syndrome Critical Region” Is Sufficient in the Mouse Model to Confer Behavioral, Neurophysiological, and Synaptic Phenotypes Characteristic of Down Syndrome” [DOI:10.1523/JNEUROSCI.1547-09.2009]  examine brain structure, physiology and behavior in a line of mice that carry an extra copy of just 33 genes (this is the Ts1Rhr segment seen in the figure above).  Interestingly, these mice display many of the various traits (admittedly mouse versions) that have been associated with Down syndrome – thus greatly narrowing the search from a whole chromosome to a small number of genes.  20 out of 48 Down syndrome-related traits such as enlargement of dendritic spines, reductions of dendritic spines, brain morphology and various behaviors were  observed.  The authors suggest that 2 genes in this Ts1Rhr segment, in particular, look like intriguing candidates.  DYRK1A a gene, that when over-expressed can lead to hippocampal-dependent learning deficits, and KCNJ6, a potassium channel which could readily drive neurons to hyperpolarize if over-expressed.

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