Searching the Genetic Basis Underlying the Evolution of the Human Brain: a Bioinformatics and Functional Approach

FRANCHINI L.F.

Seminario; Seminarios en Química Biológica; 2015

The human brain is distinctive in terms of its cognitive abilities as well as its susceptibility to neurological disease. Identifying which of the millions of genomic changes that occurred during human evolution led to these and other uniquely human traits is extremely challenging. Evolutionary signatures of functional shifts could be detected by comparing noncoding regions that are highly conserved across mammals or primates and rapidly accumulated nucleotide substitutions only in the lineage leading to humans. These regions are named human-accelerated elements (HAEs). As gene loci densely populated with HAEs are more likely to have contributed to human-specific novelties, we sought to identify the transcriptional units and genomic 1Mb intervals of the entire human genome carrying the highest number of HAEs. We found that the brain developmental transcription factor neuronal PAS domain-containing protein 3 (NPAS3) contains the largest cluster of noncoding-accelerated regions in the human genome with up to 14 elements that are highly conserved in mammals, including primates, but carry human-specific nucleotide substitutions. We then tested the ability of the 14 HAEs identified at the NPAS3 locus to act as transcriptional regulatory sequences in a reporter expression assay performed in transgenic zebrafish. We found that 11 out of the 14 HAEs present in NPAS3 act as transcriptional enhancers during development, particularly within the nervous system. Performing comparative studies in transgenic zebrafish and mice we have also identified several HAEs that gained or lost function in the human genome. As NPAS3 is known to play a crucial role during mammalian brain development, our results indicate that the high density of HAEs present in the human NPAS3 locus could have modified the spatiotemporal expression pattern of NPAS3 in the developing human brain and, therefore, contributed to human brain evolution.