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Dominant and Protective Role of the CYTH4 Primate-Specific GTTT-Repeat Longer Alleles Against Neurodegeneration

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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.

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Fig. 1

Abbreviations

AD:

Alzheimer’s disease

BP:

Bipolar disorder

CYTH4:

Cytohesin 4

MS:

Multiple sclerosis

STR:

Short tandem repeat

TSS:

Transcription start site

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Acknowledgments

This research was funded by the University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

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    Authors and Affiliations

    1. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

      M. Rezazadeh, H. R. Khorram Khorshid & M. Ohadi

    2. Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

      M. Rezazadeh & J. Gharesouran

    3. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran

      A. Movafagh, M. Taheri, H. Darvish & B. Emamalizadeh

    4. Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran

      N. Shahmohammadibeni

    5. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

      M. Behmanesh

    6. Sina Hospital, Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran

      M. A. Sahraian

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    1. M. Rezazadeh
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    Correspondence to M. Ohadi.

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    M. Rezazadeh and J. Gharesouran contributed equally to this work.

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    Rezazadeh, M., Gharesouran, J., Movafagh, A. et al. Dominant and Protective Role of the CYTH4 Primate-Specific GTTT-Repeat Longer Alleles Against Neurodegeneration. J Mol Neurosci 56, 593–596 (2015). https://doi.org/10.1007/s12031-015-0542-5

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    • DOI: https://doi.org/10.1007/s12031-015-0542-5

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