Retrotransposition, Diversity and the Brain

The human brain is remarkably complex, permitting sophisticated behavioural rep- toires, such as languages, tool use, self-awareness, symbolic thought, cultural learning and consciousness. Each human being is different, due in part to the uniqueness of the neuronal heterogeneity and interconnections in our brains. Brain complexity and neuronal diversity are strongly related. The diversity of single neurons provides the underpinnings for how neuronal circuits operate. How and when neuronal diversity is generated, both in embryonic and adult neurogenesis, remain unknown. In the immune system, the highly diverse array of antigen receptors can be - tributed to the stochastic nature of the recombination process in somatic precursor cells, causing permanent changes in DNA and gene expression. This diverse population is then the target of selective processes that favor the correct antigen-receptor match and eliminate those with inadequate speci?cities, accounting for the rapid kinetics and immense diversity observed in vivo. Evidence for a possible similarity between the nervous and immune systems came from studies with mice de?cient in DNA double strand break (DSB) repair. Lessons learned from the discovery of the mechanism for diversityinthe immune system maybe usefultothe investigation ofthe mechanism of diversity in neurons.

Retroelements are ancient mobile DNA found in most organisms. Long dismissed as useless, selfish or "junk" DNA, they were thought to be mere intracellular parasites from our distant evolutionary past. Together with their mutant relatives, L1 sequences constitute almost 50% of the mammalian genome. L1s can retrotranspose in a defined window of the neuronal differentiation, changing the genetic information in single neurons in a "random" fashion, allowing the brain to develop in distinct different ways. Such strategy contributes to expand the number of functionally distinct neurons that could be produced from a given stem cell gene pool. This characteristic of variety and flexibility may contribute to the uniqueness of an individual brain, even between genetically identical twins. These mobile elements may be part of conserved core process responsible for evoking facilitated complex non-random phenotypical variation on which selection may act. A detailed understanding of the basic mechanisms of L1 activity may shed light on one possible mechanism for generating neural diversity.

The book results from a fascinating and stimulating exchange of ideas at the interface of the complexity of brain organization and function, the mechanisms for generating diversity and genetic mobility. This meeting of leading geneticists, molecular biologists and neuroscientists was organized by the Fondation IPSEN. Its ambitious goal was to expand the current limits of research in neurobiology not only to the benefit of those interested in the cellular and molecular processes but also for the understanding of high-level cognitive functions and the understanding of complex mental diseases. The reader can judge how far the book achieves this.