|Domain of unknown function (DUF1220)|
DUF1220 is a protein domain of unknown function that shows a striking human lineage-specific (HLS) increase in copy number and may be important to human brain evolution. The copy number of DUF1220 domains increases generally as a function of a species evolutionary proximity to humans. DUF1220 copy number is highest in human (~289, with some person-to-person variations). 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. DUF1220 domains are approximately 65 amino acids in length and are encoded by a two-exon doublet. 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 signs of positive selection, especially in primates, and are expressed in several human tissues including brain, where their expression is restricted to neurons.
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. 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. DUF1220 protein domains are found almost exclusively in the NBPF 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. 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. 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. The ancestral DUF1220 domain is not part of the NBPF family but rather is found as a single copy within the PDE4DIP (Myomegalin) gene. 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.
Association with Brain Size and Evolutionary Adaptation
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. Two independent reports  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. 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.
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.
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 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 those resulting from 1q21.1 duplication syndrome and 1q21.1 deletion syndrome.
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.
Associations with Psychiatric Disease and Cognitive Function
DUF1220 copy number variation has more recently been investigated in autism and schizophrenia, as both disorders are 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 and severity of negative symptoms in schizophrenia. In contrast, copy number increase of DUF1220 subtypes CON1 and HLS1 is associated with reduced severity of positive symptoms in schizophrenia. 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.
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. This association has important implications for understanding the interplay between cognitive function and autism phenotypes.
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