DUF1220

Domain of unknown function (DUF1220)
Identifiers
Symbol	DUF1220
Pfam	PF06758
InterPro	IPR010630
PROSITE	PS51316
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

DUF1220 is a protein domain of unknown function that shows a striking human-specific 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 200, with some person-to-person variations). It is reduced in African great apes (estimated 37 copies in chimpanzees), further reduced in orangutan and Old World monkeys, single copy in most 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, 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

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.^[2] 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.^[3] MGC8902 and similar sequences appear 49 times in the human reference genome. Almost all of these 49 occurrences lie in the regions 1q21.1 and 1q21.2 of chromosome 1, and many of them are now defined as distinct genes within the NBPF family. 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.^[4][5]

Links with Disease 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.^[6] 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.^[7][8] In primates there is a significant correlation between DUF1220 copy number and brain size. For these reasons and because DUF1220 sequences at 1q21.1 have undergone a dramatic increase in copy number in humans and appear to be under positive selection, a model has been developed that proposes that 1) DUF1220 is involved in the evolution of brain size, 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.^[6]

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.^[6]

References

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. ^ 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 Biol 2: 937–954. doi:10.1371/journal.pbio.0020207. PMC 449870. PMID 15252450. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=449870. 
3. ^ 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". Mol. Biol. Evol. 22 (11): 2265–74. doi:10.1093/molbev/msi222. PMID 16079250. 
4. ^ Bond J, Woods,CG (February 2006). "Cytoskeletal genes regulating brain size". Curr. Opin. Cell Biol 18 (1): 95–101. doi:10.1016/j.ceb.2005.11.004. PMID 16337370. 
5. ^ 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): 1266–1277. doi:10.1101/gr.6557307. PMID 17666543. 
6. ^ ^{a b c} Dumas L, Sikela JM (October 2009). "DUF1220 domains, cognitive disease and human brain evolution". Cold Spring Harb. Symp. Quant. Biol. Evolution: The Molecular Landscape 74: 375–382. doi:10.1101/sqb.2009.74.025. PMC 2902282. PMID 19850849. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2902282. 
7. ^ Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T, Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong CT, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung SW, Patel A (December 2008). "Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.". Nat. Genet. 40 (12): 1466–1471. doi:10.1038/ng.279. PMC 2680128. PMID 19029900. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2680128. 
8. ^ Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de RT, Devriendt K, Bongers EM, de LN, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo GM, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Raber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De CA, Goossens L, Mortier G, Speleman F, van BE, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE (October 2008). "Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.". N. Engl. J Med. 359: 1685–1699. doi:10.1056/NEJMoa0805384. PMC 2703742. PMID 18784092. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2703742. 

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

Further reading

• Check E. Multiple copies of a mystery gene may make us human. Nature Published online 31 August 2006
• Pennisi E. "Mining the Molecules That Made Our Mind." Science 29 September 2006: Vol. 313. no. 5795, pp. 1908–1911
• Lemonick MD. "What Makes Us Different?" Time. 9 October 2006.