Genetic studies in relation to kuru: an overview

Kuru is a subacute neurodegenerative disease presenting with limb ataxia, dysarthria, and a shivering tremor. The disease progress to complete motor and mental incapacity and death within 6 to 24 months. Neuropathologically, a typical pattern of neuronal loss, astrocytic and microglial proliferation, characteristic "kuru-type" amyloid plaques, and PrP deposits in the cerebral cortex and cerebellum are observed. Kuru is the prototype of a group of human transmissible spongiform encephalopathies (TSEs), or "prion" diseases, that include hereditary, sporadic and infectious forms. The latest member of this group, the variant Creutzfeldt-Jakob disease (vCJD), linked to transmission of bovine spongiform encephalopathy (BSE) to humans, shows features similar to kuru. Kuru has emerged at the beginning of the 1900s in a small indigenous population of New-Guinean Eastern Highlands, reached epidemic proportions in the mid-1950s and disappeared progressively in the latter half of the century to complete absence at the end of the 1990s. Early studies made infection, the first etiologic assumption, seem unlikely and led to a hypothesis that kuru might be a genetically determined or genetically mediated illness. After transmissibility of kuru had been discovered and all major epidemiologic phenomena adequately explained by the spread of an infectious agent with long incubation period through the practice of cannibalism, the pattern of occurrence still continued to suggest a role for genetic predisposition. Recent studies indicate that individuals homozygous for Methionine at a polymorphic position 129 of the prion protein were preferentially affected during the kuru epidemic. The carriers of the alternative 129Met/Val and 129Val/Val genotypes had a longer incubation period and thus developed disease at a later age and at a later stage of the epidemic. Observations made during the kuru epidemic are helpful in the understanding of the current vCJD outbreak, and vice versa clinical and experimental data accumulated in studies of other TSE disorders contribute to better understanding of the documented kuru phenomena.     

Genetic susceptibility to chronic Chagas disease: an overview of single nucleotide polymorphisms of cytokine genes

Chagas disease is a parasitic infection that is a significant public health problem in Latin America. The mechanisms responsible for susceptibility to the infection and the mechanisms involved in the development of cardiac and digestive forms of chronic Chagas disease remain poorly understood. However, there is growing evidence that differences in susceptibility in endemic areas may be attributable to host genetic factors. The aim of this overview was to analyze the genetic susceptibility to human Chagas disease, particularly that of single nucleotide polymorphisms of cytokine genes. A review of the literature was conducted on the following databases: PubMed/MEDLINE and Scopus. The search strategy included using the following terms: "Cytokines", "Single Nucleotide Polymorphisms" and "Chagas Disease". After screening 25 citations from the databases, 19 studies were selected for the overview. A critical analysis of the data presented in the articles suggests that genetic susceptibility to Chagas disease and chronic Chagas cardiomyopathy is highly influenced by the complexity of the immune response of the host. Follow-up studies based on other populations where Chagas disease is endemic (with distinct ethnic and genetic backgrounds) need to be conducted. These should use a large sample population so as to establish what cytokine genes are involved in susceptibility to and/or progression of the disease.     

Genetic susceptibility to Alzheimer disease

Alzheimer disease (AD) is the leading cause of dementia in the elderly. Less than a decade ago, it was questioned as to whether or not genes were even involved in anything but rare early onset AD. Since that time, using a variety of genetic epidemiological and molecular biological techniques, four loci have been identified that play a role in the genetic susceptibility of AD, AD presents as a prototype of the power of genetic techniques in defining the etiology of a complex disease.     

Genetic susceptibility to infectious disease

Our understanding of the variation in individual clinical responses to pathogens has become increasingly relevant, particularly in the face of new emerging epidemics as well as the increasing number of multi-drug-resistant organisms. An effective immune response to infection has contributed to the development of host genetic diversity through selective pressure, with an increasing number of studies characterizing the role that host genetics plays in disease susceptibility. Knowledge of the role host mechanisms play in the pathogenesis of infectious disease can contribute to the design of new therapeutic strategies. Rapid advances in the field of human genomics offer great opportunities for adopting this approach to find new insights into pathogenesis.     

Genetic ecotoxicology: an overview

The techniques currently available for detecting genotoxin exposure are briefly described and evaluated with regard to the goals of genetic ecotoxicology. The occurrence and significance of genotoxin-induced neoplasia in marine organisms is described. Although there are numerous examples of hotspots where tumour incidences in fish and shellfish have been correlated with raised concentrations of anthropogenic chemicals, causal mechanisms are seldom established. Insufficient information is available to gauge the seriousness of genotoxicity for marine organisms on regional or global scales. The possibility of using marine organisms as sentinels to provide early warning of potential threats to Man is examined. Recognition of the genotoxic disease syndrome in lower animals highlights the need to explore the relationships between DNA damage (adduct formation, gene mutations, etc.) and its phenotypic consequences. Within a given population, not all individuals are equally susceptible to pollutant toxicity (including genotoxicity). The potential for using similarities in phenotypic traits to recognise subsets of individuals within populations possessing similar genotypes is discussed. Changes in heterozygosity and the evolution of genetically resistant populations following exposure to pollution are evaluated in the context of genetic ecotoxicology. Risk assessment procedures are required which enable genotoxin exposure to be related to specific consequences at the community and ecosystem levels. This necessitates both a sound scientific understanding of the mechanisms involved and the development of pragmatic ecotoxicological tools that can be employed by environmental managers.     

Genetic susceptibility to chronic periodontal disease

Evidence suggests that there is a significant genetic component to susceptibility and resistance to chronic periodontal disease. Data from both clinical studies and studies using animal models are reviewed here. Also outlined are the genomic methods that are now available for identifying susceptibility and resistance loci.     

Genetic studies on some Nepalese populations

Populations living in two different regions of Nepal have been studied. The first region (the Kali Gandaki valley) is inhabited mainly by Magars, Gurungs, Thakalis and Chetris. It has been found that they exhibit different ABO gene frequencies though living in very close areas and often in the same villages. Thus they are still genetically different entities besides being ethnically distinguishable from each other.The second region examined in the present survey (the Solu Khumbu) is inhabited by Sherpas. They were studied for markers not analysed in a previous research, namely for ABO, UMPK, PGD, GLO and LDH.     

The oral susceptibility of South African field populations of Culicoides to African horse sickness virus

Twenty‐two isolates of African horse sickness virus (AHSV), representing its distinct serotypes, geographical and historical origins, were fed to three populations of South African livestock‐associated Culicoides spp. (Diptera, Ceratopogonidae). Infective blood meals included 12 recent isolates, nine historical reference strains and one live attenuated vaccine strain serotype 7 (AHSV‐7) of the virus. Field‐collected midges were fed through a chicken‐skin membrane on sheep blood spiked with one of the viruses, which concentrations ranged from 5.4 to 8.8 log₁₀TCID₅₀/mL of blood. After 10 days incubation at 23.5°C, AHSV was isolated from 11 Culicoides species. Standard in vitro passaging of AHSV‐7, used for the preparation of live attenuated vaccine, did not reduce its ability to infect Culicoides species. Virus recovery rates in orally infected Culicoides midges differed significantly between species and populations, serotypes, isolates and seasons. Significant variations in oral susceptibility recorded in this study emphasize a complex inter‐relationship between virus and vector, which is further influenced by multiple intrinsic and extrinsic factors. As it is not possible to standardize all these factors under laboratory conditions, conclusive assessment of the role of field‐collected Culicoides midges in the transmission of orbiviruses remains problematic. Nevertheless, results of this study suggest the potential for multi‐vector transmission of AHSV virus in South Africa.     

Genetic quality of domesticated African tilapia populations

Anecdotal and empirical evidence exists for substantial (up to 40%) declines in growth among Oreochromis populations domesticated in both large and small‐scale fish farms in Africa. These declines are at least partly attributable to poor genetic management, including inadvertent selection, inbreeding, bottle‐necks and founder effects. Due to restricted cash flow and investment capital, genetic management and selective breeding for the improvement of domesticate populations are difficult for small‐scale farmers, but feasible on larger‐scale farms. In managing domesticated gene pools, feral populations can serve as a broodstock reservoir, making the use of indigenous species advantageous. A development model of large‐scale hatcheries producing selected lines of sex‐reversed, indigenous tilapia for sale to smaller‐scale farmers is proposed as a solution to the problems of poor genetic management in African aquaculture.     

Antimicrobial peptides: an overview of a promising class of therapeutics

Antibiotic resistance is increasing at a rate that far exceeds the pace of new development of drugs. Antimicrobial peptides, both synthetic and from natural sources, have raised interest as pathogens become resistant against conventional antibiotics. Indeed, one of the major strengths of this class of molecules is their ability to kill multidrug-resistant bacteria. Antimicrobial peptides are relatively small (6 to 100 aminoacids), amphipathic molecules of variable length, sequence and structure with activity against a wide range of microorganisms including bacteria, protozoa, yeast, fungi, viruses and even tumor cells. They usually act through relatively non-specific mechanisms resulting in membranolytic activity but they can also stimulate the innate immune response. Several peptides have already entered pre-clinical and clinical trials for the treatment of catheter site infections, cystic fibrosis, acne, wound healing and patients undergoing stem cell transplantation. We review the advantages of these molecules in clinical applications, their disadvantages including their low in vivo stability, high costs of production and the strategies for their discovery and optimization.     

Genetic correlation and response to selection in simulated populations

Summary Effects of truncation selection of a primary trait upon genetic correlation between the primary trait and an unselected secondary trait were observed during 30 generations. Populations were 24 male and 24 female parents per generation randomly mated with replacement, the number of offspring set by intensity of selection. Each trait was controlled by genes with equal effects and complete dominance segregating independently from starting frequencies of 0.5 at each of 48 loci. Three levels each of genetic correlation, selection, and environmental variation were simulated.Genetic correlation decreased faster under more intense selection by lower than by upper truncation but behaved similarly in both by remaining near initial level when as many as one-half of the offspring were saved for parents. Truncation selection decreased genetic correlation in the offspring selected to be parents whether selection was by upper or lower truncation. Estimates of genetic correlation from covariances between phenotypes of parent and offspring were erratic for both directions of selection.Michigan Agricultural Experiment Station Journal Article4841. Part of North Central Regional Project NC-2.     

Genetic susceptibility to mycobacterial disease in humans

Mycobacterial disease remains a serious global health problem. Tuberculosis causes more than 2 million deaths a year, and leprosy is still a cause of severe disability in many parts of the world. As a result of the study of individuals with marked susceptibility to usually nonpathogenic mycobacteria, as well as case-control studies with candidate genes and genome-wide screens of affected populations, there is substantial evidence for the role of genetic factors in the susceptibility to mycobacterial disease. These studies have defined immunological processes essential for the control of mycobacteria infections in humans.     

Genetic correlation and response to selection in simulated populations

Summary One of two quantitative traits was selected and correlated response in the other trait was measured in each of 30 generations for models of additive genes and of complete dominance. Each trait was controlled by 48 loci with equal effects, segregating independently from frequencies of 0.5 in the initial generation. Intensity of selection regulated the number of offspring from randomly mating 24 males and 24 females each generation. Three each of genetic correlations between traits, intensities of selection, and amounts of environmental variation were simulated.In the additive model correlated responses of the unselected trait to selection of the primary trait agreed closely with responses expected from theoretical considerations. In the model of complete dominance, responses of genotypic means of the unselected trait to selection of the primary trait in opposite directions were quite symmetrical for the first few generations but became distinctly asymmetrical in later generations. With little selection, response was fairly linear but became distinctly curvilinear as intensity of selection increased and environmental variance decreased. Between 15th and 30th generations some gains in the correlated trait to the 15th generation were lost.Michigan Agricultural Experiment Station Journal Article 4847. Part of North Central Regional Project NC-2.     

Genetic correlation and response to selection in simulated populations

Summary Effects of truncation selection of a primary trait upon genetic correlation with a secondary trait were examined over 30 generations in genetic populations simulated by computer. Populations were 24 males and 24 females mated randomly with replacement; number of offspring was determined by intensity of selection. Each trait was controlled by 48 loci segregating independently, effects were equal at every locus, and gene frequency was arbitrarily set at 0.5 at each locus in the initial generation. All combinations of three genetic correlations, three intensities of selection, and three environmental variances were simulated. Gene action was additive. Genetic correlation was set by number of loci which affected both traits and was measured each generation as the product-moment correlation of genotypic values and estimated by two methods of combining phenotypic covariances between parent and offspring.Genetic correlations in each offspring generation remained consistently near initial correlations for all environmental variances when fraction of offspring saved as parents was as large as one-half. When the fraction of offspring saved was as small as one-fifth, genetic correlations decreased but most rapidly with heritability high and after the 15th generation of selection. Truncation selection caused genetic correlation to decrease in those offspring selected to become parents of the next generation. Amount of reduction depended on heritability of the selected trait rather than on degree of truncation selection. Estimates of genetic correlation from phenotypic covariances between parent and offspring fluctuated markedly from real correlations in the small populations simulated.Michigan Agricultural Experiment Station Journal Article 4836. Part of North Central Regional Project NC-2.     

Genetic susceptibility to coronary artery disease: from promise to progress

Family history is an important independent risk factor for coronary artery disease (CAD), and identification of susceptibility genes for this common, complex disease is a vital goal. Although there has been considerable success in identifying genetic variants that influence well-known risk factors, such as cholesterol levels, progress in unearthing novel CAD genes has been slow. However, advances are now being made through the application of large-scale, systematic, genome-wide approaches. Recent findings particularly highlight the link between CAD and inflammation and immunity, and highlight the biological insights to be gained from a genetic understanding of the world's biggest killer.     

Alzheimer's disease therapeutics: new approaches to an ageing problem

Abnormal proteinaceous deposits are found in the brain of patients with many different neurodegenerative diseases. In many of these diseases, the production of the deposits is probably associated with disease pathogenesis. In Alzheimer's disease (AD), the amyloid protein (A beta), is produced by the action of enzymes known as secretases, which cleave the beta-amyloid protein precursor. A beta is secreted from cells in the brain, after which it oligomerizes and is deposited in the extracellular compartment of the brain to form amyloid plaques and amyloid angiopathy. Targeting the production of A beta and its aggregation is now a key strategy in the development of novel therapeutic agents for the treatment of AD. This review examines the potential of immunization strategies, cholesterol-lowering drugs, protease inhibitors and nicotinic drugs for the treatment of AD.     

Behavioural studies on eriophyoid mites: an overview

Eriophyoid mites are excellent candidates for ethological research using the approaches of behavioural ecology and sociobiology. These tiny haplodiploid mites are highly specialized plant parasites, producing galls, forming nests, inhabiting refuges or living freely on plants. They reproduce via spermatophores deposited on a substrate and without pairing, which is a fascinating, though still poorly understood, mode of reproduction widespread in some groups of arthropods. Eriophyoid males can be involved in external sperm competition. In some species they also guard pre-emergent females and deposit spermatophores beside them. Although slow-walking, the minute eriophyoid mites can disperse for long distances on air currents or specific animal carriers. After landing on a plant they can distinguish between suitable and unsuitable hosts. Biological observations on a deuterogynous species indicate that parasociality could occur among eriophyoid mites. Many eriophyoids are of economic importance. Knowledge of their behaviour may promote understanding their ecology, may resolve problems in their phylogeny and may help developing methods for their control. In this paper, attention is directed to dispersal modes of eriophyoid mites, their feeding and host acceptance, spermatophore deposition and mating, defence against predators, and social behaviour.