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 copies that are present in connection with Olduvai seems to have a direct correlation with several phenotypes of the brain including the increase in brain size as seen through evolution.
In the human genome, DUF1220 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. Sequences encoding DUF1220 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.
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.
DUF1220 copy number variation have 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 DUF1220 subtype CON1 is linearly associated with increasing severity of social impairment in autism. This evidence is relevant for current theories proposing that the two disorders 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 is a neurological condition in which there are issues in brain development. In contrast with autism, copy number increase of DUF1220 subtypes CON1 and HLS1 is associated with reduced severity of positive symptoms in schizophrenia. As a result of the direct correlation between brain size and schizophrenia, along with the correlations between brain size and the DUF1220 protein domain, it can be assumed that there is also a correlation between schizophrenia and the DUF1220 protein domain.
Cognitive brain 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 DUF1220 and brain size found that DUF1220 copy number decrease is associated with microcephaly in individuals with 1q21 CNVs. Of all 1q21 sequences tested, DUF1220 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 DUF1220 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 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 towards 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.
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. 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. 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. The first Olduvai domain located outside of myomegalin is seen approximately 100–150 million years ago, when the domain was included in a duplication and transposition event which created a new gene, NBPF1, which would eventually later give rise to a family of duplicated NBPF genes. At least one NBPF gene has been found in Laurasiatherians, Euarchontoglires and elephants (but not other Afrotherians), but not in Xenarthrans (containing sloths). It was also found that several rodents, bats and eulipotyphla (containing hedgehogs) had lost the gene.
It was found in 2012 that the exceptional increase in human Olduvai copy number was a result of multiple duplications within the NBPF genes primarily involving a sequential series of three variants of the domain. These three variants were also found in gorilla and chimpanzee genomes but are not repeated in triplet form and are only present in around five copies overall. Based on this, the variants were given the names HLS1, HLS2 and HLS3, for human lineage-specific, and together they were named the HLS DUF1220 triplet. Hyper-amplification of the triplet resulted in the addition of ~149 copies of Olduvai specifically to the human lineage since its divergence from the genus Pan (chimpanzees and bonobos) approximately 6 million years ago.
Evolutionary adaptation in humans
In 2009, it was proposed that the larger brain size conferred by a high number of Olduvai domain copies in humans carried an evolutionary advantage which led to the persistence and maintenance of Olduvai copies within this high range. 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, and the researchers referenced various studies from 2005 to 2009 that found that a higher number of copies contributed to autism severity while a lower number contributed to schizophrenia severity. Since these disorders are fairly common among humans, it was proposed that this explained their prevalence. This model 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.
In 2012, a genetic explanation for the high instability and persistence of the Olduvai-containing regions was put forward: it was found that the HLS Olduvai domains had been affected by a known pericentric inversion (in which the region around a chromosome's centromere inverts) that occurred between 1p11.2 and 1q21.2 in the human lineage after the separation from chimpanzees. This was theorised 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 which can lead to non-allelic homologous recombination, in which deletions and duplications are much more propense to occur. This, combined with the fact that higher copies of Olduvai domains may have had an evolutionary advantage, could've resulted in the rapid duplication and persistence of Olduvai domains in humans.
Relation to NOTCH2NL genes in brain development
There are four human-specific NOTCH2NL genes: NOTCH2NLA, NOTCH2NLB and NOTCH2NLC, located on 1q21.1, and NOTCH2NLR located on 1p11.2. While chimpanzee and gorilla have copies of NOTCH2NL, none are functional. Immediately adjacent to, and downstream of, each of these four NOTCH paralogs is an NBPF gene with its DUF1220 domains in the same orientation as its NOTCH2NL partner. This striking genomic arrangement suggests that each of the additional copies of NOTCH2NL that appeared in the human genome did not duplicate as a single gene, but rather did so as a two-gene module, composed of one NOTCH2NL gene and one NBPF gene. While the NOTCH2NL paralogs (and their NBPF partners) went from one gene to four in humans, DUF1220 copies encoded by these NBPF genes underwent human-specific hyper-amplification, increasing from 13 copies (encoded by NBPF26) to 132 (i.e., adding 119 DUF1220 copies encoded by NBPF10, NBPF14 and NBPF19).
The Olduvai domain was first identified in 2004 in a study of copy number differences between human and great ape species using genome-wide array comparative genomic hybridization (CGH), which takes single DNA strands from each source and hybridizes them, or joins them such that they line up, and uses fluorescent dyeing, which shows different colours where the two strands no longer line up. The study found 134 genes that showed human lineage-specific increases in copy number, one of which, NBPF15 (then known as MGC8902, cDNA IMAGE:843276), contained six Olduvai domains. The domain remained unnamed as of that time and was given a Pfam placeholder name for domains of unknown function when entered into its database.
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. The researchers noticed that a novel protein domain that seemed to match the DUF1220 Pfam entry was present in multiple copies in this gene and in several other places on chromosome 1, which led them to establish 22 NBPF genes, and they named the domain the NBPF repeat.
In 2018, DUF1220 was renamed 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.
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