Identifying the genes that evolved to give humans big brains

These two papers [see attached] go, hand-in-glove, with the previous GEITP article (shared yesterday) –– which described human-ape brain differences that had evolved during evolution. Human brains are characterized by a large neocortex that forms the foundation for development of human-specific cognitive functions (i.e. the mental processes of acquiring knowledge and understanding –– through thought, experience, and the senses), but evolutionary changes to the human genome underlying this increase in size and complexity are not well understood (i.e. why are we smarter than the apes? –– or why do we at least THINK we are smarter than the apes?). Structural genomic variants (DNA sequence alterations that code for brain or other anatomical structures) account for ~80% of human-specific base-pairs (bp; pairs of nucleotides).

Of particular interest are genetic loci –– where segmental duplications of a chromosomal segment have created entirely new human-specific gene paralogs (genes closely related in DNA sequence to another gene, in the same organism –– which are derived from a single ancestral gene that was duplicated, and that may have a different biological functions) associated with brain cortex development (e.g. new genes such as SRGAP2C, ARHGAP11B, & TBC1D3). One such region lies on human chromosome band 1q21, which was subject to a large inversion, leading sometimes to considerable gene loss, as well as gene duplication, during human evolution. The 1q21 locus contains a disproportionate number of human-specific genes. De novo deletion of one copy frequently leads to a substantial decrease in brain size (i.e. mIcrocephaly), and duplication of this region leads to increased brain size (i.e. mAcrocephaly). (Loss of both copies of this region, of course, is incompatible with life.)

The Notch-signaling pathway is a highly conserved cell-signaling system present in virtually all multicellular organisms (i.e. from sponge and sea squirt to reptiles, birds and humans). Mammalian genomes usually carry four different NOTCH genes (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) –– each of which encodes a Notch receptor. Notch-signaling is essential for radial glia stem cell proliferation and is a determinant of the number of neurons in the mammalian cortex. Authors [first attached paper] found three paralogs of human-specific NOTCH2NL that are highly expressed in radial glia. Functional analysis showed that different alleles of NOTCH2NL have varying potencies to enhance Notch-signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch-signaling, NOTCH2NL high-expression delays differentiation of neuronal progenitors, whereas deletion accelerates differentiation into cortical neurons.

Intriguingly, NOTCH2NL genes provide the breakpoints in the “1q21.1 distal deletion/duplication syndrome” in which duplications are associated with mAcrocephaly and autism, and deletions are associated with mIcrocephaly and schizophrenia. Authors conclude that the emergence of human-specific NOTCH2NL genes –– may have been pivotal in the rapid evolution of the larger human neocortex –– accompanied by loss of genomic stability at the 1q21.1 locus, with the resultant association of various recurrent neurodevelopmental disorders.

Using tailored RNA-sequencing (RNA-seq), authors [second attached paper] profiled the spatial and temporal expression of hominid-specific duplicated genes in the human fetal cortex and identified a repertoire of 35 hominid-specific genes that exhibited robust and dynamic patterns during cortical neurogenesis. Among them –– NOTCH2NL (human-specific paralogs of the NOTCH2 receptor) were prominent for their capacity to promote cortical progenitor maintenance –– ultimately leading to higher neuronal output. At the molecular level, NOTCH2NL genes function by activating the Notch-signaling pathway through inhibition of cis (i.e. nearby) Delta/Notch interactions. This study complements and expands the first study [above], revealing a large repertoire of recently evolved genes active during human corticogenesis. Even more importantly, these data strongly suggest a means by which human-specific NOTCH paralogs are likely to have contributed to the expansion of the human cortex, resulting in large differences seen between the brain of hominids versus that of apes.


Cell 2o18; 173: 1356–1379 & 1370–1384

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