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Susceptibility to JRA/JIA: complementing general autoimmune and arthritis traits.

Juvenile rheumatoid arthritis (JRA), also known as juvenile idiopathic arthritis (JIA), includes the most common chronic autoimmune arthropathies of childhood. These two nomenclatures for classification include components representing the major subclasses of disease. The chromosomal regions and the genes involved in these complex genetic traits are being elucidated, with findings often specific for a particular disease subtype. With the advent of new SNP technologies, progress is being made at an ever-increasing pace. This review discusses the difficulties of deciphering the genetic components in complex disorders, while demonstrating the similarities that JRA shares with other autoimmune disorders. Particular emphasis has been placed on positive findings either for candidate genes that have been replicated independently in JRA/JIA, or findings in JRA for which consistent results have been reported in other forms of autoimmunity.

Animals↗

Autologous immune complex nephritis associated with sickle cell trait: diagnosis of the haemoglobinopathy after renal structural and immunological studies.

A renal tubular epithelial antigen (RTE)--anti-RTE autologous immune complex nephritis associated with sickle cell anaemia (SS) has been reported, but immune complex nephritis has never been described in patients with sickle cell trait (SA). During investigation of a child with "asymptomatic proteinuria" cryoprecipitable complexes of RTE-anti-RTE were detected in the serum and granular deposits of RTE, immunoglobulins, and complement localised on the glomerular basement membranes. Morphological and ultrastructural studies showed increased mesangial matrix, sickled red blood cells in the glomeruli and vessels, and tubular and interstitial abnormalities. These findings prompted haemoglobin electrophoretic studies, which showed previously undiagnosed haemoglobin SA in this patient and her family. These observations suggest that nephritis mediated by similar immunopathogenic mechanisms may be associated with SS and SA haemoglobinopathy. Under some conditions patients with sickle cell trait may experience haemodynamic and oxygenation abnormalities, which may be aetiological factors in the immune complex nephritis associated with SS disease.

Adolescent↗

Analysis of the quantitative dermatoglyphic traits of the digito-palmar complex in patients with primary open angle glaucoma.

Patient with primary open angle glaucoma (PAOG), which is known to have a genetic predisposition, and their immediate relatives unaffected with PAOG, may have some changes in dermatoglyphic traits of the digito-palmar complex, since the trabecular meshwork develops at the same time and with the same hereditary base like dermatoglyphs, which have high genetic transmission. The objective of this study is to determine whether differences in quantitative dermatoglyphic traits of the digito-palmar complex exist between patients with glaucoma and the phenotipically healthy population and whether their family members have the same dermatoglyphic changes. The quantitative dermatoglyphic traits in patients suffering from glaucoma, first-degree members of their family and the phenotypically healthy population have been screened in this study. Descriptive statistics, univariate analysis of variance (ANOVA) and post hoc (Tukey HSD) method have been used. The results have shown that there is a link between the quantitative dermatoglyphic traits of the digito-palmar complex in patients affected by glaucoma and a first-degree healthy member of their family, as well as the difference between patients with glaucoma and their first-degree relatives, which may discriminate them from the phenotypically healthy population. The results of the study mostly affirm the existence of genetic predisposition for the development of primary open-angle glaucoma, thus emphasizing the relevance of hereditary factors in the etiopathogenesis of this disease.

Analysis of Variance↗

Evaluating disorders with a complex genetics basis. the future roles of meta-analysis and systems biology.

Growing evidence suggests that complex gene and environment interactions underlie a number of diseases including chronic inflammatory diseases of the digestive system. The rapid advances in information and technology provide opportunities to discover the risks or etiology for a variety of disorders within individual patients. However, the availability of new data and new technology has outstripped the conceptual framework of simple disorders and challenges current statistical approaches. Here we address the issues surrounding study design and sample size for complex genetic traits, with special attention to meta-analysis and systems biology. We conclude that meta-analysis should play a limited role in evaluating studies of complex genetic diseases. Instead, systems biology-based approaches should be developed to integrate multiple, focused, and mechanistic association studies with the goal of assisting in the risk assessment of patients on a person-by-person basis.

Forecasting↗

Effect of genetic heterogeneity and assortative mating on linkage analysis: a simulation study.

Linkage studies of complex genetic traits raise questions about the effects of genetic heterogeneity and assortative mating on linkage analysis. To further understand these problems, I have simulated and analyzed family data for a complex genetic disease in which disease phenotype is determined by two unlinked disease loci. Two models were studied, a two-locus threshold model and a two-locus heterogeneity model. Information was generated for a marker locus linked to one of the disease-defining loci. Random-mating and assortative-mating samples were generated. Linkage analysis was then carried out by use of standard methods, under the assumptions of a single-locus disease trait and a random-mating population. Results were compared with those from analysis of a single-locus homogeneous trait in samples with the same levels of assortative mating as those considered for the two-locus traits. The results show that (1) introduction of assortative mating does not, in itself, markedly affect the estimate of the recombination fraction; (2) the power of the analysis, reflected in the LOD scores, is somewhat lower with assortative rather than random mating. Loss of power is greater with increasing levels of assortative mating; and (3) for a heterogeneous genetic disease, regardless of mating type, heterogeneity analysis permits more accurate estimate of the recombination fraction but may be of limited use in distinguishing which families belong to each homogeneous subset. These simulations also confirmed earlier observations that linkage to a disease "locus" can be detected even if the disease is incorrectly defined as a single-locus (homogeneous) trait, although the estimated recombination fraction will be significantly greater than the true recombination fraction between the linked disease-defining locus and the marker locus.

Computer Simulation↗

Linkage analysis, kinship, and the short-term evolution of chromosomes.

Although all meiotic (or linkage) mapping strategies ultimately rely on Mendel's laws, the precise manner in which these laws are exploited in relevant statistical models determines the utility of each strategy for different traits and diseases. In this paper we review the motivation and principles behind each of the three most often used statistical strategies for mapping loci that influence complex, multifactorial traits and diseases (such as diabetes and hypertension), namely: pedigree-based parametric linkage, relative pair allele sharing analysis, and association or linkage disequilibrium analysis. It is our hope to show how Mendel's laws are exploited in each through use of two basic concepts: the short-term evolution of chromosomes, and kinship. Problems inherent in each strategy are described. We then consider how extensions, modifications, or novel derivatives of these three strategies might be fashioned that make better use of the concepts of kinship and short-term chromosome evolution. Two strategies receive emphasis: a haplotype sharing method, which considers the kinship of groups of individuals, and extended variance component models, which make use of genotype information in novel ways.

Animals↗

Genetics of essential hypertension.

Blood pressure is a complex quantitative trait that is determined by multiple environmental and genetic factors. Although some simple Mendelian forms of high blood pressure have been described, essential hypertension is characterized by a complex mode of inheritance. Based on recent advances in molecular biology and statistical genetics, it has become feasible to search for chromosome regions that may contain genes contributing to the pathogenesis of hypertension in humans. For example, recent linkage and association studies have raised the possibility that a blood pressure regulatory locus may exist in or near the angiotensinogen gene on chromosome 1. Detailed genetic experiments in animal models of hypertension may help to guide further clinical studies and lead to an improved understanding of gene action in the pathogenesis of essential hypertension.

Animals↗

Factors determining the frequency of the killer trait within populations of the Paramecium aurelia complex.

The factors maintaining the cytoplasmically inherited killer trait in populations of Paramecium tetraurelia and Paramecium biaurelia were examined using, in part, computer simulation. Frequency of the K and k alleles, infection and loss of the endosymbionts, recombination during conjugation and autogamy, cytoplasmic exchange and natural selection were incorporated in a model. Infection during cytoplasmic exchange at conjugation and natural selection were factors that would increase the proportion of killers in a population. Conversely, k alleles reduced the proportion of killers in a population, acting through conjugation and autogamy. Field studies indicate that the odd mating type is prevalent in P. tetraurelia isolated from nature. Conjugation and therefore transmission by cytoplasmic transfer would be rare. Competition studies indicate a strong selective disadvantage for sensitives at concentrations found in nature. Natural selection must therefore be the factor maintaining the killer trait in P. tetraurelia.

Alleles↗

Polygenetic traits in pancreatic disorders.

Rapid advances in information and technology provide opportunities to discover the risks or causes for various disorders within individual patients. The availability of new data and new technology has outstripped the conceptual framework of simple disorders,however, and challenges current statistical approaches. The author addresses the issues surrounding study design and sample size for complex genetic traits with special attention to meta-analysis and systems biology. The author concludes that meta-analysis should play a limited role in evaluating studies of complex genetic diseases. Instead, systems biology-based approaches should be developed to integrate multiple, focused, and mechanistic association studies, with the goal of assisting in the risk assessment of patients on a person-by-person basis.

Genetic Diseases, Inborn↗

On the power to detect SNP/phenotype association in candidate quantitative trait loci genomic regions: a simulation study.

We use coalescent methods to investigate the ability of linked neutral "markers" to reveal in simulated population samples the presence of one or more single nucleotide polymorphisms that is contributing to a trait having a complex genetic basis (QTN: quantitative trait nucleotide). Realistic mutation and recombination rates in our simulations allow us to generate SNP data appropriate for analyzing human variation across short chromosomal intervals corresponding to approximately 100 kilobases. We investigate the performance of both single marker and multiple-marker (haplotype) data for several ad hoc procedures. Our results with single SNP markers indicate that (1) the density of SNP markers need not be much higher than 10% in order to achieve near-maximal detection of a QTN; (2) a higher density of markers does not improve much on the ability to localize a QTN within an interval unless the recombination rate is high. Haplotype-based tests were investigated for the case in which more than one QTN is present in the studied interval. Larger sample sizes improve both the probability of detecting the haplotype with the largest number of QTNs, as well as the ability to infer correct haplotypes from genotypic data. Testing a series of short haplotypes across a longer interval can also be beneficial. The rate of false positives (i.e., when the most significant haplotype does not contain the greatest number of QTNs in the sample) can be very high when the contribution of individual QTNs to a trait is small. The elimination of low-frequency haplotypes does not substantially reduce the probability of detecting the haplotype with the largest number of QTNs but it can reduce the rate of false positives.

Computational Biology↗

[Advance in association studies of major histocompatibility complex (MHC) gene polymorphisms with traits of resistance against infectious disease in chickens].

Chicken is a main poultry in China. Molecular breeding for disease resistance plays an important role in the control of diseases, especially infectious diseases. Choice of genes for disease resistance is the key technology of molecular breeding. The MHC is of great interest to poultry breeding scientists for its extraordinary polymorphism and close relation with traits of resistance against infectious diseases. The article gives a detailed introduction about the association of MHC gene polymorphisms with traits of resistance against infectious diseases in chickens and looks towards the future of application of MHC in molecular breeding of chicken for disease resistance.

Animals↗

Complexity and integration in sexual ornamentation: an example with carotenoid and melanin plumage pigmentation.

Sexual ornaments often consist of several components produced by distinct developmental processes. The complexity of sexual ornaments might be favoured by mate choice of individual components in different environments which ultimately results in weak interrelationships (integration) among the developmental processes that produce these components. At the same time, sexual selection for greater exaggeration of individual components favours their stronger co-dependence on organismal resources. This should ultimately produce stronger condition-mediated integration among ornaments' components in individuals with the most exaggerated ornamentation. Here we distinguish between these two sources of integration by examining the relationship between integration and elaboration of sexual ornamentation in three bird species: two with carotenoid-based sexual ornamentation (the house finch, Carpodacus mexicanus and common redpoll, Carduelis flammea) and a species with melanin-based sexual ornamentation (house sparrow, Passer domesticus). We found that integration of components varied with elaboration of carotenoid-based ornamentation but not of melanin ornamentation. In the house finches, integration was the highest in individuals with small ornaments and decreased with ornament elaboration whereas the pattern was the opposite in common redpolls. These results suggest that in these species integration and complexity of carotenoid-based ornamental components are due to shared condition-dependence of distinct developmental pathways, whereas integration and complexity of the melanin ornamentation is due to organismal integration of developmental pathways and is largely condition- and environment-invariant. Thus, functionally, ornamentation of the house sparrows can be considered a single trait, whereas complexity of the house finch and redpoll ornamentation varies with ornament elaboration and individual condition.

Animals↗

Searching for the regulators of human gene expression.

Many common human traits are believed to be a composite reflection of multiple genetic and non-genetic factors and the genetic contribution is consequently often difficult to characterise. Recent advances suggest that subtle variation in the regulation of gene expression may contribute to complex human traits. In two reports, Cheung and colleagues scale up human genetics analysis to an impressive level in a genome-wide search for the regulators of gene expression. They perform linkage analysis on expression profiles for over 3,500 genes and then employ the HapMap resource to take positive findings through to association studies at the genome-wide level. This work gives new insights into the complexities of gene regulation and the plausibility of genome-wide study design.

Cell Line↗

Genetic aspects of breathing: on interactions between hypercapnia and hypoxia.

Indeed, specific genes in humans and mice regulate breathing pattern at baseline and breathing control during chemical stimulation. The current review addresses the question of coupling plausible candidate genes to physiological variation in control of breathing. That is, can genes discovered in mice be candidates assigned to similar physiological mechanisms as genetic control of breathing in humans? As an illustration, this review examines the interaction of hypoxia in affecting the hypercapnic ventilatory sensitivity (HCVS) curve in humans and mice. Strain distribution patterns (SDPs) incorporating ten inbred mouse strains demonstrate that hypoxic stimulation likely influences HVCS via an additive mechanism rather than synergy between hypercapnia and hypoxia (i.e. CO(2) potentiation). As a mechanism associated with the chemical control of breathing in humans, the absence of CO(2) potentiation in mice suggests that specific genes interact to establish variation in complex breathing traits among mouse strains and between species. If future studies support the current evidence, the absence of CO(2) potentiation in mice compared with humans suggest a clearly defined species difference, which may depend on alternative hypoxic interactions such as hypometabolic and central neuronal depressive mechanisms in mice. Because the complexity of breathing mechanisms varies with modest adjustments in the environment, gene-targeting strategies that achieve 'one-gene, one-phenotype' results must be complimented with alternative strategies that consider integrating complex respiratory mechanisms with gene-to-gene interactions.

Animals↗

The human mind: building bridges between neuroscience and psychiatry.

This essay proposes the existence of four unique behavioral characteristics that distinguish Homo sapiens from its nearest evolutionary kin, the great apes. These are inventiveness, capacity for language, curiosity, and self-reflection or self-analysis. Some would counterargue that none of these features are "unique" to humans. Examples would be given of animal "intelligence" involving at times surprising problem-solving abilities. Even "conversations" between humans and parrots might be cited. However, this is to misunderstand what the focus is in the article. This is not a thesis on the continuity or discontinuities of evolution. Every well-trained biologist learns about evolution and understands that the most complex human traits have some hint of related traits in nearest relatives. Rather, the emphasis of this article has been to select and emphasize certain distinctive aspects of human behavior that are the most important features distinguishing human "uniqueness." Uniqueness may be quantified by the number and complexity of processes within the four attributes presented in this article. While this may be an interesting mathematical exercise, the author would rather take it for granted that the outcome would be that humans are significantly more complex in each of the four features referred to than the great apes. For those in the mental health field, one would hope that this overview of the most highly evolved systems in human brain may provide a useful framework where creative therapeutic processes can be applied to the ultimate beneficiary, the client or patient. This article proposes that psychosis can be considered the impossibility of conflict resolution among the special neuronal assemblies that separately mediate feelings of attachment versus abandonment, security versus anxiety, calmness versus anger, fulfillment versus helplessness, and satisfaction of sexual needs. Given this model, the role of the therapist is to consider whether the client is in touch with the various equilibrium points in their current life situation or crisis. A questionnaire designed to help access information on these internal states may work better than an oral interview because it forces the client to reflect. How much conflict does the client feel in sorting out personal priorities? Does the client have any practice at resolving internal conflicts? If unpracticed, is the client likely to act out in destructive ways to self or others to resolve the pressure of internal conflicts? I am sure that we can all think of current well-publicized destructive acts in which one has to wonder precisely what model of mind the psychotherapists were using to assist the client. At a higher level, each human has the potential to be creative. Whether expressed as curiosity about the universe and nature or inventiveness, as in improving the quality of one's life or by the use of gifted language as in art and music, the therapist needs to determine how to assist the client into these kinds of self-defined fulfillments, which one hopes will reduce the other tensions of conflict resolution. There is no doubt that the journey for both the client and therapist will be challenging. Ultimately, the journey is the reward for both the client and therapist. In closing, the following quotation seems appropriate. Sydney Brenner (2002), a pioneer in molecular biology, reviewed a current book on the Science, Politics, and Ethics of the Human Genome Project (Sulston and Ferry 2002). He states, "What I found interesting in the account is that Sulston doesn't tell us anything about the genomes he has sequenced. What did he find there that excited him? What did he learn about genes, about life, about evolution, about worlds to come? It is the play of Hamlet without Hamlet" (p. 794).

Animals↗

Molecular mechanisms of bacterial virulence: type III secretion and pathogenicity islands.

Recently, two novel but widespread themes have emerged in the field of bacterial virulence: type III secretion systems and pathogenicity islands. Type III secretion systems, which are found in various gram-negative organisms, are specialized for the export of virulence factors delivered directly to host cells. These factors subvert normal host cell functions in ways that seem beneficial to invading bacteria. The genes encoding several type III secretion systems reside on pathogenicity islands, which are inserted DNA segments within the chromosome that confer upon the host bacterium a variety of virulence traits, such as the ability to acquire iron and to adhere to or enter host cells. Many of these segments of DNA appear to have been acquired in a single step from a foreign source. The ability to obtain complex virulence traits in one genetic event, rather than by undergoing natural selection for many generations, provides a mechanism for sudden radical changes in bacterial-host interactions. Type III secretion systems and pathogenicity islands must have played critical roles in the evolution of known pathogens and are likely to lead to the emergence of novel infectious diseases in the future.

Bacterial Proteins↗

Functional genomics in rodent models of hypertension.

Inbred strains of rodents have been used to study mammalian physiology and pathophysiology in an attempt to understand the contribution of genes in the pathogenesis of the disease process. In this review we focus on experimental animal models to identify quantitative trait loci (QTL) and possible strategies for identifying underlying genetic determinants responsible for hypertension. Confirmation of the existence of the QTL and dissection of the implicated region can be undertaken by production of either recombinant inbred, consomic or congenic strains. Despite complex interactions and the relatively few confirmed causative genes underlying QTL, recent developments in rat genome resources and advancement in statistical and bioinformatic methods will facilitate the identification of major gene(s) responsible for complex, polygenic traits.

Animals↗

Anchoring of canine linkage groups with chromosome-specific markers.

A high-resolution genetic map with polymorphic markers spaced frequently throughout the genome is a key resource for identifying genes that control specific traits or diseases. The lack of rigorous selection against genetic disorders has resulted in many breeds of dog suffering from a very high frequency of genetic diseases, which tend to be breed-specific and usually inherited as autosomal recessive or apparently complex genetic traits. Many of these closely resemble human genetic disorders in their clinical and pathologic features and are likely to be caused by mutations in homologous genes. To identify loci important in canine disease genes, as well as traits associated with morphological and behavioral variation, we are developing a genetic map of the canine genome. Here we report on an updated version of the canine linkage map, which includes 341 mapped markers distributed over the X and 37 autosomal linkage groups. The average distance between markers on the map is 9.0 cM, and the linkage groups provide estimated coverage of over 95% of the genome. Fourteen linkage groups contain either gene-associated or anonymous markers localized to cosmids that have been assigned to specific canine chromosomes by FISH. These 14 linkage groups contain 150 microsatellite markers and allow us to assign 40% of the linkage groups to specific canine chromosomes. This new version of the map is of sufficient density and characterization to initiate mapping of traits of interest.

Animals↗