A recently evolved TAF8 isoform arising from an <i>Alu</i> insertion increases TFIID assembly complexity in the human lineage

Despite its centrality in regulating RNA polymerase II transcription in all eukaryotes, the TFIID general transcription factor exhibits several layers of variability across different tissues and developmental stages, representing an underexplored hub of evolutionary innovation. Here, we describe a novel short isoform of TAF8 (TAF8s) - a TFIID scaffold subunit - which evolved from the use of an intronic polyadenylation site (iPAS) in the human lineage. Comparative genomics analyses show that the emergence of <i>TAF8s</i> expression in the human lineage coincides with minute DNA changes in the iPAS at the edge of a FLAM-C <i>Alu</i> element that inserted into intron 5 in the common ancestor of anthropoid primates (Simiiformes). The human-specific <i>TAF8s</i> isoform lacks nearly half of the canonical coding sequence, is widely expressed across human tissues, and constitutes a substantial fraction of the <i>TAF8</i> transcript pool. <i>TAF8s</i> is translated into a truncated protein isoform that lacks the nuclear-localization signal and localises in the cytoplasm. TAF8s interacts with its histone-fold partner TAF10 and other core TFIID subunits, while entirely losing its interactions with TAF2, thus giving rise to alternative TFIID sub-complexes in human cells. Our study suggests that the TFIID complex underwent a recent diversification through a stepwise evolutionary acquisition of complexity in the <i>TAF8</i> locus in the human lineage, leading to the expression of a novel truncated pan-isoform that might work as a modulator of TFIID assembly. We discuss the ramifications of our findings in TFIID complex diversification, its evolvability, and the genetics of TAF-related congenital disorders.