Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. The worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. Children who have FOP appear normal at birth except for congenital malformations of the great toes. During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible. Patients with atypical forms of FOP have been described. They either present with the classic features of FOP plus one or more atypical features [FOP plus], or present with major variations in one or both of the two classic defining features of FOP [FOP variants]. Classic FOP is caused by a recurrent activating mutation (617G>A; R206H) in the gene ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids. The diagnosis of FOP is made by clinical evaluation. Confirmatory genetic testing is available. Differential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors, aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification. Although most cases of FOP are sporadic (noninherited mutations), a small number of inherited FOP cases show germline transmission in an autosomal dominant pattern. At present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Preventative management is based on prophylactic measures against falls, respiratory decline, and viral infections. The median lifespan is approximately 40 years of age. Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome.     

Genetic Transformation of Crops for Insect Resistance: Potential and Limitations

Transgenic resistance to insects has been demonstrated in plants expressing insecticidal genes such as δ -endotoxins from Bacillus thuringiensis (Bt), protease inhibitors, enzymes, secondary plant metabolites, and plant lectins. While transgenic plants with introduced Bt genes have been deployed in several crops on a global scale, the alternative genes have received considerably less attention. The protease inhibitor and lectin genes largely affect insect growth and development and, in most instances, do not result in insect mortality. The effective concentrations of these proteins are much greater than the Bt toxin proteins. Therefore, the potential of some of the alternative genes can only be realized by deploying them in combination with conventional host plant resistance and Bt genes. Genes conferring resistance to insects can also be deployed as multilines or synthetic varieties. Initial indications from deployment of transgenics with insect resistance in diverse cropping systems in USA, Canada, Argentina, China, India, Australia, and South Africa suggest that single transgene products in standard cultivar backgrounds are not a recipe for sustainable pest management. Instead, a much more complex approach may be needed, one which may involve deployment of a combination of different transgenes in different backgrounds. Under diverse climatic conditions and cropping systems of tropics, the success in the utilization of transgenics for pest management may involve decentralized national breeding programs and several small-scale seed companies. While several transgenic crops with insecticidal genes have been introduced in the temperate regions, very little has been done to use this technology for improving crop productivity in the harsh environments of the tropics, where the need for increasing food production is most urgent. There is a need to develop appropriate strategies for deployment of transgenics for pest management, keeping in view the pest spectrum involved, and the effects on nontarget organisms in the ecosystem.     

Genetic Aspects of Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) is a syndrome associated with persistent inflammation of the mucous membranes of the nose and paranasal sinuses. There are two forms of CRS: chronic rhinosinusitis with nasal polyposis (CRSwNP) and chronic rhinosinusitis without nasal polyposis (NP) (CRSsNP). Available data indicate that innate immunity, adaptive immunity, tissue remodeling, and influence of microorganisms can play a modified role in the development of CRSwNP. The genetic predisposition to the development of CRS is also possible. Today there are several groups of genes which influence the development of chronic rhinosinusitis. They include the genes associated with CFTR locus, HLA genes, genes of innate immunity, genes involved in the development of TH2-inflammatory reactions, genes responsible for tissue remodeling of paranasal sinuses, genes involved in the metabolism of arachidonic acid, genes of xenobiotic transformation, and other pro-inflammatory genes. Identification of genetic susceptibility to CRS would make it possible to develop personalized approaches for prevention, tactics, and effective treatment of chronic rhinosinusitis.     

The Genetic Improvement of Entomopathogenic Nematodes and Their Symbiont Bacteria: Phenotypic Targets, Genetic Limitations and an Assessment of Possible Hazards

The methodologies of classical genetics and genetic engineering can be used for the genetic improvement of entomopathogenic nematodes (EPNs) and their symbiont bacteria. Many of the complex behavioural and physiological traits which are targets for genetic improvement are likely to be controlled polygenically, thus selective breeding for improvements to these traits would be appropriate. Much basic research needs to be carried out before researchers will be able to effect improvements to EPNs and their symbionts by genetic engineering. There is a lack of basic information on the genetics and biochemistry of the characteristics that might be altered by transgenic methods in EPNs, and their bacteria, and existing transformation protocols need to be made more effective.     

Niche Shape and Genetic Aspects of Character Displacement

Character displacement involving a single, diallelic locus ineach of two competing species is investigated via computer simulation.The niche, as the sum of the utilization efficiencies of thepopulation for combinations of environmental variables, is distinguishedfrom the resource peak, which is a set of combinations of environmentalvariables actually present at exploitable frequencies in theenvironment. The two populations compete for a single resourcepeak made up of five subunits. Each genotype in each specieshas an optimum peak subunit, but survives in all of them. Theintermediate subunit is optimal for a genotype in each species.Movement is restricted between subunits, which are thus treatedhere as microhabitats. The simulation covers a geographicalrange with each species occurring alone where its birth rateis high, with the birth rate declining as the range of the otherspecies is approached; sympatry occurs in a region of intermediatebirth rates for both species. The character displacement involvescharacters determined by the genotypes at the competition locus.The shape of the resource peak has a profund effect on the formtaken by character displacement. A "steep" peak (one with theintermediate subunit much more frequent than the rest) resultsin a sharp step in the morphoclines, with two stable equilibriumpoints at the point of equal birth rates. A "bimodal" peak (onewith equally frequent subunits, each optimum for a genotypefor one species only) leads to a gradual change. Other peaktypes also have characteristic effects, showing that ecologicalinferences can be drawn from the form taken by character displacement.     

Genetic Aspects of Circadian Dyschronism: Comparison Between Asiatic-Japanese and Caucasian-French Populations

Differences in period (T) length of a variety of arcadian rhythms of a given subject (internal desynchronization or circadian dyschronism) have been demonstrated in shift workers and subjects exposed to natural environmental Zeitgebers. The aims of the present study were to compare the frequency distributions of circadian TS of the oral temperature (OT) rhythm in an Asiatic-Japanese (AJ) population to that of a Caucasian-French (CF) population, as well as to evaluate the possibility that in both populations the observed circadian dyschronism is facilitated by a similar inherited control mechanism. There were 98 healthy adult males in the CF group (including 78 shift workers) and 42 healthy subjects in the AJ group (all shift workers). OT was measured for at least 8 days, four to six times every 24 h. Power spectrum analyses were used to quantify accurately the prominent OT circadian T. In both populations, TS of the sleep-wake rhythm seldom differed from 24 h (four of 42 in the AJ group, none in the CF group), despite irregularities in working hours. In contrast, 30% of OT rhythm TS differed from 24 h in both populations (exhibiting TS of > 24 h or TS of < 24 h). The T distributions exhibited a trimodal (symmetric from both sides) distribution. The trimodal distribution in TS of OT observed in the AJ group did not differ from that observed in the CF group. In both groups the interval of deviation from TS of 24 h predominantly clustered in multiples of +0.8 h and -0.8 h [e.g., 24 h + n(0.8 h), yielding TS of 24.8 h, 25.6 h, etc.]. The observed distribution of TS in AJ and its multiplitive structure were nearly identical to those observed in the CF and were compatible with the Dian-Circadian model suggested for the genetic background of circadian dyschronism of CF.     

Genetic estimates of population structure and gene flow: Limitations, lessons and new directions

Indirect methods using genetic markers are the primary measure of gene flow levels among interbreeding populations. Results from studies employing these methods are often ambiguous and open to multiple interpretation. This is primarily due to low resolution of molecular markers and low precision of model-based estimates. Studies of paternity, kinship and phylogeography generate the most reliable results. Future studies should employ more powerful analytical methods, analyse loci independently, and attempt to distinguish confounding contributions of vicariance to isolation-by-distance studies. Moreover, direct assessment of movement remains the most valid approach to many key issues in population biology.     

Atherogenic Dyslipidemia in Children: Evaluation of Clinical,Biochemical and Genetic Aspects

The precursors of atherogenic dyslipidemia (AD) are not well defined. Therefore, we investigated 62 non-obese, non-diabetic AD and 221 normolipemic children. Anthropometric parameters, blood pressure and biochemical measures were obtained in index children, their parents and all available siblings. The heritability (h²) of anthropometric and biochemical traits was estimated by SOLAR. Rare and common variants in APOA1 and LPL genes were screened by re-sequencing. Compared to normolipemic, AD children showed increased body mass index, waist circumference, plasma glucose, insulin, ApoB, HOMA-IR, hs-CRP and lower adiponectin (p<0.001 for all). Metabolic syndrome was present in 40% of AD while absent in controls. All traits (except adiponectin and hs-CRP) showed a strong familial aggregation, with plasma glucose having the highest heritability (89%). Overall, 4 LPL loss-of-function mutations were detected (p.Asp9Asn, p.Ser45Asn, p.Asn291Ser, p.Leu365Val) and their cumulative prevalence was higher in AD than in control children (0.073 vs. 0.026; P=0.038). The LPL p.S447* gain-of-function mutation, resulted to be less frequent in AD than in control children (0.064 vs. 0.126; P=0.082). No variant in the APOA1 gene was found. Our data indicate that AD is a rather common dyslipidemia in childhood; it associates with metabolic abnormalities typical of insulin resistant state and shows a strong familial aggregation. LPL variants may contribute to the development of AD phenotype.     

Biochemical and Genetic Aspects of Nystatin Resistance in Saccharomyces cerevisiae

Two phenotypically distinct sets of nystatin-resistant mutants were investigated. One set is resistant, respiratory competent, and requires no lipid for growth. The other set is more resistant, respiratory deficient, and lipid requiring (unsaturated fatty acid or sterol). Both sets show altered sterol composition as demonstrated by the Liebermann-Burchard colorimetric reaction, ultraviolet spectrophotometry, and gas-liquid chromatography. Genetic analysis indicates that all nystatin-resistant mutants can be placed into one of six distinct genetic groups. The phenotype's nystatin resistance, lipid requirement, and respiratory deficiency are recessive. There was one case of allelism for mutants from different sets. Revertants of mutants which have the tripartite phenotype retain a residual level of nystatin resistance, but they are no longer lipid requiring or respiratory deficient. Growth studies in mutants which have the tripartite phenotype reveal that the addition of ergosterol to the growth medium results in decreased resistance to nystatin.