Olduvai domain

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.[7]^[8] 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.^[9]

Schizophrenia

Schizophrenia is a neurological condition in which there are issues in brain development.^[10] In contrast with autism, copy number increase of DUF1220 subtypes CON1 and HLS1 is associated with reduced severity of positive symptoms in schizophrenia.^[11]

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.

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.^[13]

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.^[13]

It was found that CON2's effects on IQ were

This association has important implications for understanding the interplay between cognitive function and autism phenotypes.[14] 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.^[15]

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.

Studies of deletions and duplications in the 1q21.1 region have consistently revealed microcephaly in association with deletions and macrocephaly in association with duplications.^[16][17][18]

Evolution

Genome sequences indicate that the Olduvai protein domain first appears as part of the

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.^[3]

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.^[18] 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.^[15]

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