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.
… excerpt ends here. Continue reading the full article.
