[4][5] An independent study of 12 primate species found a robust association between Olduvai copy number and brain size and, more specifically, neocortex volume.
[2] The various HLS domains do not show any interactions, as suggested by nuclear magnetic resonance backbone chemical shift analyses.
Specifically, it appears to function to increase the number of neural stem cells by prolonging the developmental period of neurons.
[9] Consistent with this effect, introduction of the NBPF15 gene, encoding 6 Olduvai domains, in human neural stem cells promoted proliferation.
[10] Olduvai copy number variation has recently been investigated in autism, which is a disorder associated with deletions and duplications of 1q21, yet the causative loci within such regions have not previously been identified.
[15] In contrast with autism, copy number increase of Olduvai subtypes CON1 and HLS1 is associated with reduced severity of positive symptoms in schizophrenia.
[4] A 2015 study found that Olduvai copy number is linearly correlated with increased cognitive function, as measured by total IQ and mathematical aptitude scores, a finding replicated in two independent groups from different countries.
[4] These volume and area increases in the grey matter of all cerebral lobes were found to significantly correlate with higher IQ scores.
The second cohort had previously had a genetic analysis rule out any effect on IQ of other genome-wide copy number variations they had, further suggesting a critical period of activity of CON1 and CON2.
[20][21][22] Genome sequences indicate that the Olduvai protein domain first appears as part of the myomegalin gene (PDE4DIP) on chromosome 1q36 in mammals at least 200 million years ago.
[3] Myomegalin is a paralog (duplicated relative) of CDK5RAP2, a centrosomal protein involved in the cell cycle, of neurons especially that lacks Olduvai sequences but, when mutated, has been implicated in microcephaly.
[23][24] Orthologs of myomegalin can be seen in vertebrates as far back as bony fish, around 450 million years ago; however, the Olduvai domain is not clearly seen until the emergence of mammals.
At the same time, the Olduvai domains, like many other repetitive genetic elements, are highly susceptible to increases and decreases in number of copies, through duplications or deletions.
[22] This “genomic trade-off” model, in which Olduvai sequences can have beneficial or detrimental effects depending on how they vary, was elaborated on in more detail in a 2018 article that included one of the original authors, in light of new evidence in the intervening years.
This was theorized to have contributed to their hyper-amplification specifically in humans because pairs of chromosomes in which one contains a pericentric inversion and the other does not (a form of heterozygosity) have difficulties in recombination.
[25] The paired Olduvai/NOTCH2NL sequences are also strikingly co-regulated, showing high co-expression in outer radial glial cells in the developing human cortex.
Taken together, these findings suggest that human-specific Olduvai domains and adjacent NOTCH2NL genes may function in a coordinated, complementary fashion to promote neurogenesis and human brain expansion in a dosage-related manner.
All four of these expanded NBPF genes lie in the chromosome 1q21 region, which is known to be a duplication-rich hotspot of human genome instability and evolution.
[1][27] It has been shown that these human-specific Olduvai domains are post-translationally processed by the furin protease, with a cleavage site occurring once at each triplet.
[29] These results indicate that all expanded human-specific NBPF genes encode proproteins consisting of many independent Olduvai triplet proteins, which are activated by furin processing.
The Olduvai protein domain was first identified in 2004 in a study of gene copy number differences between human and great ape species using genome-wide array comparative genomic hybridization (arrayCGH).
[1] The NBPF (neuroblastoma breakpoint family) gene family, which contains all the known Olduvai domains except the one found in myomegalin, was independently identified by Vandepoele et al. in 2005 as a result of a gene (which was named NBPF1) being found to have existed at and been disrupted by a chromosomal translocation at 1q36 (i.e. it was located at the breakpoint) in a boy with neuroblastoma reported by G. Laureys et al. in 1990.