Beginning early in fetal development, the androgen receptor (AR) gene helps regulate bodily exposure to testosterone. Most studies of individuals have found an inverse correlation between the number of CAG repeats on this gene and serious forms of physical aggression. This two-phased study was primarily undertaken to determine if a link between AR CAGn and physical aggression also exists at an ecological level of analysis. To make this assessment, we first conducted a bivariate analysis of the average number of AR CAG repeats for a large number of countries and the rates of crime victimization in those same countries. Except for motor vehicle theft, as the national average number of CAG repeats increased, crime victimization rates decreased. This inverse relationship was especially strong for violent offenses. In the second phase of this study, we sought to determine if per capita gross domestic product, pathogen prevalence, and average intelligence might be mediating some of the AR CAG repeats-criminality relationship. Mediation analysis analysis indicated that, once gross domestic product and pathogenic prevalence were controlled, average intelligence was able to eliminate most of the links between CAG repeats and crime victimization rates, especially in the case of violent offenses. These findings suggest that the AR gene is not influencing criminality primarily by altering testosterone brain exposure (as we suspected). Instead, it may affect criminality mainly by affecting cognitive ability. In fact, once average national intelligence is included in the mediation analysis model, direct relationships between CAG repeats and measures of homicide, assault, and robbery were no longer statistically significant. Findings from this two-phased study point toward the AR gene as having multiple effects on brain functioning, particularly regarding intellectual development as hypothesized by Manning [62]. Replication is obviously needed.
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http://dx.doi.org/10.1016/j.earlhumdev.2024.106113 | DOI Listing |
Genetics
January 2025
Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.
Mismatch repair (MMR) is a highly conserved DNA repair pathway that recognizes mispairs that occur spontaneously during DNA replication and coordinates their repair. In Saccharomyces cerevisiae, Msh2-Msh3 and Msh2-Msh6 initiate MMR by recognizing and binding insertion deletion loops (in/dels) up to ∼ 17 nucleotides (nt.) and base-base mispairs, respectively; the two complexes have overlapping specificity for small (1-2 nt.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Program in Genetics, Molecular, and Cellular Biology, Tufts University Graduate School of Biomedical Sciences, Boston, MA 02111.
CAG/CTG repeats are prone to expansion, causing several inherited human diseases. The initiating sources of DNA damage which lead to inaccurate repair of the repeat tract to cause expansions are not fully understood. Expansion-prone CAG/CTG repeats are actively transcribed and prone to forming stable R-loops with hairpin structures forming on the displaced single-stranded DNA (S-loops).
View Article and Find Full Text PDFLife (Basel)
December 2024
Laboratorio de Terapia Génica Experimental, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de Mexico 11340, Mexico.
Huntington's disease is a genetic disorder characterized by progressive neuronal cell damage in some areas of the brain; symptoms are commonly associated with chorea, rigidity and dystonia. The symptoms in Huntington's Disease are caused by a pathological increase in the number of Cytokine-Adenine-Guanine (CAG) repeats on the first exon of the Huntingtin gene, which causes a protein to have an excessive number of glutamine residues; this alteration leads to a change in the protein's conformation and function. Therefore, the purpose of this work was to design, synthesize and evaluate an antisense oligonucleotide (ASO; 95 nucleotides) HTT 90-5 directed to the Huntingtin CAG repeats in primary leukocyte culture cells from a patient with Huntington's Disease; approximately 500,000 leukocytes per well extracted from venous blood were used, to which 100 pMol of ASO were administered, and the expression of Huntingtin was subsequently evaluated at 72 h by RT-PCR.
View Article and Find Full Text PDFbioRxiv
December 2024
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 5 South, Baltimore, MD21287.
Huntington's Disease (HD), a progressive neurodegenerative disorder with no disease-modifying therapies, is caused by a CAG repeat expansion in the HD gene encoding polyglutamine-expanded huntingtin (HTT) protein. Mechanisms of HD cellular pathogenesis and cellular functions of the normal and mutant HTT proteins are still not completely understood. HTT protein has numerous interaction partners, and it likely provides a scaffold for assembly of multiprotein complexes many of which may be altered in HD.
View Article and Find Full Text PDFNat Neurosci
January 2025
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems.
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