From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Domain of unknown function (DUF1220)
Symbol DUF1220
Pfam PF06758
InterPro IPR010630

DUF1220 is a protein domain that shows a striking human lineage-specific (HLS) increase in copy number and may be important to human brain evolution.[1] The DUF1220 domain name has recently been changed to the Olduvai domain based on data obtained since initial discovery of the domain. [2] 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).[3] 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.[3] 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 rhythmicity, resonance[4] 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 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.[5] 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 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.[6] 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.[3] 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.[3] 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.[7][8]

Association with brain size and evolutionary adaptation[edit]

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.[9] Two independent reports [10][11] 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.[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]

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.[13]

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 [9][14] 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.[9]

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.[9][14]

Associations with autism, schizophrenia and cognitive function[edit]

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[15][16] and severity of negative symptoms in schizophrenia.[17] In contrast, copy number increase of DUF1220 subtypes CON1 and HLS1 is associated with reduced severity of positive symptoms in schizophrenia.[17] 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.[18]

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.[13][19]. This association has important implications for understanding the interplay between cognitive function and autism phenotypes.[20] 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. [14]


  1. ^ a b c Popesco MC, Maclaren EJ, Hopkins J, Dumas L, Cox M, Meltesen L, McGavran L, Wyckoff GJ, Sikela JM (September 2006). "Human lineage-specific amplification, selection, and neuronal expression of DUF1220 domains". Science. 313 (5791): 1304–7. doi:10.1126/science.1127980. PMID 16946073. 
  2. ^ Sikela JM, van Roy F (2018). "A proposal to change the name of the NBPF/DUF1220 domain to the Olduvai domain". F1000Research. 6 (2185): 2185. doi:10.12688/f1000research.13586.1. PMID 29399325. 
  3. ^ a b c d O'Bleness MS, Dickens CM, Dumas LJ, Kehrer-Sawatzki H, Wyckoff GJ, Sikela JM (September 2012). "Evolutionary history and genome organization of DUF1220 protein domains". G3. 2 (9): 977–86. doi:10.1534/g3.112.003061. PMC 3429928Freely accessible. PMID 22973535. 
  4. ^ Perez, J. C.: DUF1220 Homo sapiens and Neanderthal fractal periods architectures breakthrough. SDRP Journal of Cellular and Molecular Physiology 1 (2017) 1-34[1]
  5. ^ Fortna A, Kim Y, MacLaren E, Marshall K, Hahn G, Meltesen L, Brenton M, Hink R, Burgers S, Hernandez-Boussard T, Karimpour-Fard A, Glueck D, McGavran L, Berry R, Pollack J, Sikela JM (July 2004). "Lineage-specific gene duplication and loss in human and great ape evolution". PLoS Biology. 2 (7): E207. doi:10.1371/journal.pbio.0020207. PMC 449870Freely accessible. PMID 15252450. 
  6. ^ Vandepoele K, Van Roy N, Staes K, Speleman F, van Roy F (November 2005). "A novel gene family NBPF: intricate structure generated by gene duplications during primate evolution". Molecular Biology and Evolution. 22 (11): 2265–74. doi:10.1093/molbev/msi222. PMID 16079250. 
  7. ^ Bond J, Woods CG (February 2006). "Cytoskeletal genes regulating brain size". Current Opinion in Cell Biology. 18 (1): 95–101. doi:10.1016/j.ceb.2005.11.004. PMID 16337370. 
  8. ^ Dumas L, Kim YH, Karimpour-Fard A, Cox M, Hopkins J, Pollack JR, Sikela JM (September 2007). "Gene copy number variation spanning 60 million years of human and primate evolution". Genome Research. 17 (9): 1266–77. doi:10.1101/gr.6557307. PMC 1950895Freely accessible. PMID 17666543. 
  9. ^ a b c d Dumas L, Sikela JM (2009). "DUF1220 domains, cognitive disease, and human brain evolution". Cold Spring Harbor Symposia on Quantitative Biology. 74: 375–82. doi:10.1101/sqb.2009.74.025. PMC 2902282Freely accessible. PMID 19850849. 
  10. ^ Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, et al. (December 2008). "Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities". Nature Genetics. 40 (12): 1466–71. doi:10.1038/ng.279. PMC 2680128Freely accessible. PMID 19029900. 
  11. ^ Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, et al. (October 2008). "Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes". The New England Journal of Medicine. 359 (16): 1685–99. doi:10.1056/NEJMoa0805384. PMC 2703742Freely accessible. PMID 18784092. 
  12. ^ a b Dumas LJ, O'Bleness MS, Davis JM, Dickens CM, Anderson N, Keeney JG, Jackson J, Sikela M, Raznahan A, Giedd J, Rapoport J, Nagamani SS, Erez A, Brunetti-Pierri N, Sugalski R, Lupski JR, Fingerlin T, Cheung SW, Sikela JM (September 2012). "DUF1220-domain copy number implicated in human brain-size pathology and evolution". American Journal of Human Genetics. 91 (3): 444–54. doi:10.1016/j.ajhg.2012.07.016. PMC 3511999Freely accessible. PMID 22901949. 
  13. ^ a b Davis JM, Searles VB, Anderson N, Keeney J, Raznahan A, Horwood LJ, Fergusson DM, Kennedy MA, Giedd J, Sikela JM (January 2015). "DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores". Human Genetics. 134 (1): 67–75. doi:10.1007/s00439-014-1489-2. PMID 25287832. 
  14. ^ a b c Sikela JM, Searles Quick VB (January 2018). "Genomic trade-offs: are autism and schizophrenia the steep price of the human brain?". Human Genetics. 137 (1): 1–13. doi:10.1007/s00439-017-1865-9. PMID 29335774. 
  15. ^ Davis JM, Searles VB, Anderson N, Keeney J, Dumas L, Sikela JM (March 2014). "DUF1220 dosage is linearly associated with increasing severity of the three primary symptoms of autism". PLoS Genetics. 10 (3): e1004241. doi:10.1371/journal.pgen.1004241. PMC 3961203Freely accessible. PMID 24651471. 
  16. ^ Davis JM, Searles Quick VB, Sikela JM (June 2015). "Replicated linear association between DUF1220 copy number and severity of social impairment in autism". Human Genetics. 134 (6): 569–75. doi:10.1007/s00439-015-1537-6. PMID 25758905. 
  17. ^ a b Searles Quick VB, Davis JM, Olincy A, Sikela JM (December 2015). "DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases". Translational Psychiatry. 5: e697. doi:10.1038/tp.2015.192. PMC 5068589Freely accessible. PMID 26670282. 
  18. ^ Crespi B, Badcock C (June 2008). "Psychosis and autism as diametrical disorders of the social brain". The Behavioral and Brain Sciences. 31 (3): 241–61; discussion 261–320. doi:10.1017/S0140525X08004214. PMID 18578904. 
  19. ^ Weiss, Volkmar: Das IQ-Gen - verleugnet seit 2015: Eine bahnbrechende Entdeckung und ihre Feinde. Ares Verlag, Graz 2017, ISBN 978-3-902732-87-3
  20. ^ Crespi BJ (2016-01-01). "Autism As a Disorder of High Intelligence". Frontiers in Neuroscience. 10: 300. doi:10.3389/fnins.2016.00300. PMC 4927579Freely accessible. PMID 27445671. 

Further reading[edit]

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