DUF1220
Encyclopedia
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. 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 chimpanzee
s), 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.
(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. 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.
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
.
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
of unknown function
Domain of unknown function
A Domain of unknown function is a protein domain that has no characterised function. These families have been collected together in the Pfam database using the prefix DUF followed by a number, with examples being DUF2992 and DUF1220...
that shows a striking human-specific 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 (over 200, with some person-to-person variations). It is reduced in African great apes (estimated 37 copies in chimpanzee
Chimpanzee
Chimpanzee, sometimes colloquially chimp, is the common name for the two extant species of ape in the genus Pan. The Congo River forms the boundary between the native habitat of the two species:...
s), 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.
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. The study found 134 genes that showed human lineage-specific increases in copy number, one of which, MGC8902MGC8902
MGC8902 is the gene implicated in the function of the neocortex. Researchers predict MGC8902 encodes for multiple sections of a protein, called DUF1220, whose function is unknown but which is abundant in the neocortex and in particular subsets of brain cells....
(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. 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
PDE4DIP
Myomegalin also known as phosphodiesterase 4D-interacting protein or cardiomyopathy-associated protein 2 is a protein that in humans is encoded by the PDE4DIP gene.-Further reading:...
(Myomegalin) gene. PDE4DIP encodes a centrosomal protein and is a homolog of CDK5RAP2
CDK5RAP2
CDK5 regulatory subunit-associated protein 2 is a protein that in humans is encoded by the CDK5RAP2 gene.-Interactions:CDK5RAP2 has been shown to interact with CDK5R1.-Further reading:...
, a gene that lacks DUF1220 sequences and, when mutated, has been implicated in microcephaly.
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. 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. 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.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
1q21.1 duplication syndrome
1q21.1 duplication syndrome or 1q21.1 microduplication is a rare aberration of chromosome 1. , the international rare chromosome disorder group, has 38 genetically confirmed registered cases of this duplication worldwide ....
and 1q21.1 deletion syndrome
1q21.1 deletion syndrome
1q21.1 deletion syndrome or 1q21.1 microdeletion is a rare aberration of chromosome 1. , the international rare chromosome disorder group, has 48 genetically confirmed registered cases of this deletion worldwide ....
.
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.