Selection of Olduvai Domains during Evolution: A Role for Primate-Specific Splicing Super-Enhancer and RNA Guanine Quadruplex in Bipartite NBPF Exons

Olduvai protein domains (also known as DUF1220 or NBPF) have undergone the greatest human-specific increase in the copy number of any coding region in the genome. Their repeat number was strongly associated with the evolutionary expansion of brain volumes, neuron counts and cognitive abilities, as well as with disorders of the autistic spectrum. Nevertheless, the domain function and cellular mechanisms underlying the positive selection of Olduvai DNA sequences in higher primates remain obscure. Here, I show that the inclusion of Olduvai exon doublets in mature transcripts is facilitated by a potent splicing enhancer that was created through duplication within the first exon. The enhancer is the strongest among the NBPF transcripts and further promotes the already high splicing activity of the unexpanded first exons of the two-exon domains, safeguarding the expanded Olduvai exon doublets in the mature transcriptome. The duplication also creates a predicted RNA guanine quadruplex that may regulate the access to spliceosomal components of the super-enhancer and influence the splicing of adjacent exons. Thus, positive Olduvai selection during primate evolution is likely to result from a combination of multiple targets in gene expression pathways, including RNA splicing.