The Olduvai domain, known until 2018 as DUF1220 (domain of unknown function 1220) and the NBPF repeat,[1] 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.[2] 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).[3] 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.[1]
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.[3] 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.[4]
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.[2] The various HLS domains do not show any interactions as suggested by nuclear magnetic resonance backbone chemical shift analyses.[5]