Haplotype differences for copy number variants in the 22q11.23 region among human populations: a pigmentation-based model for selective pressure.

Two gene clusters are tightly linked in a narrow region of chromosome 22q11.23: the macrophage migration inhibitory factor (MIF) gene family and the glutathione S-transferase theta class. Within 120 kb in this region, two 30-kb deletions reach high frequencies in human populations. This gives rise to four haplotypic arrangements, which modulate the number of genes in both families. The variable patterns of linkage disequilibrium (LD) between these copy number variants (CNVs) in diverse human populations remain poorly understood. We analyzed 2469 individuals belonging to 27 human populations with different ethnic origins. Then we correlated the genetic variability of 22q11.23 CNVs with environmental variables. We confirmed an increasing strength of LD from Africa to Asia and to Europe. Further, we highlighted strongly significant correlations between the frequency of one of the haplotypes and pigmentation-related variables: skin color (R2=0.675, P<0.001), distance from the equator (R2=0.454, P<0.001), UVA radiation (R2=0.439, P<0.001), and UVB radiation (R2=0.313, P=0.002). The fact that all MIF-related genes are retained on this haplotype and the evidences gleaned from experimental systems seem to agree with the role of MIF-related genes in melanogenesis. As such, we propose a model that explains the geographic and ethnic distribution of 22q11.23 CNVs among human populations, assuming that MIF-related gene dosage could be associated with adaptation to low UV radiatio

Structures of (5′S)-8,5′-Cyclo-2′-deoxyguanosine Mismatched with dA or dT

pubs.acs.org/cr

The biological effects of diagnostic cardiac imaging on chronically exposed physicians: the importance of being non-ionizing

Ultrasounds and ionizing radiation are extensively used for diagnostic applications in the cardiology clinical practice. This paper reviewed the available information on occupational risk of the cardiologists who perform, every day, cardiac imaging procedures. At the moment, there are no consistent evidence that exposure to medical ultrasound is capable of inducing genetic effects, and representing a serious health hazard for clinical staff. In contrast, exposure to ionizing radiation may result in adverse health effect on clinical cardiologists. Although the current risk estimates are clouded by approximations and extrapolations, most data from cytogenetic studies have reported a detrimental effect on somatic DNA of professionally exposed personnel to chronic low doses of ionizing radiation. Since interventional cardiologists and electro-physiologists have the highest radiation exposure among health professionals, a major awareness is crucial for improving occupational protection. Furthermore, the use of a biological dosimeter could be a reliable tool for the risk quantification on an individual basis

Theoretical analysis of DNA intrastrand cross linking by formation of 8,5'-cyclodeoxyadenosine.

Formation of intramolecular cross links by addition of C(5') deoxyribose radicals to the C(8)-N(7) double bond of an attached adenine base was analyzed by ab initio quantum-chemical methods. Conformational preferences that influence the stereospecificity of the reaction were investigated. A good correlation was found between the ratio of experimental yields of R and S stereoisomers of 8,5'-cyclodeoxyadenosine and the relative energy of conformations of the C(5') radical that are precursors to these isomers. Molecular mechanics based on the AMBER force field was used to model the effect of 8,5'-cyclodeoxyadenosine on the conformation of the DNA dodecamer d(CGCGAATTCGCG)2 with the lesion at the A6 position. The R and S stereoisomers of the intrastrand cross link cause comparable levels of DNA distortion with the major conformational changes occurring in backbone torsional angles at the site of the lesion

Phenotype versus Genotype Methods for Copy Number Variant Analysis of Glutathione S-Transferases M1

Several variants have been identified for genes encoding Glutathione S-transferase (GST) enzymes; some are associated with significant alteration of protein function. One of the most extensively studied is a copy number variant (CNV) in the GSTM1 gene. In this study, we compared phenotype (positive, null) and genotype (1/1, 1/0, 0/0) methods in order to assess dissimilarities obtained using these two different approaches to evaluate possible methodology-related bias. We analyzed a sample of 1947 individuals belonging to 18 human populations with different ethnic origins. We also evaluated whether the presence of missense substitutions in the GSTM1 gene might influence the association of the CNV with phenotype distribution. Through the comparison of GSTM1 CNV frequencies in phenotype and genotype among human populations, we observed that differences increase in high heterogeneous populations. Furthermore, we identified two missense variants (rs199816990 and rs202002774) that may distort the outcome of genetic association studies on Asian populations. These results indicate that the phenotype analysis may strongly alter the genetic association. Therefore, genotype discrimination analysis should be used to analyze GSTM1 CNV. To understand the role of GSTM1 in human health, the analysis of CNV should be combined with the investigation of single nucleotide polymorphisms with functional effect

Modulation of the GSTT1 activity by the GSTM1 phenotype in a sample of Italian farm-workers

Glutathione S-transferase (GST) isozymes catalyze nucleophilic attack by reduced Glutathione (GSH) on a variety of electrophilic compounds and play a central role in biotransformation of xenobiotics (Hayes et al., Annu Rev Pharmacol Toxicol 45:51-88, 2005). We performed a case-control study to evaluate the GSTM1 and GSTT1 polymorphisms and to investigate if exposure to pesticides conditions the GSTT1 activity level in 115 healthy controls and 90 farm-workers exposed to pesticides. Polymorphisms were investigated using a GSTM1 or a GSTT1-specific PCR. Enzyme activity was measured by means of DCM as co-substrate, as described by Bruhn et al. (Biochem Pharmacol 56:1189-1193, 1998). There was no significant difference between the farm-workers and the healthy controls regarding the distribution of various alleles of the GSTM1 and GSTT1 genes and the GSTT1 enzyme activity. In farm-workers, the GSTM1 null genotype was associated with a significant increase of GSTT1 activity, suggesting a regulative mechanism common to GSTM1 and GSTT1 enzymes after exposure to xenobiotics

Electrospray ionization mass spectrometry for natural and radiation-induced modifications in histone proteins

Chick erythrocyle histone H2B was irradiated in the presence of thymine, the principle cross-linking base recognized in earlier studies, and the products were examined directly by electrospray ionization mass spectrometry (ESI-MS). Following exposure to 5 Gy of ionizing radiation the relative abundance of two unique species were increased by nearly 50% in irradiated samples over background response at the same m/z. The first corresponds to a mass increment increase similar to the expected value for thymine-H2B adduct formation (126.1 Da measured, 125.1 Da calculated). The mass increment increase for the second component (140.7 Da) was less easily explained. Additional dose-yield data are needed to confirm the significance of these changes

Electrospray ionization mass spectrometry for natural and radiation-induced modifications in histone proteins

Chick erythrocyle histone H2B was irradiated in the presence of thymine, the principle cross-linking base recognized in earlier studies, and the products were examined directly by electrospray ionization mass spectrometry (ESI-MS). Following exposure to 5 Gy of ionizing radiation the relative abundance of two unique species were increased by nearly 50% in irradiated samples over background response at the same m/z. The first corresponds to a mass increment increase similar to the expected value for thymine-H2B adduct formation (126.1 Da measured, 125.1 Da calculated). The mass increment increase for the second component (140.7 Da) was less easily explained. Additional dose-yield data are needed to confirm the significance of these changes

Radiation-induced electron migration along DNA

Radiation-induced electron migration along DNA is a mechanism by which randomly produced stochastic energy deposition events can lead to nonrandom types of damage along DNA manifested distal to the sites of the initial energy deposition. Electron migration along DNA is significantly influenced by the DNA base sequence and DNA conformation. Migration along 7 base pairs in oligonucleotides containing guanine bases was observed for oligonucleotides irradiated in solution which compares to average migration distances of 6 to 10 bases for Escherichia coli DNA irradiated in solution and 5.5 base pairs for Escherichia coli DNA irradiated in cells. Evidence also suggests that electron migration can occur preferentially in the 5{prime} to 3{prime} direction along DNA. Our continued efforts will provide information regarding the contribution of electron transfer along DNA to formation of locally multiply damaged sites created in DNA by exposure to ionizing radiation