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PubMed2004

Individual colour patches as multicomponent signals.

Colour patches are complex traits, the components of which may evolve independently through a variety of mechanisms. Although usually treated as simple, two-dimensional characters and classified as either structural or pigmentary, in reality colour patches are complicated, three-dimensional structures that often contain multiple pigment types and structural features. The basic dermal chromatophore unit of fishes, reptiles and amphibians consists of three contiguous cell layers. Xanthophores and erythrophores in the outermost layer contain carotenoid and pteridine pigments that absorb short-wave light; iridophores in the middle layer contain crystalline platelets that reflect light back through the xanthophores; and melanophores in the basal layer contain melanins that absorb light across the spectrum. Changes in any one component of a chromatophore unit can drastically alter the reflectance spectrum produced, and for any given adaptive outcome (e.g. an increase in visibility), there may be multiple biochemical or cellular routes that evolution could take, allowing for divergent responses by different populations or species to similar selection regimes. All of the mechanisms of signal evolution that previously have been applied to single ornaments (including whole colour patches) could potentially be applied to the individual components of colour patches. To reach a complete understanding of colour patch evolution, however, it may be necessary to take an explicitly multi-trait approach. Here, we review multiple trait evolution theory and the basic mechanisms of colour production in fishes, reptiles and amphibians, and use a combination of computer simulations and empirical examples to show how multiple trait evolution theory can be applied to the components of single colour patches. This integrative perspective on animal colouration opens up a host of new questions and hypotheses. We offer specific, testable functional hypotheses for the most common pigmentary (carotenoid, pteridine and melanin) and structural components of vertebrate colour patches.

Animals↗
PubMed2001

The genetics of cognitive processes: candidate genes in humans and animals.

It has been hypothesized that numerous genes contribute to individual variation in human cognition. An extensive search of the scientific literature was undertaken to identify candidate genes which might contribute to this complex trait. A list of over 150 candidate genes that may influence some aspect of cognition was compiled. Some genes are particularly strong candidates based on evidence for involvement in cognitive processes in humans, mice, and Drosophila melanogaster. This survey confirms that many genes are associated with cognitive variation and highlights the potential importance of animal models in the study of human cognition.

Animals↗
PubMed1998

Molecular genetic investigations of autism.

Genetic factors are likely to play a major role in the etiology of autism. The genetics of the disorder is however complex, probably involving the action of several genes. In an attempt to identify autism susceptibility loci we are currently undertaking a systematic screening of the whole human genome using multiplex families. We describe the resources and the methods needed to achieve such a task, including extensive collection of family data, semiautomated genotyping technology, and specialized statistical approaches for linkage analysis of complex traits.

Autistic Disorder↗
PubMed2004

Modeling with measured genotypes: effects of the vitamin D receptor gene, age, and latent genetic and environmental factors on bone mineral density.

We use empirical data to demonstrate a recently proposed framework for including measured genotypes in structural equation models (Van den Oord and Snieder, 2002). The sample consisted of 227 MZ pairs, 197 DZ pairs, and 41 DZ twins without co-twin. The mean age of the female twins was 57 years. The analysis aimed at studying the effect of the vitamin D receptor (VDR) gene polymorphism (VDRGP) on bone mineral density (BMD). Whereas age affected the BMD measures via independent pathways, the effects of the VDRGP plus latent genetic and environmental factors were consistent with a common pathway model. VDRGP explained 0.3% to 0.5% of the variance. These analyses demonstrated that (i) regardless of how much is known about the gene and its products at a molecular level, meaningful questions can be addressed concerning how genes co-act with other variables at a "higher" phenotypic level; (ii) measured genotypes can be treated like any other variable so that the whole structural equation models framework can in principle directly be applied; and (iii) measured genotypes do not need to have large effects to study mechanisms underlying complex traits, and it may even be argued that particularly genes with small effects are better studied within the context of models with multiple variables.

Age Factors↗
PubMed2004

After the genome--the phenome?

What next? The Human Genome Project signifies complexity rather than simplification in the relationship between genotype and phenotype. Genotypes are embedded in genomes. Individuality in phenotypes is embedded in components of the phenome (transcriptome, metabolome, proteome, etc.). The phenome, its layers, and its nodes, links and networks, require elucidation; there is a need for a Human Phenome Project (Freimer and Sabatti 2003). Biology has largely been a reductive science in the recent past; integrative biology lies ahead. Clinician-scientists (including human biochemical geneticists) will be recognized as key participants in the 'medical' Phenome Project as it reveals components of individuality, and their contributions, in simple or combinatorial fashion, to Mendelian and complex traits; better ways to treat 'genetic disease' will be by-products of the project. Although the Word is common to all, most men live as if each had a private wisdom of his own.Herakleitos

Genomics↗
PubMed1999

Procedure to protect confidentiality of familial data in community genetics and genomic research.

The collection of familial data is an essential step for community genetics programs or genetic research. Ethical issues concerning privacy and confidentiality present a major challenge in such programs. In order to keep familial data confidential, we have developed a family-based numerical coding procedure which allows the use of confidential data and the determination of familial relationships without risk of disclosure. This procedure is composed of two parts: the physical separation of identifying information and individual data; and the use of a code containing all the information required to build family trees. This procedure has been used in Eastern Quebec since 1995, mainly for screening, genetic counseling, research on familial dyslipidemias, public health intervention, and research projects on the genetics of complex traits, such as arterial hypertension and coronary artery disease.

Abstracting and Indexing↗
PubMed2000

Factors influencing sib risks for multiple sclerosis.

Multiple sclerosis (MS) is now thought to be a complex trait determined by genetic and non-genetic (environmental) factors. The study group, identified from the Canadian Collaborative Project on Genetic Susceptibility to MS, consisted of 1,083 MS index cases, 2,166 of their parents and 3,112 of their sibs. The results, together with those of a previous study on an independent data set, suggest that gender, age of MS onset and having one parent with MS may individually and interactively alter sib risks for MS. These data are important for genetic counselling and for molecular genetic (genome screens, candidate gene analyses) studies.

Adolescent↗
PubMed2001

Association of a single nucleotide polymorphism in CPB2 encoding the thrombin-activable fibrinolysis inhibitor (TAF1) with blood pressure.

Thrombin-activable fibrinolysis inhibitor (TAFI) is a hepatically secreted zymogen, whose substrates include bradykinin. The CPB2 gene encoding TAFI is a candidate gene for blood pressure. A recently identified single nucleotide polymorphism (SNP) in the CPB2 coding region, designated as 1057C > T, results in an amino acid change at TAFI residue 325 (Ile > Thr325). We found that the genotype based on this SNP was significantly associated with blood pressure in aboriginal Canadians. Specifically, analysis of variance showed that homozygotes for CPB2 1057T had significantly lower diastolic blood pressure than subjects with other CPB2 genotypes. CPB2 genotype accounted for approximately 3% of the total variation in diastolic blood pressure. consistent with the expected magnitude of a modest genetic effect in a complex trait such as blood pressure. Although the mechanism underlying the association is unclear, the findings are of interest because TAFI may provide a link between coagulation and blood pressure regulation.

Adolescent↗
PubMed2001

Association studies of bipolar disorder.

Association studies in outbred populations represent an important paradigm for investigation of complex traits, such as bipolar disorder, both to follow-up regions of interest from linkage studies (by systematic linkage disequilibrium mapping and positional candidate studies) and for pure functional studies. The advantages of the association method include its relative robustness to genetic heterogeneity and the ability to detect much smaller effect sizes than are detectable using feasible sample sizes in linkage studies. The candidate gene approach is potentially very powerful, particularly when used within the context of a VAPSE (variation affecting protein structure or expression) paradigm, but a major problem is that the efficiency in the choice of candidates is inevitably a function of the level of previous understanding of disease pathophysiology. To date, most candidate gene studies in bipolar disorder have focussed on the major neurotransmitter systems that are influenced by medication used in clinical management of the disorder. Early studies often used anonymous markers in the hope of detecting linkage disequilibrium but recently direct examination of polymorphisms of known or presumed functional relevance has become more usual. Most studies in the literature have been of the unrelated case-control design with samples rarely exceeding 200-300 subjects. No definitive findings have yet emerged although there have been some interesting preliminary findings including those with polymorphisms within the genes encoding catechol-o-methyl transferase (COMT), monoamine oxidase A (MAOA) and the serotonin transporter (hSERT; 5-HTT). In this article we critically review the current status of the literature within the context of the important methodological issues and limitations inherent in the use of association studies for genetic dissection of bipolar disorder. We conclude by examining likely future directions and developments in the field.

Bipolar Disorder↗
PubMed1987

Two conceptions of maturity examined in the findings of a longitudinal study.

The third vector score (competence) of the revised California Psychological Inventory (CPI) and ego level as assessed by the Loevinger Sentence Completion Test (SCT) are measures of alternative ways of conceptualizing maturity: as the ability of the individual to function effectively in society or as the degree of intrapsychic differentiation and autonomy. A longitudinal study of women (for the CPI, N = 107; for the SCT, N = 90) provides these two measures of maturity at age 43. Competence and ego level were correlated with antecedent and concurrent measures selected from inventories and life history material concerning work, marriage, relations with parents, and so forth, to assess aspects of maturity adapted from Allport: self-extension in significant endeavors, reality orientation in perception of self and others and in the conduct of one's activities, capacity for intimacy, emotional security, and individuality of personal integration. Results from the age-21 data indicate that competence and ego level are enduring trait complexes. Despite considerable overlap, they differ conspicuously in the greater emphasis of competence on emotional security and of ego level on individuality of personal integration. Analysis of the patterning of competence and ego level in the whole sample and in homogeneous groups high on one or both measures suggests psychological reasons why the two types of maturity diverge and why the relation of ego level to adjustment seems to be curvilinear.

Adaptation, Psychological↗
PubMed1997

Intelligence, personality, and interests: evidence for overlapping traits.

The authors review the development of the modern paradigm for intelligence assessment and application and consider the differentiation between intelligence-as-maximal performance and intelligence-as-typical performance. They review theories of intelligence, personality, and interest as a means to establish potential overlap. Consideration of intelligence-as-typical performance provides a basis for evaluation of intelligence-personality and intelligence-interest relations. Evaluation of relations among personality constructs, vocational interests, and intellectual abilities provides evidence for communality across the domains of personality of J. L. Holland's (1959) model of vocational interests. The authors provide an extensive meta-analysis of personality-intellectual ability correlations, and a review of interest-intellectual ability associations. They identify 4 trait complexes: social, clerical/conventional, science/math, and intellectual/cultural.

Adolescent↗
PubMed2000

DNA.

The authors predict that in a few years, many areas of psychology will be awash in specific genes responsible for the widespread influence of genetics on behavior. As the focus shifts from finding genes (genomics) to understanding how genes affect behavior (behavioral genomics), it is important for the future of psychology as a science that pathways between genes and behavior be examined not only at the molecular biological level of cells or the neuroscience level of the brain but also at the psychological level of analysis. After a brief overview of quantitative genetic research, the authors describe how genes that influence complex traits like behavioral dimensions and disorders in human and nonhuman animals are being found. Finally, the authors discuss behavioral genomics and predict that DNA will revolutionize psychological research and treatment early in the 21st century.

Animals↗
PubMed1999

Susceptibility to testicular germ-cell tumours in a 129.MOLF-Chr 19 chromosome substitution strain.

The identification of genes that control susceptibility to testicular germ-cell tumours (TGCTs), the most common cancer affecting young men, has been difficult. In laboratory mice, TGCTs arise from primordial germ cells in only the 129 inbred strains, and susceptibility is under multigenic control. The spontaneously arising mutation Ter (ref. 5) on mouse chromosome 18 (Refs 6,7) increases TGCT frequency on a 129/Sv background. We originally used Ter in genetic crosses to identify loci that control tumorigenesis. A genome scan of tumour-bearing progeny from backcrosses between the 129/Sv-Ter/+ and MOLF/Ei strains provided modest evidence that MOLF-derived alleles on chromosome 19 enhance development of bilateral TGCTs (ref. 9). To obtain independent evidence for linkage to the MOLF chromosome, we made an autosomal chromosome substitution strain (CSS; or 'consomic strain') in which chromosome 19 of 129/Sv+/+ was replaced by its MOLF-derived homologue. The unusually high frequency of TGCTs in this CSS (even in the absence of the Ter mutation) provides evidence confirming the genome survey results, identifies linkage for a naturally occurring strain variant allele that confers susceptibility to TGCTs and illustrates the power of CSSs in complex trait analysis.

Alleles↗
PubMed2001

Human disease genes.

The complete human genome sequence will facilitate the identification of all genes that contribute to disease. We propose that the functional classification of disease genes and their products will reveal general principles of human disease. We have determined functional categories for nearly 1,000 documented disease genes, and found striking correlations between the function of the gene product and features of disease, such as age of onset and mode of inheritance. As knowledge of disease genes grows, including those contributing to complex traits, more sophisticated analyses will be possible; their results will yield a deeper understanding of disease and an enhanced integration of medicine with biology.

Disease↗
PubMed1995

A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group.

Genetic-environmental interactions probably underlie spontaneous human autoimmune disorders, a category of complex traits thought to include multiple sclerosis (MS). The geographical distribution and familial aggregation of this disease have often been ascribed to the role of infectious agents, but there is no consensus. Increased family risks range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives over the general population prevalence of 0.1% (ref. 6). We screened a population-based sample of 15,000 individuals with MS by using standardized, personally administered questionnaires to identify adopted index cases and/or those who had adopted relatives. The frequency of MS among first-degree non-biological relatives living with the index case was no greater than expected from Canadian population prevalence data and significantly less than for biological relatives. These findings indicate that familial aggregation of MS is genetically determined: no effect of shared environment was detectable.

Adoption↗
PubMed2000

MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability.

DNA mismatch repair is important because of its role in maintaining genomic integrity and its association with hereditary non-polyposis colon cancer (HNPCC). To identify new human mismatch repair proteins, we probed nuclear extracts with the conserved carboxy-terminal MLH1 interaction domain. Here we describe the cloning and complete genomic sequence of MLH3, which encodes a new DNA mismatch repair protein that interacts with MLH1. MLH3 is more similar to mismatch repair proteins from yeast, plants, worms and bacteria than to any known mammalian protein, suggesting that its conserved sequence may confer unique functions in mice and humans. Cells in culture stably expressing a dominant-negative MLH3 protein exhibit microsatellite instability. Mlh3 is highly expressed in gastrointestinal epithelium and physically maps to the mouse complex trait locus colon cancer susceptibility I (Ccs1). Although we were unable to identify a mutation in the protein-coding region of Mlh3 in the susceptible mouse strain, colon tumours from congenic Ccs1 mice exhibit microsatellite instability. Functional redundancy among Mlh3, Pms1 and Pms2 may explain why neither Pms1 nor Pms2 mutant mice develop colon cancer, and why PMS1 and PMS2 mutations are only rarely found in HNPCC families.

Amino Acid Sequence↗
PubMed2001

Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes.

Most human sequence variation is in the form of single-nucleotide polymorphisms (SNPs). It has been proposed that coding-region SNPs (cSNPs) be used for direct association studies to determine the genetic basis of complex traits. The success of such studies depends on the frequency of disease-associated alleles, and their distribution in different ethnic populations. If disease-associated alleles are frequent in most populations, then direct genotyping of candidate variants could show robust associations in manageable study samples. This approach is less feasible if the genetic risk from a given candidate gene is due to many infrequent alleles. Previous studies of several genes demonstrated that most variants are relatively infrequent (<0.05). These surveys genotyped small samples (n<75) and thus had limited ability to identify rare alleles. Here we evaluate the prevalence and distribution of such rare alleles by genotyping an ethnically diverse reference sample that is more than six times larger than those used in previous studies (n=450). We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter. Both genes have unique roles in neuronal transmission, and variants in either gene might be associated with neurobehavioral phenotypes.

Alleles↗
PubMed2006

Analysis of the variations in IL-28RA gene and their association with allergic rhinitis.

IL-28RA is one of the important candidate genes for complex trait of genetic diseases, but there is no published information of the genetic variation in this gene. We scanned the seven exons and their boundary introns sequence of IL-28RA including the promoter regions to analyze genetic variation sites, and identified eighteen single nucleotide polymorphisms (SNPs) and two variation sites. We chose seven SNPs (g.-1193 A>C, g.-30 C>T, g.17654 C>T, g.27798 A>G, g.31265 C>T, g.31911 C>T and g.32349 G>A) of them for large sample size genotyping, and assessed the association of genotype and allele frequencies of these SNPs between allergic rhinitis patients and non-allergic rhinitis controls. We also compared the genotype frequencies between Korean controls and Han Chinese control or Korean Chinese control. We investigated the frequencies of haplotype constructed by these SNPs between allergic rhinitis patients and non-allergic rhinitis controls. Our results suggested that the g.32349 G>A polymorphism of IL-28RA might be associated with susceptibility to allergic rhinitis (P=0.032), but seems to have no relationship with serum total IgE levels. The haplotype frequencies by these SNPs also show significant association between controls and allergic rhinitis patients.

Adult↗