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

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.[1] 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 (over 270, with some person-to-person variations).[2] 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.[2] 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.[1]

DUF1220 history[edit]

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.[3] 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.[4] 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.[2] Hyper-amplification of the triplet resulted in the addition of ~149 copies of DUF1220 specifically to the human lieage since its divergence from the Pan species, chimpanzee and bonobo, approximately 6 million years ago.[2] 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.[5][6]

Links with disease 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.[7] Two independent reports [8][9] 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. More recently, Dumas et al.[10] used targeted 1q21 array CGH to follow up on this possibility and implicated DUF1220 copy number loss in 1q21-associated microcephaly. 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 of DUF1220 copy number with brain size as well as with brain cortical neuron number.[10] 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 the primary 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.

From this perspective, the large number of 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.[7]

These observations suggest that the 1q21.1 genome instability problems DUF1220 sequences are thought to promote may be one of the triggers of 1q21.1 duplication syndrome and 1q21.1 deletion syndrome.[7]

Inheritance of general intelligence[edit]

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.[11]


  1. ^ a b c Popesco MC, Maclaren EJ, Hopkins J, Dumas L, Cox M, Meltesen L et al. (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. ^ a b c d O'Bleness MS, Dickens CM, Dumas LJ, Kehrer-Sawatzki H, Wyckoff GJ, Sikela JM (2012). "Evolutionary history and genome organization of DUF1220 protein domains". G3 (Bethesda) 2 (9): 977–86. doi:10.1534/g3.112.003061. PMC 3429928. PMID 22973535. 
  3. ^ Fortna A, Kim Y, MacLaren E, Marshall K, Hahn G, Meltesen L et al. (2004). "Lineage-specific gene duplication and loss in human and great ape evolution". PLoS Biol. 2 (7): E207. doi:10.1371/journal.pbio.0020207. PMC 449870. PMID 15252450. 
  4. ^ Vandepoele K, Van Roy N, Staes K, Speleman F, van Roy F (2005). "A novel gene family NBPF: intricate structure generated by gene duplications during primate evolution". Mol. Biol. Evol. 22 (11): 2265–74. doi:10.1093/molbev/msi222. PMID 16079250. 
  5. ^ Bond J, Woods CG (2006). "Cytoskeletal genes regulating brain size". Curr. Opin. Cell Biol. 18 (1): 95–101. doi:10.1016/j.ceb.2005.11.004. PMID 16337370. 
  6. ^ Dumas L, Kim YH, Karimpour-Fard A, Cox M, Hopkins J, Pollack JR et al. (2007). "Gene copy number variation spanning 60 million years of human and primate evolution". Genome Res. 17 (9): 1266–77. doi:10.1101/gr.6557307. PMC 1950895. PMID 17666543. 
  7. ^ a b c Dumas L, Sikela JM (2009). "DUF1220 domains, cognitive disease, and human brain evolution". Cold Spring Harb. Symp. Quant. Biol. 74: 375–82. doi:10.1101/sqb.2009.74.025. PMC 2902282. PMID 19850849. 
  8. ^ Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T et al. (2008). "Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities". Nat. Genet. 40 (12): 1466–71. doi:10.1038/ng.279. PMC 2680128. PMID 19029900. 
  9. ^ Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K et al. (2008). "Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes". N. Engl. J. Med. 359 (16): 1685–99. doi:10.1056/NEJMoa0805384. PMC 2703742. PMID 18784092. 
  10. ^ a b Dumas LJ, O'Bleness MS, Davis JM, Dickens CM, Anderson N, Keeney JG et al. (2012). "DUF1220-domain copy number implicated in human brain-size pathology and evolution". Am. J. Hum. Genet. 91 (3): 444–54. doi:10.1016/j.ajhg.2012.07.016. PMID 22901949. 
  11. ^ Davis JM, Searles VB, Anderson N, Keeney J, Raznahan A, Horwood LJ et al. (2015). "DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores". Hum. Genet. 134 (1): 67–75. doi:10.1007/s00439-014-1489-2. PMID 25287832. 

Further reading[edit]

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