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Domain of unknown function (DUF1220)

DUF1220 is a protein domain that shows a striking human lineage-specific (HLS) increase in copy number and may be involved in human brain evolution.[1] The protein domain has also been linked to several neurogenetic disorders such as schizophrenia and increased severity of autism.[2] In 2018, the name of the DUF1220 domain was changed to the Olduvai domain based on data obtained since initial discovery of the domain.[3]

The copy number of DUF1220 domains increases generally as a function of a species's evolutionary proximity to humans. The increase in the number of copies that are present in connection with DUF1220 also seem to have a direct correlation with several phenotypes of the brain including the increase in brain size as seen through evolution.[4] DUF1220 copy number is the highest in humans (~289, with some person-to-person variations)[5] and shows the largest HLS increase in copy number (an additional 160 copies) of any protein coding region in the human genome. DUF1220 copy number is reduced in African great apes (estimated 125 copies in chimpanzees), further reduced in orangutan (92) and Old World monkeys (35), single- or low-copy in non-primate mammals and absent in non-mammals.[5] DUF1220 domains are approximately 65 amino acids in length and are encoded by a two-exon doublet. The various HLS domains do not show any interactions as suggested by Nuclear magnetic resonance backbone chemical shift analyses. [6] 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. Sequences encoding DUF1220 domains show rhythmicity, resonance[7] and signs of positive selection, especially in primates, and are expressed in several human tissues including brain, where their expression is restricted to neurons.[1]


The ancestral DUF1220 protein domain was first seen at least 100–150 million years ago as part of the PDE4DIP (Myomegalin) gene.[2] PDE4DIP encodes a centrosomal protein and is a homolog of CDK5RAP2, a gene that lacks DUF1220 sequences and, when mutated, has been implicated in microcephaly.[8][9] Emergence of the protein domain could have been seen as a precursor that emerged in some non-mammalian organisms around 450 million years ago, however, the domain was not clearly seen until the emergence of the mammalian lineages.[2] The timeframe for these findings was determined based upon the genomes of the four sister placental mammals; elephants, hoofed animals, carnivores, and supra primates.[2] The gene showing a human-specific increase in DUF1220 copy number was first identified as the result of a genome-wide array CGH study of lineage-specific copy number differences between human and great ape species.[10] The study found 134 genes that showed human lineage-specific increases in copy number, one of which, MGC8902 (also known as NBPF15, cDNA IMAGE:843276), encoded 6 DUF1220 domains.[1] DUF1220 protein domains are found almost exclusively in the NBPF(Neuroblastoma Breakpoint Family) gene family (which includes the MGC8902 gene), which was independently identified as a result of the first member of this family being disrupted in an individual with neuroblastoma.[11] It was recently found that the exceptional increase in human DUF1220 copy number was the results of intragenic domain hyper-amplification primarily involving the three-domain unit called the HLS DUF1220 triplet.[5] Hyper-amplification of the triplet resulted in the addition of ~149 copies of DUF1220 specifically to the human lineage since its divergence from the Pan species, chimpanzee and bonobo, approximately 6 million years ago.[5]

Association with brain size[edit]

The dosage of the DUF1220 protein domain increases along with brain size which is seen through the evolution from primates to humans.[2] An increasingly large number of disease-associated copy number variations (CNVs) have been reported in the 1q21.1 region and these CNVs either encompass or directly flank DUF1220 domain sequences.[12] Two independent reports [13][14] have linked reciprocal 1q21.1 deletions and duplications in this region with microcephaly and macrocephaly, respectively, raising the possibility that DUF1220 copy number may be involved in influencing human brain size. 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.[15] 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.[15]

More recent research using MRI measurements of brain surface areas and volumes in healthy individuals has better localized associations with DUF1220 copy number. This work has implicated DUF1220 copy number in multiple brain volume and surface area measurements.[16]

Tandem involvement of DUF1220 domains and NOTCH2NL genes in human brain evolution[edit]

There are four human-specific NOTCH2NL genes: NOTCH2NL-A, NOTCH2NL-B and NOTCH2NL-C, located on 1q21.1, and NOTCH2NL-R located on 1p11.2. While chimpanzee and gorilla have copies of NOTCH2NL, none are functional. Immediately adjacent to, and downstream of, each of these four NOTCH paralogs is an NBPF gene with its DUF1220 domains in the same orientation as its NOTCH2NL partner. This striking genomic arrangement suggests that each of the additional copies of NOTCH2NL that appeared in the human genome did not duplicate as a single gene, but rather did so as a two-gene module, composed of one NOTCH2NL gene and one NBPF gene. While the NOTCH2NL paralogs (and their NBPF partners) went from one gene to four in humans, DUF1220 copies encoded by these NBPF genes underwent human-specific hyper-amplification, increasing from 13 copies (encoded by NBPF26) to 132 (i.e., adding 119 DUF1220 copies encoded by NBPF10, NBPF14, and NBPF19).[17]

Evolutionary adaptation[edit]

Improved characterization of the genomic architecture of chromosome 1 in a new genomic assembly has allowed for more refined analysis of the location and sequence of DUF1220 domains. Included among the findings was the identification of 20 additional DUF1220 domains in the genome that were added via a duplication from 1q21.2 to 1p11.2. This in turn may have mediated the HLS pericentric inversion on chromosome 1, an important evolutionary event.

For the above reasons and because DUF1220 sequences at 1q21.1 have undergone a dramatic and evolutionarily rapid increase in copy number in humans, a model [12][18] has been developed that proposes that:

1) increasing DUF1220 domain dosage is a driving force behind the evolutionary expansion of the primate (and human) brain,

2) the instability of the 1q21.1 region has facilitated the rapid increase in DUF1220 copy number in humans, and

3) the evolutionary advantage of rapidly increasing DUF1220 copy number in the human genome has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders. These include autism and schizophrenia (as discussed below) and other disorders resulting from 1q21.1 duplication syndrome and 1q21.1 deletion syndrome.[12]

From this perspective, disease-associated 1q21.1 CNVs may be the price the human species paid, and continues to pay, for the adaptive benefit of having large numbers of DUF1220 copies in its genome.[12][18]

Associations with autism[edit]

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.[19][20] This evidence is relevant for current theories proposing that the two disorders 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.[21]

Associations with schizophrenia[edit]

Schizophrenia is a neurological condition in which there are issues in brain development.[22] In contrast with Autism, copy number increase of DUF1220 subtypes CON1 and HLS1 is associated with reduced severity of positive symptoms in schizophrenia.[23] As a result of the direct correlation between brain size and schizophrenia, along with the correlations between brain size and the DUF1220 protein domain, it can be assumed that there is also a correlation between schizophrenia and the DUF1220 protein domain.

Cognitive brain function[edit]

Cognitive dysfunction is a feature of multiple neuropsychiatric diseases, and many individuals with 1q21 deletion and duplication syndromes have developmental delay. Given this, the role of DUF1220 in cognitive function has been investigated. Results of this research demonstrate that DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores, a finding identified in two independent populations.[16][24] This association has important implications for understanding the interplay between cognitive function and autism phenotypes.[25] These findings also provide additional support for the involvement of DUF1220 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.[18]


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Further reading[edit]

This article incorporates text from the public domain Pfam and InterPro: IPR010630