Olduvai domain

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 NBPF genes: CON1, CON2, HLS1, HLS2, HLS3, and CON3. 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.

The arrangement of the copies follows a higher order.