A human transcriptomic deletion links cortical expansion and cancer [Bulk RNA-seq]

Despite this, relatively few studies have investigated the functional impacts of human-specific alternative splicing. Here, we analyze RNA-sequencing data from nine iPSC-derived cell types and identify dozens of human transcriptomic conserved deletions (htCONDELs): evolutionary divergence in splicing that leads to the partial or full removal of conserved protein-coding sequence from the human transcriptome.

We investigated one example in detail: an htCONDEL in the gene HMMR, which encodes a microtubule binding, centrosomal protein that regulates mitosis. We found that this htCONDEL, which produces a human-specific isoform lacking a conserved microtubule-binding domain, enables cells to flexibly divide with a broader range of mitotic spindle orientations in vitro. Introducing the human HMMR isoform into mice similarly alters the orientation of cell division in the developing neocortex and increases the production of outer radial glia-cell like, the expansion of which played an essential role in increasing human brain size.