title: Dominant and Protective Role of the CYTH4 Primate-Specific GTTT-Repeat Longer Alleles Against Neurodegeneration.
abstract: Primate-specific genes and regulatory mechanisms could provide insight into human brain functioning and disease. In a genome-scale analysis of the entire protein-coding genes listed in the GeneCards database, we have recently reported human genes that contain "exceptionally long" short tandem repeats (STRs) in their core promoter, which may be of adaptive/selective evolutionary advantage in this species. The longest tetra-nucleotide repeat identified in a human gene core promoter belongs to the CYTH4 gene. This GTTT-repeat is specific to Hominidae and Old World monkeys, and the shortest allele of this repeat, (GTTT)6, is linked with neural dysfunction and type I bipolar disorder in human. In the present study, we sought a possibly broader role for the CYTH4 gene core promoter GTTT-repeat in neural functioning and investigated its allelic distribution in a total of 949 human subjects, consisting of two neurodegenerative disorders, multiple sclerosis (MS) (n = 272) and Alzheimer's disease (AD) (n = 257), and controls (n = 420). The range of the alleles of this GTTT-repeat in the human sample studied was between 6- and 9-repeats. The shortest allele, (GTTT)6, was significantly in excess in the MS and AD patients in comparison with the controls (p < 0.004). The 6/6, 6/7, and 7/7 genotypes were in excess in the MS and AD patients, whereas the overall frequency of all other genotypes (consisting of at least one longer allele, i.e., 8- or 9-repeat) was higher in the controls (p < 0.005), indicating a dominant and protective effect for the longer alleles against neurodegeneration. This is the first indication of the involvement of a primate-specific STR in neurodegeneration in humans. We propose an adaptive evolutionary role for the expansion of the CYTH4 gene core promoter GTTT-repeat in the human brain, which is supported by a link between the shortest allele of this repeat with neuropsychiatric disorders.
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: M
authors.initials: M
authors.lastname: Rezazadeh
authors.forename: J
authors.initials: J
authors.lastname: Gharesouran
authors.forename: A
authors.initials: A
authors.lastname: Movafagh
authors.forename: M
authors.initials: M
authors.lastname: Taheri
authors.forename: H
authors.initials: H
authors.lastname: Darvish
authors.forename: B
authors.initials: B
authors.lastname: Emamalizadeh
authors.forename: N
authors.initials: N
authors.lastname: Shahmohammadibeni
authors.forename: H R
authors.initials: HR
authors.lastname: Khorram Khorshid
authors.forename: M
authors.initials: M
authors.lastname: Behmanesh
authors.forename: M A
authors.initials: MA
authors.lastname: Sahraian
authors.forename: M
authors.initials: M
authors.lastname: Ohadi
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics*; D017124:Conserved Sequence; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats; D009103:Multiple Sclerosis / Q000235:genetics*; D011110:Polymorphism, Genetic; D011323:Primates / Q000235:genetics
chemical_list: C404511:CYTH4 protein, human; D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors
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