The genomic region encompassing the Major Histocompatibility Complex (MHC) contains polymorphic frozen blocks which have developed by local imperfect sequential duplication associated with insertion and deletion (indels). In the alpha block surrounding HLA-A, there are ten duplication units or beads on the 62.1 ancestral haplotype. Each bead contains or contained sequences representing Class I, PERB11 (MHC Class I chain related (MIC) and human endogenous retrovirus (HERV) 16. Here we consider explanations for co-occurrence of genomic polymorphism, duplication and HERVs and we ask how these features encode susceptibility to numerous and very diverse diseases. Ancestral haplotypes differ in their copy number and indels in addition to their coding regions. Disease susceptibility could be a function of all of these differences. We propose a model of the evolution of the human MHC. Population-specific integration of retroviral sequences could explain rapid diversification through duplication and differential disease susceptibility. If HERV sequences can be protective, there are exciting prospects for manipulation. In the meanwhile, it will be necessary to understand the function of MHC genes such as PERB11 (MIC) and many others discovered by genomic sequencing.
Myostatin, or growth and differentiation factor 8 (GDF8), has been identified as the factor causing a phenotype known as double muscling, in which a series of mutations render the gene inactive, and therefore, unable to regulate muscle fibre deposition. This phenotype occurs at a high frequency in some breeds of cattle such as Belgian Blue and Peidmontese. Phylogenetic analysis has shown that there has been positive selection pressure for non-synonymous mutations within the myostatin gene family, around the time of the divergence of cattle, sheep and goats, and these positive selective pressures on non-ancestral myostatin are relatively recent. To date, there have been reports of nine mutations in coding regions of myostatin that cause non-synonymous changes, of which three cause missense mutations, including two in exon 1 and one in exon 2. The remaining six mutations, located in exons 2 and 3, result in premature stop codons, which are the mutations responsible for the double-muscling phenotype. Unfortunately, breed management problems exist for double-muscled cattle, such as birthing difficulties, which can be overcome through genetically controlled breeding programmes, as shown in this review.
Asthma is a genetically complex disease, and the investigation of putative linkages to candidate loci in independent populations is an important part of the gene discovery process. This study investigated the linkage of microsatellite markers in the 5q and 11q regions to asthma-associated quantitative traits in 121 Australian Caucasian nuclear families. The families were recruited on the basis of a child proband: a cohort of 95 randomly recruited families of unselected probands (n = 442 subjects) and a cohort of 26 families of probands selected on the basis of severe symptomatic asthma (n = 134 subjects). The quantitative traits assessed included serum levels of total IgE and specific IgE to house dust mite and mixed grass, blood eosinophil counts, and the dose-response slope (DRS) of FEV1 to histamine provocation. Multipoint linkage analysis using Haseman-Elston sib-pair methods provided evidence of significant linkage between the chromosome 5q markers and loge total serum IgE levels, specific serum IgE levels, and loge blood eosinophil counts. The chromosome 11q markers showed evidence of significant linkage to specific serum IgE levels. Neither region demonstrated significant linkage to the loge DRS to histamine. Phenotypes were residualized for age and sex. These data are consistent with the existence of loci regulating asthma-associated quantitative traits in both the 5q31-33 and 11q13 chromosomal regions.
Insufficient blood levels of the neurohormone vitamin D are associated with increased risk of COVID-19 severity and mortality. Despite the global rollout of vaccinations and promising preliminary results, the focus remains on additional preventive measures to manage COVID-19. Results conflict on vitamin D’s plausible role in preventing and treating COVID-19. We examined the relation between vitamin D status and COVID-19 severity and mortality among the multiethnic population of the United Arab Emirates. Our observational study used data for 522 participants who tested positive for SARS-CoV-2 at one of the main hospitals in Abu Dhabi and Dubai. Only 464 of those patients were included for data analysis. Demographic and clinical data were retrospectively analyzed. Serum samples immediately drawn at the first hospital visit were used to measure serum 25-hydroxyvitamin D [25(OH)D] concentrations through automated electrochemiluminescence. Levels < 12 ng/mL were significantly associated with higher risk of severe COVID-19 infection and of death. Age was the only other independent risk factor, whereas comorbidities and smoking did not contribute to the outcomes upon adjustment. Sex of patients was not an important predictor for severity or death. Our study is the first conducted in the UAE to measure 25(OH)D levels in SARS-CoV-2-positive patients and confirm the association of levels < 12 ng/mL with COVID-19 severity and mortality.
The major histocompatibility complex (MHC) consists of polymorphic frozen blocks (PFBs) that are linked to form megabase haplotypes. These blocks consist of polymorphic sequences and define regions where recombination appears to be inhibited. We have been able to show, using a highly polymorphic sequence centromeric of HLA-B (within the beta block), that PFBs are conserved and contain specific insertions/deletions and substitutions that are the same for individuals with the same MHC haplotype but that differ between at least most different haplotypes. A sequence comparison between ethnic-specific haplotypes shows that these sequences have remained stable and predate the formation of these haplotypes. To determine whether the same conserved block has been involved in the generation of multiple haplotypes, we compared the block typing profiles of different ethnic specific haplotypes. Block typing profiles have previously been shown to be identical in individuals with the same MHC haplotype but, generally, to differ between different haplotypes. It was found that some PFBs are common to more than one haplotype, implying a common ancestry. Subsequently, haplotypes have been generated by the shuffling and exchange of these PFBs. The regions between these PFBs appear to permit the recombination sites and therefore could be expected to exhibit either low polymorphism or a localized "hotspot."
BackgroundSubstance use disorder (SUD) is a global problem with no boundaries, which also afflicts individuals from countries of the Arabian Peninsula. Data from this region is limited. In an effort to develop targeted prevention and intervention initiatives in the United Arab Emirates (UAE), it was necessary to identify the nature of substance use by describing the characteristics of those using different substances. Consequently, this study in the UAE was conceived to describe the pattern of SUD in a first-ever cohort that was systematically recruited from the country’s National Rehabilitation Centre (NRC) in Abu Dhabi.MethodsTwo hundred and fifty male patients were recruited from the NRC. Information on substance use was collected using a questionnaire that was completed at an interview with patients who consented to participate. The questionnaire was based on information that the study was designed to capture. It was reviewed by members of institutional ethics committees and approved prior to use. Two hundred and fifty male subjects from the Emirates Family Registry (EFR) were used as a comparison group.ResultsIn the cohort studied, SUD correlated with smoking and marital status. Poly-substance users formed the majority of the cohort (84.4 %) with various combinations of substances identified across different age groups. Opioid and alcohol were the most common substances used. The use of pharmaceutical opioids, primarily Tramadol (67.2 % of opioid users), was higher among the youngest age group studied (<30 years old), while older opioid users (≥30 years old) commonly used illicit opioids (Heroin). The use of prescribed medication for non-medical use also included Pregabalin (mean of 8.3 capsules ± 0.5 per day), Procyclidin (6.1 tablets + 0.6 per day) and Carisoprodol (4.2 tablets ± 0.4 per day) and was again highest in the age group below 30 years.ConclusionThis 2015 study highlights the importance of examining the pattern of poly-substance use in a population in order to develop targeted prevention programs to arrest the prevailing trends. It has drawn attention to the rise in use of prescription medication in the UAE, in particular among younger patients (<30 years), and continuing use of illicit opioid amongst males above 30 years. Specific prevention and intervention strategies, targeting differences between these distinct demographic profiles will capture a large subset of sufferers.
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