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PubMed1979

Multifactorial genetic models for quantitative traits in humans.

Quantitative traits measured in human families can be analyzed to partition the total population variance into genetic and environmental components, or to elucidate the genetic mechanism involved. We review the estimation of variance components directly from human pedigree data, or in the form of path coefficients from correlations between pairs of relatives. To elucidate genetic mechanisms, a mixed model that allows for segregation at a major locus, a polygenic effect and a sibling environmental correlation is described for nuclear families. In each case appropriate likelihoods are derived as a basis, using numerical maximum likelihood methods, for parameter estimation and hypothesis testing. A general model is then described that allows for several familial sources of environmental variation, assortative mating, and both major gene and polygenic effects; and an algorithm for calculating the likelihood of a pedigree under this model is indicated. Finally, some of the remaining problems in this area of biometric analysis are pointed out.

Genetic Variation↗
PubMed2003

Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration.

A primary feature of age-related macular degeneration (AMD) is the presence of extracellular deposits between the retinal pigment epithelium (RPE) and underlying Bruch's membrane, leading to RPE dysfunction, photoreceptor death and severe visual loss. AMD accounts for about 50% of blind registrations in Western countries and is a common, genetically complex disorder. Very little is known regarding its molecular basis. Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder with striking clinical and pathological similarity to AMD. Here we show that L-ORD is genetically heterogeneous and that a proposed founder mutation in the CTRP5 (C1QTNF5) gene, which encodes a novel short-chain collagen, changes a highly conserved serine to arginine (Ser163Arg) in 7/14 L-ORD families and 0/1000 control individuals. The mutation occurs in the gC1q domain of CTRP5 and results in abnormal high molecular weight aggregate formation which may alter its higher-order structure and interactions. These results indicate a novel disease mechanism involving abnormal adhesion between RPE and Bruch's membrane.

Age of Onset↗
PubMed1998

A biochemical and genetic model for parasite resistance to antifolates. Toxoplasma gondii provides insights into pyrimethamine and cycloguanil resistance in Plasmodium falciparum.

We have exploited the experimental accessibility of the protozoan parasite Toxoplasma gondii and its similarity to Plasmodium falciparum to investigate the influence of specific dihydrofolate reductase polymorphisms known from field isolates of drug-resistant malaria. By engineering appropriate recombinant shuttle vectors, it is feasible to examine mutations by transient or stable transformation of T. gondii parasites, in bacterial and yeast complementation assays, and through biochemical analysis of purified enzyme. A series of mutant alleles that mirror P. falciparum variants reveals that the key mutation Asn-108 (Asn-83 in T. gondii) probably confers resistance to pyrimethamine by affecting critical interactions in the ternary complex. Mutations such as Arg-59 (T. gondii 36) have limited effect in isolation, but in combination with other mutations they enhance the competitive ability of folate by increasing the speed of product turnover. Val-16 (T. gondii 10) confers low level resistance to cycloguanil but hypersensitivity to pyrimethamine. This mutation precludes Asn-108, probably because compression of the folate binding pocket introduced by this combination is incompatible with enzyme function. These studies permit detailed biochemical, kinetic, and structural analysis of drug resistance mutations and reconstruction of the probable phylogeny of antifolate resistance in malaria.

Alleles↗
PubMed2005

Development of a new genetic model for absence epilepsy: spike-wave seizures in C3H/He and backcross mice.

To characterize the genetic basis of spike-wave discharges (SWDs) detected by electroencephalography (EEG) in C3H/He mice, substrains of C3H mice were evaluated by EEG and sensitivity to ethosuximide. Crosses with the SWD-negative strain C57BL/6J were performed to map the underlying gene(s). C3H/He substrains exhibited a modest incidence (average of 19 SWDs per hour) of 7-8 Hz SWDs when at rest, compared with the C3HeB/Fe subline (four SWDs per hour). In the mapping backcross, however, many mice showed a very high incidence (50-220 SWDs per hour) throughout the recording period. SWDs were first detected at 3.5 weeks of age, were associated with behavioral arrest, were suppressed by ethosuximide, and were strongest in the cerebral cortex and thalamus. The major C3H determinant of SWDs, spkw1 (spike-wave 1), mapped to chromosome (Chr 9), and together with a C57BL/6J determinant on Chr 8, spkw2, accounted for more than one-half of the phenotypic variation in the backcross mice. The modest SWD incidence in C3H/He mice and the high incidence in backcrosses implies that SWD could be a confounding variable for other behaviors. Because C3H/He mice have no other brain abnormalities, they are an attractive alternative for studying idiopathic absence epilepsy.

Analysis of Variance↗
PubMed1993

A molecular genetic model of human bladder carcinogenesis.

Human bladder carcinogenesis stands as a paradigm for research on the molecular genetic mechanisms of chemical carcinogenesis. The pathogenesis of bladder cancer is multistage with a typical onset later in life. Epidemiological studies associate occupational exposure to aromatic amines with increased bladder cancer risk. Biochemical studies show aromatic amine metabolism, covalent binding, and DNA adduct formation in human uroepithelial cells (HUC). Smoking increases bladder cancer risk. A possible link with certain strains of human papilloma virus (HPV) infection has recently been suggested. Molecular analyses of bladder cancers reveal multiple genetic alterations, including mutational activation of oncogenes and inactivation of suppressor genes. A working hypothesis proposes that bladder carcinogens cause mutations in cancer genes (oncogenes and suppressor genes) in HUC that, possibly together with HPV infection and viral DNA integration, lead to the development of bladder cancer. In this review, we describe how this model is currently being tested using a multistep HUC in vitro transformation system.

Female↗
PubMed2004

Quantitative genetic models of sexual selection.

Modeling of R.A. Fisher's ideas about the evolution of male ornamentation using quantitative genetics began in the 1980s. Following an initial period of enthusiasm, interest in these models began to wane when theoretical studies seemed to show that the rapid evolution of ornaments would not occur if there were costs associated with female mate choice. Recent theoretical work has shown, however, that runaway evolution and other kinds of extensive diversification of ornaments and preferences can occur, even when female choice is costly. These new models highlight crucial parameters that profoundly influence evolutionary trajectories, but these parameters have been neglected in empirical studies. Here, we review quantitative genetic models of sexual selection with the aim of fostering communication and synergism between theoretical and empirical enterprises. We also point out several areas in which additional empirical work could distinguish between alternative models of evolution.

Journal Article↗
PubMed2002

The FORKO mouse as a genetic model for exploring estrogen replacement therapy.

OBJECTIVE: To evaluate how chronically estrogen deficient female FORKO mice with genetic disruption of the FSH receptor respond to estrogen therapy. STUDY DESIGN: Subcutaneous estrogen agonist or antagonist therapy was initiated to study reproductive tissue response, adipose tissue mass and plasma lipid profiles. RESULTS: Within 36-48 hours of agonist administration, the classic measures of estrogenic activity were evident in the uterus and vagina. Older animals also responded to therapy during a 10-day period, indicating that estrogen receptor signaling systems are unaffected by aging. In these obese mutants, this short treatment decreased adipose tissue in all areas and corrected lipid abnormalities. Tamoxifen, a nonsteroidal mixed estrogen agonist and antagonist, had marginal effects on the uterus and body fat of FORKO mice, indicating differences in interaction. CONCLUSION: In FORKO mice lacking ovarian estrogen, the receptors remain fully functional. Hence, this is a useful model for studying estrogen replacement therapy and helps resolve questions related to efficacy and actions.

Adipose Tissue↗
PubMed2005

Cardiomyocyte function associated with hyperactivity and/or hypertension in genetic models of LV hypertrophy.

We examined cardiomyocyte intracellular calcium ([Ca2+]i) dynamics and sarcomere shortening dynamics in genetic rat models of left ventricular (LV) hypertrophy associated with or without hypertension (HT) and with or without hyperactive (HA) behavior. Previous selective breeding of the spontaneously hypertensive rat (SHR) strain, which is HA and HT, with the Wistar-Kyoto (WKY) rat strain, which is not hyperactive (NA) and not hypertensive (NT), has led to two unique strains: the WKHA strain, selected for HA and NT, and the WKHT strain, selected for NA and HT. Cardiomyocytes were isolated from young adult males and females of each strain, paced at 2, 3, and 4 Hz in 1.2 mM external Ca2+ concentration at 37 degrees C, and cardiomyocyte [Ca2+]i and sarcomere dynamics were recorded simultaneously. Under these conditions, LV cardiomyocyte systolic and diastolic [Ca2+]i dynamics and diastolic sarcomere dynamics in the WKHT were significantly enhanced compared with WKY controls, suggesting an underlying LV hypertrophic response that successfully compensated for HT in the absence of HA. LV cardiomyocyte [Ca2+]i dynamics in the WKHA and SHR were strikingly similar to each other and only slightly reduced compared with WKY. LV cardiomyocyte systolic and diastolic sarcomere dynamics, on the other hand, were significantly reduced in the SHR compare with WKHA and more so in male than in female SHR. We conclude from these data that HT alone is an insufficient descriptor of the cause of LV hypertrophy and diminished LV cardiomyocyte function in the SHR rat. These data further suggest that HA (augmented by male sex) in the SHR may interact with the HT state to initiate impaired cardiomyocyte function and thereby inhibit or undermine an otherwise compensatory response that may occur with HT in the absence of HA.

Animals↗
PubMed1989

Alternative genetic models for the inheritance of the phenylthiocarbamide taste deficiency.

Pedigree segregation analysis was used to examine several one- and two-locus models of the inheritance of phenylthiocarbamide (PTC) taste deficiency that extend the traditional one-locus recessive model by the addition of either another allele or another locus, and in some cases predict two types of nontasters. These models allow nontaster by nontaster matings to produce taster offspring, consistent with our data and several previous studies which use the Harris and Kalmus [Annals of Eugenics 15:24-32, 1949] dilution method. The models fit our data set of 1,152 individuals from 120 families significantly better than the one-locus recessive model. The best fit was obtained with a two-locus model in which one locus controls PTC tasting and the other locus controls a more general taste ability. This model is consistent with research on the physiology of PTC tasting and with results from genetic linkage studies. Further study is suggested to evaluate better the accuracy of the proposed model.

Alleles↗
PubMed2006

Learning from small fry: the zebrafish as a genetic model organism for aquaculture fish species.

In recent years, the zebrafish has become one of the most prominent vertebrate model organisms used to study the genetics underlying development, normal body function, and disease. The growing interest in zebrafish research was paralleled by an increase in tools and methods available to study zebrafish. While zebrafish research initially centered on mutagenesis screens (forward genetics), recent years saw the establishment of reverse genetic methods (morpholino knock-down, TILLING). In addition, increasingly sophisticated protocols for generating transgenic zebrafish have been developed and microarrays are now available to characterize gene expression on a near genome-wide scale. The identification of loci underlying specific traits is aided by genetic, physical, and radiation hybrid maps of the zebrafish genome and the zebrafish genome project. As genomic resources for aquacultural species are increasingly being generated, a meaningful interaction between zebrafish and aquacultural research now appears to be possible and beneficial for both sides. In particular, research on nutrition and growth, stress, and disease resistance in the zebrafish can be expected to produce results applicable to aquacultural fish, for example, by improving husbandry and formulated feeds. Forward and reverse genetics approaches in the zebrafish, together with the known conservation of synteny between the species, offer the potential to identify and verify candidate genes for quantitative trait loci (QTLs) to be used in marker-assisted breeding. Moreover, some technologies from the zebrafish field such as TILLING may be directly transferable to aquacultural research and production.

Animals↗
PubMed2004

Genetic models in pathogenesis.

To decipher the complexity of host-pathogen interactions the widest possible range of model hosts and of analytical methods is required. As some virulence mechanisms and certain host responses have been conserved throughout evolution, even simple organisms can be used as model hosts to help our understanding of infectious diseases. The availability of molecular genetic tools and a cooperative community of researchers are pivotal to the emergence of model systems. In this review, we first summarize the genetic screens that can be used to identify pathogen virulence factors, then we present a comparative overview of existing or emerging genetically tractable host models.

Animals↗
PubMed1992

The hypertriglyceridemic rat as a genetic model of hypertension and diabetes.

Hypertriglyceridemia was demonstrated in untreated hypertensive patients as well as in animals with genetic and experimental hypertension. The main purpose of the present study was to evaluate the possibility to use the hereditary hypertriglyceridemic (HTG) nonobese rats in hypertensive research. Direct measurement of blood pressure demonstrated significantly higher systolic, diastolic and mean arterial pressures in HTG rats in comparison with control Wistar rats. There was significant positive correlation between blood pressure and plasma triglyceride concentration (r = 0.585, n = 40, p less than 0.001). In addition, there were significantly increased plasma norepinephrine and epinephrine concentrations in HTG rats, suggesting that the stimulation of sympathetic nervous system could be one of the pathogenetic mechanisms involved in the increase of blood pressure of HTG rats.

Animals↗
PubMed2006

Perfect simulation from nonneutral population genetic models: variable population size and population subdivision.

We show how the idea of monotone coupling from the past can produce simple algorithms for simulating samples at a nonneutral locus under a range of demographic models. We specifically consider a biallelic locus and either a general variable population size mode or a general migration model for population subdivision. We investigate the effect of demography on the efficacy of selection and the effect of selection on genetic divergence between populations.

Algorithms↗
PubMed2000

Genetic modeling of human urinary bladder carcinogenesis.

We developed a model of human urinary bladder cancer progression from in situ precursor lesions to invasive carcinoma using whole organ histologic and genetic mapping. The model represents a high-density and detailed analysis regarding allelic losses on chromosomes 4, 8, 9, 11, and 17 as revealed by testing of 234 samples obtained from five cystectomy specimens. The samples corresponded to microscopically identified intraurothelial precursor conditions ranging from dysplasia to carcinoma in situ and invasive cancer. The initial analysis of paired normal and tumor DNA samples disclosed allelic losses in 72 of 225 tested hypervariable DNA markers. Subsequent use of these markers on all mucosal samples revealed that 47 had alterations with a statistically significant relation to urothelial neoplasia. The allelic losses clustered in 33 distinct chromosomal regions, indicating the location of putative tumor suppressor genes involved in the development and progression of urinary bladder cancer. Some of the markers with statistically significant allelic losses mapped to the regions containing well-characterized tumor suppressor genes but many were located in previously unknown loci. The majority of statistically significant allelic losses (70%) occurred early in low-grade intraurothelial dysplasia, and some of them involved adjacent areas of morphologically normal mucosa preceding the development of microscopically recognizable precursor lesions. The remaining 30% of markers developed allelic losses in the later phases of urothelial neoplasia, implicating their involvement in progression to invasive disease. Markers exhibiting allelic losses in early phases of urothelial neoplasia could be used for detection of occult preclinical or even premicroscopic phases of urinary bladder cancer, whereas markers that showed allelic losses in the later phases of the process could serve as indicators of progression to invasive disease. The approach used in this study facilitates genome-wide modeling of cancer progression and provides important chromosomal landmarks for more specific studies of multistep urinary bladder carcinogenesis.

Aged↗
PubMed1984

Alterations in cerebellar glutamic acid decarboxylase (GAD) activity in a genetic model of torsion dystonia (rat).

Glutamic acid decarboxylase (GAD) activity was studied in specific brain regions of a newly identified genetic (rat) model of human torsion dystonia. GAD activity was found to be significantly increased in the deep cerebellar nuclei of dystonic rats at 16, 20, and 24 days of age. GAD activity in the other regions examined (vermis, cerebellar hemispheres, caudate nucleus, and globus pallidus) did not differ from that of age-matched normal littermate controls. Diazepam treatment significantly reduced the frequency of dystonic movements in the mutant.

Animals↗