Evolving evidence on a link between the ZMYM3 exceptionally long GA-STR and human cognition

The human X-linked zinc finger MYM-type protein 3 (ZMYM3) contains the longest GA-STR identified across protein-coding gene 5� UTR sequences, at 32-repeats. This exceptionally long GA-STR is located at a complex string of GA-STRs with a human-specific formula across the complex as follows: (GA)8-(GA)4-(GA)6-(GA)32 (ZMYM3-207 ENST00000373998.5). ZMYM3 was previously reported among the top three genes involved in the progression of late-onset Alzheimer�s disease. Here we sequenced the ZMYM3 GA-STR complex in 750 human male subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 268) and matched controls (n = 482). We detected strict monomorphism of the GA-STR complex, except of the exceptionally long STR, which was architecturally skewed in respect of allele distribution between the NCD cases and controls F (1, 50) = 12.283; p = 0.001. Moreover, extreme alleles of this STR at 17, 20, 42, and 43 repeats were detected in seven NCD patients and not in the control group (Mid-P exact = 0.0003). A number of these alleles overlapped with alleles previously found in schizophrenia and bipolar disorder patients. In conclusion, we propose selective advantage for the exceptional length of the ZMYM3 GA-STR in human, and its link to a spectrum of diseases in which major cognition impairment is a predominant phenotype. © 2020, The Author(s)

Evolving evidence on a link between the ZMYM3 exceptionally long GA‑STR and human cognition

The human X-linked zinc fnger MYM-type protein 3 (ZMYM3) contains the longest GA-STR identifed across protein-coding gene 5′ UTR sequences, at 32-repeats. This exceptionally long GA-STR is located at a complex string of GA-STRs with a human-specifc formula across the complex as follows: (GA)8(GA)4-(GA)6-(GA)32 (ZMYM3-207 ENST00000373998.5). ZMYM3 was previously reported among the top three genes involved in the progression of late-onset Alzheimer’s disease. Here we sequenced the ZMYM3 GA-STR complex in 750 human male subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n= 268) and matched controls (n= 482). We detected strict monomorphism of the GA-STR complex, except of the exceptionally long STR, which was architecturally skewed in respect of allele distribution between the NCD cases and controls [F (1, 50)= 12.283; p= 0.001]. Moreover, extreme alleles of this STR at 17, 20, 42, and 43 repeats were detected in seven NCD patients and not in the control group (Mid-P exact= 0.0003). A number of these alleles overlapped with alleles previously found in schizophrenia and bipolar disorder patients. In conclusion, we propose selective advantage for the exceptional length of the ZMYM3 GA-STR in human, and its link to a spectrum of diseases in which major cognition impairment is a predominant phenotype

Aortic responsiveness to nitric oxide is affected by seasonal variation

Cardiac attacks and sudden cardiac deaths are more common in cold seasons. Up to now the underlying pathophysiologic mechanism of the seasonal variation in cardiovascular accidents is scarcely known. There are many physiological mechanisms which exhibit seasonal variation (e.g. blood pressure). Nitric oxide (NO) is a potent vasodilator, and impaired responsiveness to its physiological effects has been reported in many pathological situations including cardiovascular accidents. The aim of the present study was to evaluate the role of NO-dependent mechanisms on seasonal variation in aortic relaxation in vitro in rats. Male Sprague-Dawley rats grown up in different seasons in natural light/dark situation were used in the study, while the temperature and humidity were kept constant throughout the study (22 ± 1 °C). The in vitro aortic ring responsiveness to an NO donor was studied in different seasons. Intact and denuded rings were pre-contracted with phenylephrine and vaso-relaxatory response to sodium isosorbide dinitrate (10-8 to 10-4 M) was recorded in vitro. The vaso-relaxatory response to isosorbide dinitrate (10-6 M) was higher in aortic rings obtained in summer compared with those in winter and fall. There was a significant difference in EC50 of sodium isosorbide dinitrate-induced vaso-relaxation of rings obtained from rats which were grown up in summer and winter (EC50: 2.23 ± 0.069 versus 4.31 ± 0.088, P < 0.05). The maximum response (Rmax) to isosorbide dinitrate was, however, identical in rings obtained from these rats. In conclusion, the in vitro responsiveness of aorta to NO is affected by seasonal light/dark periods the rats are exposed. This might be one of the reasons why more sudden cardiac deaths occur also in humans during winter. © 2006 Elsevier Ireland Ltd. All rights reserved

S-allyl cysteine protects against lipopolysaccharide-induced acute kidney injury in the C57BL/6 mouse strain: Involvement of oxidative stress and inflammation

Sepsis is a serious and life-threatening medical condition with a higher rate of patients' morbidity and mortality and with complications such as acute kidney injury (AKI). S-allyl cysteine (SAC) is the active constituent of the medicinal plant garlic (Allium sativum) with multiple beneficial effects including anti-inflammatory and antioxidant properties. In this research, we tried to determine the protective effect of SAC pretreatment in a mouse model of AKI. To induce AKI, lipopolysaccharide (LPS) was injected once (10 mg/kg, i.p.) and SAC was administered at doses of 25, 50, or 100 mg/kg (p.o.) 1 h before LPS. Treatment of LPS-challenged C56BL/6 animals with SAC lowered serum level of creatinine and blood urea nitrogen (BUN), partially restored renal oxidative stress-related biomarkers including malondialdehyde (MDA), glutathione (GSH), and activity of superoxide dismutase (SOD) and catalase in addition to improvement of mitochondrial membrane potential (MMP). Furthermore, SAC was capable to bring renal nuclear factor-kappaB (NF-κB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), Annexin V, and DNA fragmentation partially back to their control levels. Additionally, SAC pretreatment was capable to exert a protective effect, as shown histologically by lower tubular injury and pathologic changes in the kidney. In summary, SAC is capable to alleviate LPS-induced AKI through mitigation of renal oxidative stress, inflammation, and apoptosis in addition to preservation of mitochondrial integrity and its favorable effect exhibits a dose-dependent pattern. © 2019 Elsevier B.V

Dyads of GGC and GCC form hotspot colonies that coincide with the evolution of human and other great apes

Abstract Background GGC and GCC short tandem repeats (STRs) are of various evolutionary, biological, and pathological implications. However, the fundamental two-repeats (dyads) of these STRs are widely unexplored. Results On a genome-wide scale, we mapped (GGC)2 and (GCC)2 dyads in human, and found monumental colonies (distance between each dyad < 500 bp) of extraordinary density, and in some instances periodicity. The largest (GCC)2 and (GGC)2 colonies were intergenic, homogeneous, and human-specific, consisting of 219 (GCC)2 on chromosome 2 (probability < 1.545E-219) and 70 (GGC)2 on chromosome 9 (probability = 1.809E-148). We also found that several colonies were shared in other great apes, and directionally increased in density and complexity in human, such as a colony of 99 (GCC)2 on chromosome 20, that specifically expanded in great apes, and reached maximum complexity in human (probability 1.545E-220). Numerous other colonies of evolutionary relevance in human were detected in other largely overlooked regions of the genome, such as chromosome Y and pseudogenes. Several of the genes containing or nearest to those colonies were divergently expressed in human. Conclusion In conclusion, (GCC)2 and (GGC)2 form unprecedented genomic colonies that coincide with the evolution of human and other great apes. The extent of the genomic rearrangements leading to those colonies support overlooked recombination hotspots, shared across great apes. The identified colonies deserve to be studied in mechanistic, evolutionary, and functional platforms

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Background: Approximately 2 of the human core promoter short tandem repeats (STRs) reach lengths of �6 repeats, which may in part be a result of adaptive evolutionary processes and natural selection. A single-exon transcript of the human nescient helix loop helix 2 (NHLH2) gene is flanked by the longest CA-repeat detected in a human protein-coding gene core promoter (Ensembl transcript ID: ENST00000369506.1). NHLH2 is involved in several biological and pathological pathways, such as motivated exercise, obesity, and diabetes. Methods: The allele and genotype distribution of the NHLH2 CA-repeat were investigated by sequencing in 655 Iranian subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 290) and matched controls (n = 365). The evolutionary trend of the CA-repeat was also studied across vertebrates. Results: The allele range was between 9 and 25 repeats in the NCD cases, and 12 and 24 repeats in the controls. At the frequency of 0.56, the 21-repeat allele was the predominant allele in the controls. While the 21-repeat was also the predominant allele in the NCD patients, we detected significant decline of the frequency (p < 0.0001) and homozygosity (p < 0.006) of this allele in this group. Furthermore, 12 genotypes were detected across 16 patients (5.5 of the entire NCD sample) and not in the controls (disease-only genotypes; p < 0.0003), consisting of at least one extreme allele. The extreme alleles were at 9, 12, 13, 18, and 19 repeats (extreme short end), and 23, 24, and 25 repeats (extreme long end), and their frequencies ranged between 0.001 and 0.04. The frequency of the 21-repeat allele significantly dropped to 0.09 in the disease-only genotype compartment (p < 0.0001). Evolutionarily, while the maximum length of the NHLH2 CA-repeat was 11 repeats in non-primates, this CA-repeat was �14 repeats in primates and reached maximum length in human. Conclusion: We propose a novel locus for late-onset NCD at the NHLH2 core promoter exceptionally long CA-STR and natural selection at this locus. Furthermore, there was indication of genotypes at this locus that unambiguously linked to late-onset NCD. This is the first instance of natural selection in favor of a predominantly abundant STR allele in human and its differential distribution in late-onset NCD. © 2020 The Author(s) Published by S. Karger AG, Basel