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PubMed1999

Exploring genetic analysis of complex traits through the paradigm of alcohol dependence: summary of GAW11 contributions.

We discuss the Genetic Analysis Workshop 11 analyses of data from the Collaborative Study on the Genetics of Alcoholism from a methodological perspective, concentrating on approaches and issues relevant to linkage and association studies of complex human phenotypes. Genome screening by parametric linkage, nonparametric linkage, association, and combined linkage/association methods are discussed. Issues particular to complex disease include etiologic heterogeneity, multivariate phenotype modeling, and parent-of-origin effects. Other methodological topics discussed are new and enhanced methods, ascertainment, weighting of nonindependent sib pairs, and data cleaning and validation.

Alcoholism↗
PubMed2005

Strategic analysis in evolutionary genetics and the theory of games.

This paper is written in memory of John Maynard Smith. In a brief survey it discusses essential aspects of how game theory in biology relates to its counterpart in economics, the major transition in game theory initiated by Maynard Smith, the discrepancies between genetic and phenotypic models in evolutionary biology, and a balanced way of reconciling these models. In addition, the paper discusses modern problems in understanding games at the genetic level using the examples of conflict between endosymbionts and their hosts, and the molecular interactions between parasites and the mammalian immune system.

Animals↗
PubMed1992

Does frequency-dependent selection optimize fitness?

In evolutionary biology, the axiom that natural selection tends ideally to maximize inclusive fitness of the individual or some other suitable quantity is often advanced (Cody, 1974; Maynard Smith, 1978; Krebs & McCleery, 1984; Houston et al., 1988). Moreover, the evolutionists generally distinguish two situations (Dawkins, 1980; Maynard Smith, 1982): one in which fitness is independent of the frequency of the phenotypes present in the population (frequency-independent selection), and one in which it does depend on this frequency (frequency-dependent selection). This led some authors such as Parker (1984), and more recently Parker & Maynard Smith (1990), to consider "a 2-speed optimization": frequency-independent selection should lead to a "simple optimum" at the end of the selective process, since all the individuals should have the same strategy and the mean fitness of the population should be maximized; frequency-dependent selection, formulated in terms of the theory of games, should lead to a "competitive optimum" even though the "evolutionary stable strategy" (or "ESS"; Maynard Smith & Price, 1973) characterizing the equilibrium "is not the strategy that maximizes fitness in a population sense" (Parker & Maynard Smith, 1990: 30). Our aim in this short communication is to criticize the concept of "competitive optimum" by Parker & Maynard Smith, as well as the general ability of natural selection to "maximize fitness", even in "phenotypic models" (Lloyd, 1977). These models, devoid of genetic constraints since each strategist is assumed to reproduce its own kind, are especially suitable for examining the ideal effect of natural selection.

Animals↗
PubMed2005

Sperm mobility: deduction of a model explaining phenotypic variation in roosters (Gallus domesticus).

In previous work, variation in sperm mobility phenotype was attributed to the proportion of ejaculated fowl sperm containing dysfunctional mitochondria. In the present work, latent mitochondrial dysfunction was inferred from patterns of sperm egress from the oviduct's sperm-storage tubules. In addition, experiments were performed to help explain how mitochondrial function could be compromised in viable sperm cells. Confocal microscopy demonstrated that sperm Ca2+ content differed between low and high sperm-mobility phenotypes when sperm were stained with rhod-2 AM, a Ca2+ -specific dye. Fluorescence was associated with the nuclear envelope, a variant of the endoplasmic reticulum, and greater fluorescence was observed in sperm from low sperm-mobility males. Fluorescence was reduced by 50% when motile sperm were rendered immotile by incubation with a Ca2+ chelator. Thus, a relationship was established between a dynamic intracellular Ca2+ pool and sperm motility. Sperm N-methy-D-aspartic acid (NMDA) receptors were inferred by the action of D-homocysteinesulfinic acid, a potent NMDA receptor agonist. Seminal plasma from low sperm mobility males was characterized by an elevated glutamate concentration. Thapsigargin, which inhibits the smooth endoplasmic reticulum Ca2+ pump and thereby promotes Ca2+ efflux, rendered sperm immotile. This effect was blocked by cyclosporin A, which prevents the formation of the mitochondrial permeability transition pore (PTP) in response to elevated mitochondrial Ca2+ content. In summary, we propose that 1) glutamate enables Ca2+ uptake into sperm before ejaculation, 2) excessive Ca2+ uptake triggers formation of the PTP in a subpopulation of sperm, and 3) sperm mobility is decreased in proportion.

Animals↗
PubMed1997

Immunological study of unresponsive state in rat hepatic transplant model. 1. Phenotypic and functional analyses of infiltrating cells.

In order to elucidate the immunological characteristics of rat liver transplantation, graft-infiltrating cells (GIC) isolated from rat hepatic allografts were analyzed phenotypically and functionally. GIC from long-surviving recipients (Brown Norway livers into Lewis hosts) and acutely rejecting recipients (DA livers into Lewis hosts) were compared. The relative proportions of all T cells and activated T cells determined by flow cytometry were significantly higher in acutely rejecting Lewis recipients than in long-surviving recipients on day 6 after grafting. Phenotypic kinesis of GIC on days 6, 14, and 45 after transplantation from long-surviving Lewis hosts was analyzed. Each proportion of all T cells, OX8-positive cells (cytotoxic T and natural killer cells), and OX39-positive cells (IL-2 receptor), was greatest on day 6 and decreased by day 45. Cytotoxic activity of GIC toward donor lymphocytes on day 6 was greater in acutely rejecting versus long-surviving recipients. These results demonstrate that an immunosuppressive mechanism is already present on day 6 posttransplantation, and that infiltration or activation of cytotoxic T cells is inhibited in the long-surviving rat hepatic allografts.

Animals↗
PubMed1988

[The Recklinghausen model: innumerable phenotypes and scarce genotypes].

Since several decades, clinical reports about neurofibromatosis are overwhelming general practitioners, neurologists and other specialists. Since some years cellular biology (specially experimental studies on the neural crest) and molecular genetics light up somewhat the contrast between innumerable phenotypes and the rare punctual mutations which are at the source of the disease. The author reviews the different theories which are attempting to explain the process of malignant transformation in these kinds of diseases (role of eventual oncogenes and recent experiment types of Hinrichs in transgenic mice).

Cell Transformation, Neoplastic↗
PubMed1984

An evaluation of three statistics of structured exploratory data analysis.

The power of structured exploratory data analysis (SEDA) to discriminate among major genic, polygenic, and nongenetic determination of phenotypes was investigated using computer simulation. Three classes of SEDA indices (the major gene index, the offspring between parents function, and the midparent-child correlation coefficient) were evaluated. These three statistics, in combination, were reasonably sensitive in detecting the presence of a major locus and in discriminating between phenotypes with genetic effects and those with no genetic component. However, they were unable to discriminate between major genic and polygenically determined phenotypic models.

Chromosome Mapping↗
PubMed2006

A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba.

We present results from a genome-wide scan of a six generation pedigree with 28 affected members with apparently dominant bipolar I disorder from eastern Cuba. Genotypes were obtained using the early access version of the Genechip Mapping 10K Xba array from AFFYMETRIX. Parametric and non-parametric linkage analyses under dominant and recessive models were performed using GENEHUNTER v2.1r5. Two phenotypic models were included in the analyses: bipolar I disorder and recurrent depressive disorder, or bipolar I disorder only. LOD scores were calculated for the entire family combined, and for four subdivisions of the family. For the entire family a suggestive parametric LOD score was obtained under the dominant model and the broader phenotype at 14q11.2-12 (LOD = 2.05). In the same region, a non-parametric LOD score close to genome-wide significance was also obtained, based on the entire family (NPL = 7.31, P-value = 0.07). For two individual branches of the pedigree, genome-wide significance (P < 0.005) was obtained with NPL scores of 8.71 and 12.99, respectively, also in the same region on chromosome 14. Chromosome 5q21.3-22.3 also showed close to genome-wide significant linkage for the complete pedigree (NPL = 7.26, P = 0.07), also supported by significant linkage in one individual branch (NPL = 9.86, P < 0.005). In addition, genome-wide significant nonparametric results (P-values <0.005) were obtained for individual branches at 5p13.1-q12.3, 6p22.3, 8q13.3-21.13, and 10q22.3-23.32. Finally, 2p25.1-25.3, 2p13.3-14, 3p14.2, 6p22.3-24.1, 7p14.1-14.2, 8q12.2-12.3, 10q21.1-21.2, 14q13.1-21.1, 15q15.1-21.2, and 22q12.3-13.32 showed suggestive linkage in the complete family. Most of these potential susceptibility loci overlap with, or are close, to previous linkage findings. The locus on 5q may, however, represent a novel susceptibility locus.

Bipolar Disorder↗
PubMed2002

The evolution of trade-offs: testing predictions on response to selection and environmental variation.

The concept of phenotypic trade-offs is a central element in evolutionary theory. In general, phenotypic models assume a fixed trade-off function, whereas quantitative genetic theory predicts that the trade-off function will change as a result of selection. For a linear trade-off function selection will readily change the intercept but will have to be relatively stronger to change the slope. We test these predictions by examining the trade-off between fecundity and flight capability, as measured by dorso-longitudinal muscle mass, in four different populations of the sand cricket, Gryllus firmus. Three populations were recently derived from the wild, and the fourth had been in the laboratory for 19 years. We hypothesized that the laboratory population had most likely undergone more and different selection from the three wild populations and therefore should differ from these in respect to both slope and intercept. Because of geographic variation in selection, we predicted a general difference in intercept among the four populations. We further tested the hypothesis that this intercept will be correlated with proportion macropterous and that this relationship will itself vary with environmental conditions experienced during both the nymphal and adult period. Observed variation in the phenotypic trade-off was consistent with the predictions of the quantitative genetic model. These results point to the importance of modeling trade-offs as dynamic rather than static relationships. We discuss how phenotypic models can incorporate such variation. The phenotypic trade-off between fecundity and dorso-longitudinal muscle mass is determined in part by variation in body size, illustrating the necessity of considering trade-offs to be multi factorial rather than simply bivariate relationships.

Animals↗
PubMed2001

Modeling age x major gene interaction by a variance component approach.

The variance component method has become popular for linkage analysis due to its computational simplicity and generally high power. In this paper we model phenotypic variability of an individual as a mixed effects model in which both the major gene as well as the polygene effects interact with age. We applied the proposed model to the simulated data of Genetic Analysis Workshop 12. We considered the quantitative trait, Q4, in the outbred population. Two major genes influence this trait, each interacting with age independently. Consequently, trait variability is a function of age and also there is interaction of major gene effects with age. By using our model we were able to detect interaction between the major gene effects and age for this trait.

Adolescent↗
PubMed2004

Bayesian association-based fine mapping in small chromosomal segments.

A Bayesian method for fine mapping is presented, which deals with multiallelic markers (with two or more alleles), unknown phase, missing data, multiple causal variants, and both continuous and binary phenotypes. We consider small chromosomal segments spanned by a dense set of closely linked markers and putative genes only at marker points. In the phenotypic model, locus-specific indicator variables are used to control inclusion in or exclusion from marker contributions. To account for covariance between consecutive loci and to control fluctuations in association signals along a candidate region we introduce a joint prior for the indicators that depends on genetic or physical map distances. The potential of the method, including posterior estimation of trait-associated loci, their effects, linkage disequilibrium pattern due to close linkage of loci, and the age of a causal variant (time to most recent common ancestor), is illustrated with the well-known cystic fibrosis and Friedreich ataxia data sets by assuming that haplotypes were not available. In addition, simulation analysis with large genetic distances is shown. Estimation of model parameters is based on Markov chain Monte Carlo (MCMC) sampling and is implemented using WinBUGS. The model specification code is freely available for research purposes from http://www.rni.helsinki.fi/~mjs/.

Algorithms↗
PubMed1998

Unifying genetic and game theoretic models of kin selection for continuous traits.

A framework is presented for unifying single locus genetic and game theoretic models of continuous traits under frequency-dependent selection when there are interactions among relatives. This framework serves two purposes. First, it is used to determine how "games between relatives" must be modeled to be genetically valid. There are two commonly employed phenotypic approaches used in this setting, and we demonstrate that, although some of their predictions are always genetically valid, others are invalid in general, and this is true for both haploid asexual and diploid sexual organisms. In particular, we show that both approaches obtain the correct equilibrium and convergence stability conditions, but neither obtains the correct condition for evolutionary stability. Unlike earlier results for discrete trait matrix games (Hines & Maynard Smith, 1979), there is no simple correspondence between phenotypic and genetic predictions, and we provide two examples to illustrate this point. It is possible however, to obtain these earlier results within the present setting by restricting attention to a particular class of fitness functions. These results demonstrate that, even when selection is weak, phenotypic models can fail if fitness is frequency-dependent. The second purpose is to determine when population mean inclusive fitness effect provides an adaptive topography in games between relative. Our results show that the fitness function must have a special form for this to be true, and this form differs between haploid and diploid organisms.

Animals↗
PubMed2001

The topology of the possible: formal spaces underlying patterns of evolutionary change.

The current implementation of the Neo-Darwinian model of evolution typically assumes that the set of possible phenotypes is organized into a highly symmetric and regular space equipped with a notion of distance, for example, a Euclidean vector space. Recent computational work on a biophysical genotype-phenotype model based on the folding of RNA sequences into secondary structures suggests a rather different picture. If phenotypes are organized according to genetic accessibility, the resulting space lacks a metric and is formalized by an unfamiliar structure, known as a pre-topology. Patterns of phenotypic evolution-such as punctuation, irreversibility, modularity--result naturally from the properties of this space. The classical framework, however, addresses these patterns by exclusively invoking natural selection on suitably imposed fitness landscapes. We propose to extend the explanatory level for phenotypic evolution from fitness considerations alone to include the topological structure of phenotype space as induced by the genotype-phenotype map. We introduce the mathematical concepts and tools necessary to formalize the notion of accessibility pre-topology relative to which we can speak of continuity in the genotype-phenotype map and in evolutionary trajectories. We connect the factorization of a pre-topology into a product space with the notion of phenotypic character and derive a condition for factorization. Based on anecdotal evidence from the RNA model, we conjecture that this condition is not globally fulfilled, but rather confined to regions where the genotype-phenotype map is continuous. Equivalently, local regions of genotype space on which the map is discontinuous are associated with the loss of character autonomy. This is consistent with the importance of these regions for phenotypic innovation. The intention of the present paper is to offer a perspective, a framework to implement this perspective, and a few results illustrating how this framework can be put to work. The RNA case is used as an example throughout the text.

Animals↗
PubMed1994

Linkage analysis between manic depressive illness and the region on chromosome 12q involved in Darier's disease.

Co-segregation between Darier's disease and manic depressive illness has been reported. A gene causing Darier's disease has recently been mapped to chromosome 12q23-q24.1, and this region may thus be considered a candidate region potentially containing a gene involved in the aetiology of manic depressive illness. At least one possible candidate gene for manic depressive illness, pro-melanin-concentrating hormone, is located on chromosome 12q23-q24. The present study investigated linkage between manic depressive illness and this region on chromosome 12q, using three microsatellite polymorphisms as genetic markers which flank the gene causing Darier's disease. For all dominant models close linkage was excluded. For broader phenotypic models linkage was excluded in the interval between markers, even in one large family alone.

Bipolar Disorder↗
PubMed2005

Familiality of temperament in bipolar disorder: support for a genetic spectrum.

BACKGROUND: The array of different diagnoses and clinical presentations seen in the family members of bipolar probands suggests a quantitative or spectrum phenotype. Consistent with this idea, it has been proposed that an underlying quantitative variation in temperament may be the primary phenotype that is genetically transmitted and that it in turn predisposes to bipolar disorder (BP). Choosing the appropriate phenotypic model for BP is crucial for success in genetic mapping studies. To test this theory, various measures of temperament were examined in the family members of bipolar probands. We predicted that a gradient of scores would be observed from those with BP to those with major depression to unaffected relatives to controls. METHODS: Members of 85 bipolar families and 63 control subjects were administered clinical interviews for diagnosis (SCID) and two temperament assessments, the TEMPS-A and TCI-125. Subjects with BP, major depressive disorder, unaffected relatives, and controls were compared on each temperament scale and on eight factors extracted from a joint factor analysis of the TEMPS-A and TCI-125. RESULTS: The four groups were found to be significantly different and with the expected order of average group scores for four of the TEMPS-A scales, three of the TCI-125 scales, and one of the extracted factors. On the fifth TEMPS-A scale, hyperthymic, controls scored higher than the other three subject groups contrary to expectations. Significant differences were seen between unaffected relatives and controls on the hyperthymic scale and on the first extracted factor, anxious/reactive. LIMITATIONS: Controls were mainly recruited through advertisements, which may have introduced an ascertainment bias. It is also possible that mood state at the time of completing the questionnaire influenced subject's rating of their temperament. Additionally, bipolar I and bipolar II subjects were placed in the same group even though they had some differing clinical features. CONCLUSIONS: Our data support the theory that some dimensions of temperament are transmitted in families as quantitative traits that are part of a broader bipolar spectrum. In particular, the hyperthymic scale of the TEMPS-A and the anxious/reactive extracted factor distinguished unaffected relatives from controls. The hyperthymic scale yielded results opposite to expectation with controls higher than any family group. This may be an artifact of the self-rated form of the questionnaire, a consequence of our grouping bipolar I and II subjects together, or the result of a "protective" factor and bears further study. Nevertheless, both of these scales may be useful quantitative traits for genetic mapping studies.

Bipolar Disorder↗
PubMed2005

Plastic and behavioral abnormalities in experimental Huntington's disease: a crucial role for cholinergic interneurons.

Huntington's disease (HD) is a fatal hereditary neurodegenerative disease causing degeneration of striatal spiny neurons, whereas cholinergic interneurons are spared. This cell-type specific pathology produces an array of abnormalities including involuntary movements, cognitive impairments, and psychiatric disorders. Although the genetic mutation responsible for HD has been identified, little is known about the early synaptic changes occurring within the striatal circuitry at the onset of clinical symptoms. We therefore studied the synaptic plasticity of spiny neurons and cholinergic interneurons in two animal models of early HD. As a pathogenetic model, we used the chronic subcutaneous infusion of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. This treatment caused striatal damage and impaired response flexibility in the cross-maze task as well as defective extinction of conditioned fear suggesting a perseverative behavior. In these animals, we observed a loss of depotentiation in striatal spiny neurons and a lack of long-term potentiation (LTP) in cholinergic interneurons. These abnormalities of striatal synaptic plasticity were also observed in R6/2 transgenic mice, a genetic model of HD, indicating that both genetic and phenotypic models of HD show cell-type specific alterations of LTP. We also found that in control rats, as well as in wild-type (WT) mice, depotentiation of spiny neurons was blocked by either scopolamine or hemicholinium, indicating that reversal of LTP requires activation of muscarinic receptors by endogenous acetylcholine. Our findings suggest that the defective plasticity of cholinergic interneurons could be the primary event mediating abnormal functioning of striatal circuits, and the loss of behavioral flexibility typical of early HD might largely depend on cell-type specific plastic abnormalities.

Acetylcholine↗
PubMed2004

The ecological genetics of conditional strategies.

We develop a quantitative genetic model for conditional strategies that incorporates the ecological realism of previous strategic models. Similar to strategic models, the results show that environmental heterogeneity, cue reliability, and environment-dependent fitness trade-offs for the alternative tactics of the conditional strategy interact to determine when conditional strategies will be favored and that conditional strategies should be a common form of adaptive variation in nature. The results also show that conditional and unconditional development can be maintained in one of two ways: by frequency-dependent selection or by the maintenance of genetic variation that exceeds the threshold for induction. We then modified the model to take into account variance in exposures to the environmental cue as well as variance in response to the cue, which allows a derivation of a dose-response curve. Here the results showed that increasing the genetic variance for response both flattens and shifts the dose-response curve. Finally, we modify the model to derive the dose-response curve for a population polymorphic for a gene that blocks expression of the conditional strategy. We illustrate the utility of the model by application to predator-induced defense in an intertidal barnacle and compare the results with phenotypic models of selection.

Adaptation, Physiological↗