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PubMed1983

Cultured cells transformed by Rous sarcoma virus: a genetically defined model and its phenotype.

The mechanism by which Rous sarcoma virus transforms cells is better understood at the molecular level than that of any other oncogenic agent. The gene (src) responsible for transformation has been identified and its nucleotide sequence has been determined. The transforming protein (pp60src) has been identified and an enzymatic activity assigned to it. The unusual enzymatic activity of pp60src (phosphorylation of proteins on tyrosine) has allowed us to identify a large number of putative targets of this protein. And genetic evidence indicates that the phosphorylation of various targets is responsible for generating the various manifestations of the transformed phenotype. What can this model system contribute to understanding of hereditary large bowel cancer? First of all, it provides an intellectual paradigm for analyzing the mechanism by which a single autosomal dominant gene can alter the metabolism and regulatory behavior of a cell. A cellular homolog of src or of some other onc gene could be responsible for hereditary colon cancer. Second, it provides a model for understanding why some "markers" of malignancy are not invariably associated with cancer: since the oncogenic protein can interact with a variety of primary targets giving rise to the various parameters of transformation, not every sort of biological effect need be necessary for malignancy. Third, it points out that the various syndromes which constitute hereditary colon cancer may well be due to a single gene: since mutations in the src gene are capable of generating a variety of distinct phenotypic alterations in infected cells, different from that generated by the wild-type virus, it certainly is conceivable that different alleles of a single transforming gene could give rise to the different types of hereditary colon cancer. Whether this is the explanation for the various forms of hereditary colon cancer, or whether they result from the activities of several different onc genes can only be determined by identification of the gene(s) at the molecular level. Finally, this model system has provided information which may prove useful in improving the specificity of cancer chemotherapy. Since production of plasminogen activator seems to correlate well with growth in soft agar and tumorigenicity, an anti-cancer prodrug which is activated specifically by cells producing plasminogen activator might be selectively toxic to malignant cells. We have in fact synthesized such drugs and shown them to be selectively toxic in vitro to malignant cells (Carl et al 1980). In vivo tests of these agents are in progress.

Avian Sarcoma Viruses↗
PubMed1999

Replicating Huntington's disease phenotype in experimental animals.

Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum. There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. Cell 72, 971-983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, Neurobiol. Dis. 3, 3-15) for review]. Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD. On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism. All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways. To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP). Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis. 3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum. The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.

Animals↗
PubMed1986

[Clinico-genetical studies of colonic cancer. II. Genetic analysis of predisposition to colonic cancer].

The structure of subjection to different clinical forms of colon cancer and to the morbidity as a whole approximates better the quasi-continued phenotypical model within which the contribution of genetic factors reaches 68-84%, that of incidental medium factors being 16-32%. Genetic study of heterogeneity of colon cancer clinical forms revealed that their pathogenetic community was quite high. However, the origin of colon cancer depends strongly on genetic factors (83.7 +/- 7.3%), in comparison with rectal cancer (67.9 +/- 7.1%). The analysis of colon cancer interrelation with other malignant neoplasms (including specific ones for women--breast and uterus cancer) revealed that the development of another malignant neoplasms was the result of the influence of partially common genes (20-50%) which predetermined the development of colon cancer and other malignant neoplasms. According to the data obtained in this study, the tables of repeated risk have been worked out which may be used for medico-genetic consultation.

Adult↗
PubMed2002

The GP problem: quantifying gene-to-phenotype relationships.

In this paper we refer to the gene-to-phenotype modeling challenge as the GP problem. Integrating information across levels of organization within a genotype-environment system is a major challenge in computational biology. However, resolving the GP problem is a fundamental requirement if we are to understand and predict phenotypes given knowledge of the genome and model dynamic properties of biological systems. Organisms are consequences of this integration, and it is a major property of biological systems that underlies the responses we observe. We discuss the E(NK) model as a framework for investigation of the GP problem and the prediction of system properties at different levels of organization. We apply this quantitative framework to an investigation of the processes involved in genetic improvement of plants for agriculture. In our analysis, N genes determine the genetic variation for a set of traits that are responsible for plant adaptation to E environment-types within a target population of environments. The N genes can interact in epistatic NK gene-networks through the way that they influence plant growth and development processes within a dynamic crop growth model. We use a sorghum crop growth model, available within the APSIM agricultural production systems simulation model, to integrate the gene-environment interactions that occur during growth and development and to predict genotype-to-phenotype relationships for a given E(NK) model. Directional selection is then applied to the population of genotypes, based on their predicted phenotypes, to simulate the dynamic aspects of genetic improvement by a plant-breeding program. The outcomes of the simulated breeding are evaluated across cycles of selection in terms of the changes in allele frequencies for the N genes and the genotypic and phenotypic values of the populations of genotypes.

Computer Simulation↗
PubMed2006

Citicoline is not protective in experimental models of Huntington's disease.

We have evaluated the neuroprotective effects of citicoline in relevant phenotypic models of Huntington's disease induced by either the mitochondrial inhibitor 3-nitropropionic acid or the N-methyl-D-aspartate agonist quinolinic acid, which, respectively, reproduce the metabolic defect or the excitotoxicity seen in the disease. We found that citicoline failed to reverse behavioural and histological alterations induced by both neurotoxins. In addition, citicoline did not reduce PC12 cell death induced by the expression of an N-terminal fragment of mutated Huntingtin. Altogether, our results suggest that citicoline is not a potential therapeutic agent for the treatment of Huntington's disease.

Animals↗
PubMed2001

Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13-14 in Taiwanese families.

In order to evaluate the linkage of schizophrenia to loci at chromosome 15q, we genotyped six microsatellite markers at chromosome 15q11-14 in 52 Taiwanese schizophrenic families. Two phenotype models (narrow: DSM-IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other nonaffective psychotic disorders) were used to define the disease phenotype. Maximum nonparametric linkage scores (NPL scores) of 3.33 (P = 0.0003) and 2.96 (P = 0.0008) were obtained at the marker D15S976 under broad and narrow models, respectively. Positive linkage results were also observed at the marker D15S1360, previously reported to have significant linkage to a neurophysiological deficit of schizophrenia, with NPL scores of 2.71 (P = 0.003) and 2.78 (P = 0.002) under broad and narrow models, respectively. The results provide suggestive linkage evidence of schizophrenia to loci at chromosome 15q13-14 in an ethnically distinct Taiwanese sample.

Chromosomes, Human, Pair 15↗
PubMed2004

Quantitative genetic models for describing simultaneous and recursive relationships between phenotypes.

Multivariate models are of great importance in theoretical and applied quantitative genetics. We extend quantitative genetic theory to accommodate situations in which there is linear feedback or recursiveness between the phenotypes involved in a multivariate system, assuming an infinitesimal, additive, model of inheritance. It is shown that structural parameters defining a simultaneous or recursive system have a bearing on the interpretation of quantitative genetic parameter estimates (e.g., heritability, offspring-parent regression, genetic correlation) when such features are ignored. Matrix representations are given for treating a plethora of feedback-recursive situations. The likelihood function is derived, assuming multivariate normality, and results from econometric theory for parameter identification are adapted to a quantitative genetic setting. A Bayesian treatment with a Markov chain Monte Carlo implementation is suggested for inference and developed. When the system is fully recursive, all conditional posterior distributions are in closed form, so Gibbs sampling is straightforward. If there is feedback, a Metropolis step may be embedded for sampling the structural parameters, since their conditional distributions are unknown. Extensions of the model to discrete random variables and to nonlinear relationships between phenotypes are discussed.

Bayes Theorem↗
PubMed2004

Discrete event modeling of CD4+ memory T cell generation.

Studies of memory T cell differentiation are hampered by a lack of quantitative models to test hypotheses in silico before in vivo experimentation. We created a stochastic computer model of CD4+ memory T cell generation that can simulate and track 10(1)-10(8) individual lymphocytes over time. Parameters for the model were derived from experimental data using naive human CD4+ T cells stimulated in vitro. Using discrete event computer simulation, we identified two key variables that heavily influence effector burst size and the persistent memory pool size: the cell cycle dependent probability of apoptosis, and the postactivation mitosis at which memory T cells emerge. Multiple simulations were performed and varying critical parameters permitted estimates of how sensitive the model was to changes in all of the model parameters. We then compared two hypotheses of CD4+ memory T cell generation: maturation from activated naive to effector to memory cells (model I) vs direct progression from activated naive to memory cells (model II). We find that direct progression of naive to memory T cells does not explain published measurements of the memory cell mass unless postactivation expansion of the memory cell cohort occurs. We conclude that current models suggesting direct progression of activated naive cells to the persistent memory phenotype (model II) do not account for the experimentally measured size of the postactivation CD4+, Ag-specific, memory T cell cohort.

Apoptosis↗
PubMed2006

Phenotypic factor analysis of family data: correction of the bias due to dependency.

Twin registries form an exceptionally rich source of information that is largely unexploited for phenotypic analyses. One obstacle to straightforward phenotypic statistical analysis is the inherent dependency, which is due to the clustering of cases within families. The present simulation study gauges the degree of the bias produced by the dependency of family data on the estimates of standard errors and chi-squared, when they are treated as independent observations in a phenotypic model, and assesses the efficiency of an estimator, which corrects for dependency. When family-clustered data are used for phenotypic analysis, in treating individuals as independent, and using standard maximum likelihood estimation, there is a tendency for the chi-square statistic to be overestimated, and the standard errors of the parameters to be underestimated. The bias increases with family resemblance, due to heritability or shared environment. The source of family resemblance -- either heritability (h(2)) and/or shared environment (c(2)) -- interacts with the composition of the sample. In the absence of c(2), samples with twins, parents and spouses show the lowest bias, whereas in the presence of c(2) samples with only twins show the lowest bias. In all conditions the bias remained below 15%. The use of the 'complex option' available in Mplus (clustering corrected robust maximum likelihood estimation) reduces the bias to the levels observed when only independent cases are considered. Thus with the use of robust estimates the bias due to family dependency becomes practically negligible in all conditions of dependency. In conclusion, the present study shows that the bias due to dependency in family data does not form a serious obstacle to phenotypic data analysis.

Chi-Square Distribution↗
PubMed2003

Physical aggression and expressive vocabulary in 19-month-old twins.

In the prevention of physical aggression, possible etiological links with language development are rarely taken into account. Indeed, little is known about when language and aggressive behavior become linked during development and which mechanisms are responsible for this association. This study investigated the association between physical aggression and language in late infancy with a genetic design that involved 562 19-month-old twins. A modest but significant correlation (r = -.20) was found between physical aggression and expressive vocabulary. Substantial heritability was found for physical aggression. Quantitative genetic modeling suggests that the correlation between expressive vocabulary and physical aggression cannot be explained by shared etiologies. However, phenotype-to-phenotype models indicate that the covariation can be entirely accounted for by a significant phenotypic path from expressive vocabulary to physical aggression. The implications of these results for early prevention of chronic physical aggression are discussed.

Aggression↗
PubMedDate not supplied

Linkage analysis between manic-depressive illness and the region on chromosome 15q involved in Prader-Willi syndrome, including two GABAA receptor subtype genes.

Cooccurrence of Prader-Willi syndrome and psychosis has been reported in a few cases. Prader-Willi syndrome is most often associated with interstitial deletion or uniparental disomy of chromosome 15q11-q13. The cooccurrence of Prader-Willi syndrome and psychosis may thus be due to deletion of, or in the case of uniparental disomy, duplication of a gene involved in the etiology of psychosis, possibly manic-depressive illness localized in this region. The region contains two assumed candidate genes for manic-depressive illness, the alpha 5 and beta 3 subunits of the gamma-aminobutyric acid (GABA)A receptor. This study investigates linkage between manic-depressive illness and this region. Furthermore, an additional case with Prader-Willi syndrome and psychosis is briefly described. No evidence of linkage was found assuming dominant or recessive modes of inheritance. Linkage to the GABAA receptor subunits was excluded assuming a dominant mode of transmission for all models, and to the proximal part of the chromosome 15q11-q13 region for broader phenotypic models. Negative though largely inconclusive lod scores were obtained assuming a recessive mode of transmission; however close linkage to the beta 3 subtype of the GABAA receptor was excluded.

Adult↗
PubMed2026

Genomic insights into stroke recovery: cross-phenotype associations.

Stroke is a major cause of long-term disability with variable recovery. While clinical factors such as initial severity play a role, genetic factors are increasingly recognized as important contributors to stroke recovery. Genotype studies are generally focused on a single post-stroke behavioural domain, but some genes might relate to broad mechanisms of plasticity. This study therefore aimed to identify cross-phenotypic genetic variants associated across two or more stroke recovery domains. DNA from Stroke, Stress, Rehabilitation, and Genetics study participants was genotyped, resulting in 9 814 610 variants. In order to examine cross-phenotypic results, we first conducted genome-wide association studies on the six recovery domains: motor (grip force), cognition (Telephone Montreal Cognitive Assessment), depression (Patient Health Questionnaire-8), stress (Primary Care Post-Traumatic Stress Disorder Screen), functional status (Stroke Impact Scale-Activities of Daily Living), and disability (modified Rankin Scale 0-2 versus 3-6), some of which were tested longitudinally, yielding nine phenotypes. Models were adjusted for age, sex, initial severity (NIH Stroke Scale score), and ancestry. Cross-phenotype associations were identified by evaluating single nucleotide polymorphisms (SNPs) associated (P < 5e-5) with multiple phenotypes. To determine how these genetic variants may relate to biological mechanisms of recovery, we conducted gene enrichment analyses. Participants (n = 565, 59% male) had mild-moderate initial stroke severity (median acute NIH Stroke Scale score = 4). After accounting for the correlation structure among the nine phenotypes, we observed 319 cross-phenotypic SNPs, 3.45 times the expected number. Five of the cross-phenotypic SNPs were linked to genes relevant to neural development, function and plasticity, e.g. ERICH1 (rs11778883-C), FOX3 (rs55726768-G), LIFR-AS1 (rs76401391-T), RPS6KA2 (rs113518460-C) and TUBGCP2 (rs147150392-C), as were enrichments in RAB5-EEA1, CTNNA1-CTNNB1, CIN85-SH3GL2 and ELMO1-DOCK2 complexes. Multiple gene enrichments were found, e.g. Stroke Impact Scale-Activities of Daily Living and Patient Health Questionnaire 8 at 3 months were enriched for CREB phosphorylation, which is important for long-term potentiation. We identified cross-phenotypic SNPs associated with multiple behavioural domains of stroke recovery. Some of these genes encode, or regulate, druggable proteins. These genetic factors are not well captured by clinical or neuroimaging assessments and so provide a unique window into stroke recovery. These findings, if validated, suggest that some genes may be broadly important to stroke recovery.

GWAS↗
PubMed2023

Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models.

The value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results across studies. Here, we performed multiple modeling experiments integrating clinical and demographic data from electronic health records (EHR) and genetic data to understand which decision points may affect performance. Clinical data in the form of structured diagnostic codes, medications, procedural codes, and demographics were extracted from two large independent health systems and polygenic risk scores (PRS) were generated across all patients with genetic data in the corresponding biobanks. Crohn's disease was used as the model phenotype based on its substantial genetic component, established EHR-based definition, and sufficient prevalence for model training and testing. We investigated the impact of PRS integration method, as well as choices regarding training sample, model complexity, and performance metrics. Overall, our results show that including PRS resulted in higher performance by some metrics but the gain in performance was only robust when combined with demographic data alone. Improvements were inconsistent or negligible after including additional clinical information. The impact of genetic information on performance also varied by PRS integration method, with a small improvement in some cases from combining PRS with the output of a clinical model (late-fusion) compared to its inclusion an additional feature (early-fusion). The effects of other modeling decisions varied between institutions though performance increased with more compute-intensive models such as random forest. This work highlights the importance of considering methodological decision points in interpreting the impact on prediction performance when including PRS information in clinical models.

Preprint↗
PubMed1992

Extended pedigree patterned covariance matrix mixed models for quantitative phenotype analysis.

Overt computational constraints in the formation of mixed models for the analysis of large extended-pedigree quantitative trait data which allow one to reliably characterize and partition sources of variation resulting from a variety sources have proven difficult to overcome. The present paper suggests that by combining a restricted patterned covariance matrix approach to modeling and partitioning the variation arising from polygenic and environmental forces with an Elston-Stewart like algorithmic approach to modeling variation resulting from a single genetic locus with large phenotypic effects one can produce a model that is at once intuitively appealing, efficient computationally, and reliable numerically. Extensions and variations of this approach are also discussed, as are some simulation and timing studies carried out in an effort to validate the accuracy and computational efficiency of the proposed methodology.

Humans↗
PubMed1998

Fetal striatal allografts reverse cognitive deficits in a primate model of Huntington disease.

Substitutive therapy using fetal striatal grafts in animal models of Huntington disease (HD) have already demonstrated obvious beneficial effects on motor indices. Using a new phenotypic model of HD recently designed in primates, we demonstrate here complete and persistent recovery in a frontal-type cognitive task two to five months after intrastriatal allografting. The striatal allografts also reduce the occurrence of dystonia, a major abnormal movement associated with HD. These results show the capacity of fetal neurons to provide a renewed substrate for both cognitive and motor systems in the lesioned adult brain. They also support the use of neural transplantation as a potential therapy for HD.

Animals↗
PubMed2004

Linkage analysis in bipolar pedigrees adds support for a susceptibility locus on 21q22.

Several studies provide suggestive evidence of a susceptibility locus for bipolar disorder at chromosome 21q22-23. In an attempt to replicate these findings, we have analyzed linkage to 11 polymorphic markers from this region in 18 Bulgarian pedigrees with affective disorder. Two-point linkage analysis under assumption of homogeneity and a dominant model with reduced penetrance produced modest positive values for some of the markers tested under a 'narrow' phenotype definition, including bipolar I and II, and schizoaffective disorder. The maximum two-point score (lod=1.76, theta=0.00) was at marker D21S1919. Non-parametric linkage analysis under the same phenotype model, yielded positive NPLall values (P<0.05) over the region between markers D21S211 and D21S416, with a peak at D21S1252 (NPL Zall=2.32, P=0.0003). The multipoint lod score (GENEHUNTER) reached a suggestive value for linkage (lod=2.10) also at marker D21S1252. The results under a recessive model were completely negative. These data add to the evidence for the existence of a susceptibility locus for bipolar affective disorder on chromosome 21q22.

Bipolar Disorder↗