Similarly, there

are over 500 regions that are highly conserved in mammals through chimpanzees but deleted in humans (suggestive of function) that may regulate more than 1,000 genes (McLean et al., 2011). To complicate matters further, mobile repeats such as Alu elements (Cordaux and Batzer, 2009) have rapidly evolved in African great apes, with the greatest number occurring in humans. Such transposable elements have been shown to regulate gene expression and thus represent another layer of regulatory complexity introduced in primates and accelerated in humans. Furthermore, to understand the role of these genomic events in human brain evolution, their function must be interrogated in a tissue- and stage-specific manner in cerebral cortex. find more In a recent tour de force, Rubenstein and colleagues combined computational analysis of sequence conservation with DNA binding assays in mouse and humans (chromatin IP, etc.) and in vivo validation in developing OSI-744 ic50 mouse to provide a catalog of human telencephalic enhancers (Visel et al.,

2013). This includes several that may be associated with human neuropsychiatric diseases and a significant proportion that are presumed human or primate specific (Visel et al., 2013). Future studies querying laminar and cell-type-specific regulation in high resolution at multiple stages will be necessary to complete a map of human cortical regulatory elements as a crucial foundational resource. Like the functional work on gene duplications, this work again demonstrates how combination of cross-species bioinformatics and mouse Rebamipide experimentation can provide mechanistic insight into brain evolution. Noncoding RNAs provide another layer of regulatory complexity that needs to be considered in understanding human brain evolution. Some have proposed that noncoding RNA and RNA editing mechanisms may serve as a major driver of brain evolution (Barry and Mattick, 2012). Unfortunately, little is known about the roles of various forms of noncoding transcripts, from miRNAs through lincRNAs in human brain (Ulitsky and Bartel, 2013). Complicating their identification

and study is the very rapid sequence divergence in many noncoding regions, whether purely regulatory or coding for transcripts, such as lincRNAs. One notable example of a noncoding RNA that is involved in human brain evolution is HAR-1, a long noncoding RNA originally identified as the most accelerated noncoding transcribed genomic region in humans (Pollard et al., 2006). HAR-1 shows strikingly restricted expression in Cajal-Retzius neurons in the marginal zone during the time of neuronal migration in the cerebral cortex, consistent with a fundamental role in human cerebral cortical development and evolution. Precisely what this role is remains to be determined, perhaps by adapting the experimental approaches pioneered in the study of duplicated genes.