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 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]

The dosage of the Olduvai protein domain increases along with brain size, which is seen through the evolution from primates to humans.[3] 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.[12] 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.[12]

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.[13]

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 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.[13] 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.[13]

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]

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]

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 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 have resulted in the rapid duplication and persistence of Olduvai domains in humans.[3]