The Olduvai domain, known until 2018 as DUF1220 (domain of unknown function 1220) and the NBPF repeat, is a protein domain that shows a striking human lineage-specific (HLS) increase in copy number and appears to be involved in human brain evolution. The protein domain has also been linked to several neurogenetic disorders such as schizophrenia (in reduced copies) and increased severity of autism (in increased copies). In 2018, it was named by its discoverers after Olduvai Gorge in Tanzania, one of the most important archaeological sites for early humans, to reflect data indicating its role in human brain size and evolution.
Olduvai domains form the core of NBPF genes, which first appeared in placental mammals and experienced a rapid expansion in monkeys (simians) through duplication to reach over 20 genes in humans. In humans, Olduvai domains are repeated often dozens of times within these genes. The only other gene an Olduvai domain has been found in is mammalian myomegalin, believed to be the origin of the NBPF genes via duplication. Myomegalin itself arose from a duplication of CDK5RAP2, and all of these genes have been implicated in the development of neurons.
Olduvai copy number is the highest in humans (~289, with person-to-person variations), reduced in African great apes (~125 copies in chimpanzees, ~99 in gorillas, ~92 in orangutans), further reduced in Old World monkeys (~35), single- or low-copy in non-primate mammals, and absent in non-mammals. Consequently, the Olduvai domain demonstrates the largest HLS increase in copy number of any protein-coding region over any other living species, an additional ~160 copies compared with chimpanzees. The increase in the number of Olduvai copies as one moves from monkeys to apes and then to humans shows strong direct correlations with several brain-related phenotypes, including brain size, neuron number, gyrification index, and gray and white matter volumes. An independent study of 12 primate species found a robust association between Olduvai copy number and brain size and, more specifically, neocortex volume.
In the human genome, Olduvai sequences are located primarily on chromosome 1 in region 1q21.1-q21.2, with several copies also found at 1p36, 1p13.3, and 1p12. They are approximately 65 amino acids in length and are encoded by a two-exon doublet. Olduvai domains can be divided into six primary subtypes that appear in the following order in primate-type NBPF genes: CON1, CON2, HLS1, HLS2, HLS3, and CON3 (CON stands for conserved, HLS for human-lineage specific). Sequences encoding Olduvai domains show rhythmicity, resonance and signs of positive selection, especially in primates, and are expressed in several human tissues including brain, where their expression is restricted to neurons. The various HLS domains do not show any interactions, as suggested by nuclear magnetic resonance backbone chemical shift analyses.
In human-specific genes, the arrangement of the copies follows a higher order (triplets).
Occurrence As mentioned before, there are six subtypes of Olduvai. In non-primate NPBF, the pattern is generally CON1-CON2, for a total of 2 to 4 Olduvai domains, with an upstream CM promoter. In primate NPBF, a new type features the pattern CON1-CON2-HLS1-HL2-HLS3-CON3, with both CM and EVI5 promoters. Humans harbor both types and a new hyperamplified type derived from the primate type with many more copies of the HLS1-HLS2-HLS3 triplet.
Function Research has found that the Olduvai domain has a role in the development of neurons. Specifically, it appears to function to increase the number of neural stem cells by prolonging the developmental period of neurons. When Olduvai copy number is reduced, neurons appear to mature faster and divide less. Conversely, when Olduvai copy number is increased, neurons appear to mature for longer and divide in higher numbers. Consistent with this effect, introduction of the NBPF15 gene, encoding 6 Olduvai domains, in human neural stem cells promoted proliferation.
In mouse transgenic experiments, when the single copy of Olduvai is removed from the mouse genome, the resulting "Olduvai-minus" mice produce fewer offspring and show significant hyperactivity.
Clinical significance
Autism 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. Such research has found that copy number of Olduvai subtype CON1, but not of other Olduvai subtypes, is linearly associated with increasing severity of social impairment in autism. This evidence is relevant for current theories proposing that autism and psychosis are fundamentally related. The precise nature of this relationship is currently under debate, with alternative lines of argument suggesting that the two are diametrically opposed diseases, exist on a continuum, or exhibit a more nuanced relationship.
Schizophrenia Schizophrenia is a neurological condition in which there are issues in brain development. In contrast with autism, copy number increase of Olduvai subtypes CON1 and HLS1 is associated with reduced severity of positive symptoms in schizophrenia.
Cognitive function and brain size The dosage of the Olduvai protein domain increases along with brain size, which is seen through the evolution from primates to humans. Targeted 1q21 array CGH investigation of the potential association between Olduvai and brain size found that Olduvai copy number decrease is associated with microcephaly in individuals with 1q21 CNVs. Of all 1q21 sequences tested, Olduvai sequences were the only ones to show consistent correlation between copy number and brain size in both disease (micro/macrocephaly) and non-disease populations. In addition, in primates there is a significant correlation between Olduvai copy number and both brain size and brain cortical neuron number.
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. The study specifically studied the Olduvai variants CON1 and CON2, noting that measurement of the very high copy number HLS1–3 variants had been challenging given technologies currently available. It found that those with a higher number of copies of CON2 had higher scores on the WISC IQ test and the Progressive Achievement Mathematics test. The strength of the association between CON2 and IQ was reported to be greater than that of any other single genetic candidate reported in any previous study. This effect was significantly more profound in males. The CON2 copy number of most of the males ranged from 26 to 33, with a mean of 29, and each additional copy was associated with an average IQ score increase of 3.3. CON1 number, on the other hand, was not found to have a significant association with IQ scores.
Brain region associations were also studied. CON1 and CON2 copy number were found to raise the volumes and areas of all four bilateral lobes of the brain studied. Most notably, right frontal lobe surface area showed the strongest association with both CON1 and CON2 copy number. This association was slightly stronger with CON2 copy number. There were no CON1 or CON2 associations with white matter volume or gyrification index. CON1 and CON2 number had been previously found to correlate to grey matter volume in another study.
These volume and area increases in the grey matter of all cerebral lobes were found to significantly correlate with higher IQ scores. Notably, bilateral temporal surface area appeared to correlate with a progressive increase in IQ, with left temporal surface area being slightly more important. However, it was found that CON2's effects on IQ remained substantial even after eliminating bilateral temporal surface area, right frontal lobe surface area, and total grey matter volume as factors. A portion of CON2's association with IQ, however, was through its effects on bilateral temporal surface area. Notably, this contribution to IQ was larger than that of its effects on right frontal lobe surface area, despite the fact that it increased this area the most. It was concluded that the Olduvai domain appears to have a role in neural stem cell proliferation, since this proliferation seems to be the major contributor to lobe surface area while also explaining the effects of Olduvai dosage that could not be explained by brain region measurements. Corroborating this are stem cell cultures that have also shown Olduvai's proliferative effects on neuronal stem cells. However, Olduvai also had effects on cortical thickness that appeared to be the result of mature neuron cell divisions, corroborated by higher neuron numbers in primates being associated with Olduvai copy number. Additionally, studies have shown that cerebral size in primates is almost exclusively correlated with a linear addition of neurons, rather than neuronal size or density.
It was found that CON2's effects on IQ were strongly dependent on sex. There was no significant association found in females. Additionally, it was found that males with higher CON2 numbers appeared to have the largest increases in IQ over other males of the same age at a mean age of 11 years old. The correlation then appeared to decrease with age. A proportional advantage was also present in younger individuals. This corroborated studies that have shown that brain growth in the brightest children, and children with autism, increases after birth and peaks at around age 11 or 12 before slowing down in adulthood. In the second group, birth head circumference was not found to significantly affect IQ, further corroborating these studies. 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.
This association has important implications for understanding the interplay between cognitive function and autism phenotypes. These findings also provide additional support for the involvement of Olduvai in a genomic trade-off model involving the human brain: the same key genes that have been major contributors to the evolutionary expansion of the human brain and human cognitive capacity may also, in different combinations, underlie psychiatric disorders such as autism and schizophrenia.
1q21.1 deletion and duplication syndromes Olduvai domains are one of the many genetic elements located in the 1q21.1 region, which has a high number of repeated elements and therefore a high tendency toward deletions and duplications. This has led to several conditions that involve this region being identified, including TAR syndrome and the more general classifications of 1q21.1 deletion syndrome and 1q21.1 duplication syndrome.
Studies of deletions and duplications in the 1q21.1 region have consistently revealed microcephaly in association with deletions and macrocephaly in association with duplications.
Evolution