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PubMed1981

A goodness-of-fit test for the polygenic threshold model: application to multiple sclerosis.

Recently it has been suggested that multiple sclerosis may be a multifactorial disorder. We found in British Columbia 364 families (sibship size greater than or equal to 2) in which at least on sibling was diagnosed as having "clinically definite" multiple sclerosis. The data were tested for goodness-of-fit to the multifactorial model using an analysis that considers various parameters including ascertainment probability heritability, and sex-dependent prevalence rates. The results suggest that multiple sclerosis does not fit the multifactorial model. As an alternative genetic model we propose that a major gene could be responsible for at least a portion of the cases of multiple sclerosis.

Alleles↗
PubMed2003

A "line item" approach to the identification of genes involved in polygenic behavioral disorders: the adrenergic alpha2A (ADRA2A) gene.

The usual approach for using single base pair polymorphisms (SNPs) for the investigation of the genetics of behavioral disorders is to examine a single diagnostic syndrome or personality trait based on variables relating to a cluster of behavioral symptoms. However, since some of these variables may address behaviors that are associated with one allele while others are associated with the other allele, the overall association may be non-significant and significant sub-syndromal associations may be missed. Thus, we have reversed the process in a technique we term a "line item" approach. As a test of the technique we have examined the association between genotypes of a C- > G-1291 Msp I promotor SNP of the ADRA2A gene and 390 individual symptoms from a structured review of DSM-IV criteria for twelve different groups of symptoms. We examined 334 individuals consisting of controls and subjects with Tourette syndrome (TS). Based on the mean scores for each genotype, those symptoms that were individually significant at alpha < or = 0.05 fell into three major groups by mode of inheritance: allele 1 codominant (11 > 12 > 22), allele 2 codominant (22 > 12 > 11), and negative heterosis (12 < 11, 22). Within each mode of inheritance group, the number of symptoms that were significant for the twelve symptom clusters was compared by chi-square analysis. This showed that symptoms were drawn from the diagnostic groups in a significantly non-random fashion. Thus, the allele 1 codominant symptoms came from the anxiety, affective, schizoid, and somatization diagnostic groups (internalizing symptoms) (chi(2) = 80.0, d.f. = 11, P < or = 0.0000001), while the allele 2 codominant symptoms came from the ADHD and oppositional defiant/conduct disorder diagnostic groups (externalizing symptoms) (chi(2) = 81.0, d.f. = 11, P < or = 0.0000001). The questions that fell in the negative heterosis type of inheritance were not significantly associated with specific diagnostic groups (P = 0.87). These results showed that the ADRA2A gene was associated with symptoms of autonomic, sympathetic dysfunction from different diagnostic groups. The advantages of the "line item" approach include (a) the identification of the symptoms associated with each allele, (b) the identification of symptom clusters independent of DSM diagnoses, (c) the elucidation of heterosis and other mode of inheritance effects, (d) the distinction between an association with a primary disorder versus a comorbid disorder, (e) the identification of associations with sub-syndromal symptom clusters that do meet full DSM-IV criteria, and (f) the identification of symptom clusters across databases.

Adolescent↗
PubMed2002

Polygenic expression of somatostatin in the sturgeon Acipenser transmontanus: molecular cloning and distribution of the mRNAs encoding two somatostatin precursors.

The sequence of somatostatin-14 (SS1) has been strongly preserved throughout the evolution of vertebrates from agnathans to mammals. In Acipenseridae (sturgeons), two isoforms of somatostatin have been characterized to date: somatostatin-14 has been identified from the gastrointestinal tract of the pallid sturgeon Scaphirhynchus albus and [Pro(2)]somatostatin-14 has been identified from the pituitary of the Russian sturgeon Acipenser gueldenstaedti. In the present study, we report the cloning of two distinct somatostatin cDNAs from the brain of the sturgeon Acipenser transmontanus. One of the cDNAs encodes a 116-amino acid protein (PSS1) that contains the SS1 sequence at its C-terminal extremity and, thus, is clearly orthologous to other vertebrate PSS1. The other cDNA encodes a 111-amino acid protein that contains the somatostatin variant [Pro(2)]somatostatin-14 at its C-terminal extremity. This second precursor exhibits more than 67% identity with the recently characterized lungfish PSS2 and goldfish PSS2. Reverse transcriptase-polymerase chain reaction analysis revealed that PSS1 is expressed in the central nervous system, the pancreas and the gut, whereas PSS2 is found in the central nervous system but not in the digestive system. In situ hybridization histochemistry showed that the PSS1 and PSS2 genes are differently expressed in numerous regions of the sturgeon brain. Interestingly, PSS1 and PSS2 mRNAs are present in the hypothalamus suggesting that, in sturgeon, both SS1 and SS2 may play hypophysiotropic functions. The PSS2 mRNA but not the PSS1 mRNA was found in the intermediate lobe of the pituitary. The present data demonstrate that two somatostatin genes are expressed in the sturgeon brain: one precursor generates somatostatin-14 and the other one gives rise to a [Pro(2)]somatostatin-14 variant, which is orthologous to goldfish, lungfish, and frog SS2.

Amino Acid Sequence↗
PubMed1994

Genetic analysis combining path analysis with regressive models: the BETA path model of polygenic and familial environmental transmission.

We have extended the class D regressive model for the purpose of combined path and segregation analyses by incorporating the BETA path model. We have done this by expressing correlations among residuals from major genotype (RMGs) of family members under the class D regressive model as functions of path coefficients under the BETA path model. The likelihood function under the combined model was factorized into a product of conditional densities, which is dominated by bivariate normal densities. Statistical inferences under the combined model are analogous to those under the class D regressive model.

Binomial Distribution↗
PubMed2004

Polygenic control of hepatocarcinogenesis in Copenhagen x F344 rats.

Cop and CFF1 rats exhibit resistance to hepatocarcinogenesis, associated with high rates of remodeling of neoplastic lesions. We have mapped hepatocarcinogenesis susceptibility, resistance and remodeling loci affecting the number, volume and volume fraction of neoplastic nodules induced by the "resistant hepatocyte" model in male CFF2 rats. Three loci in significant linkage with the number or volume of nonremodeling lesions were identified on chromosomes 1, 4 and 18. Suggestive linkage with number or volume fraction of total, nonremodeling or remodeling lesions was found for 7 loci on chromosomes 1, 2, 13, 14 and 15. All of these loci showed significant allele-specific effects on the phenotypic traits. We also detected by analysis of variance 19 2-way interactions inducing phenotypic effects not predictable on the basis of the sum of separate effects. These novel epistatic loci were in significant linkage with the number and/or volume of total, nonremodeling or remodeling nodules. These data indicate that susceptibility to hepatocarcinogenesis in Cop rats is controlled by a complex array of genes with several gene-gene interactions and that different genetic mechanisms control remodeling and nonremodeling liver nodules. Frequent deregulation in human liver cancer of genes positioned in chromosomal segments syntenic to rat susceptibility/resistance loci suggests some similarities between the genetic mechanisms involved in hepatocarcinogenesis in rats and humans.

Animals↗
PubMed2006

Gender-specific polygenic control of ethylnitrosourea-induced oncogenesis in the rat peripheral nervous system.

The inbred BD rat strains constitute a model system for analysis of the genetic basis of susceptibility or resistance to the development of neural tumors, as they exhibit distinct strain-specific differences regarding the sensitivity to tumor induction by the alkylating carcinogen N-ethyl-N-nitrosourea (EtNU). Among the different BD strains, BDIX and BDIV rats, respectively, are either highly susceptible or entirely resistant to the development of EtNU-induced malignant schwannomas of the peripheral nervous system (PNS), predominantly of the trigeminal nerves. We have previously mapped one locus associated with susceptibility/resistance to schwannoma induction to the telomeric third of chromosome 10 (Mss1) in segregating (BDIX x BDIV) crosses. We report on the genetic mapping of 6 further loci controlling tumor incidence or survival time on chromosomes 1 (Mss2), 3 (Mss3), 6 (Mss4), 13 (Mss5) and 15 (Mss6) as well as on chromosome 10 (Mss7) close to the centromere. Interestingly, most of these loci mediate gender-specific effects of variable strength ranging from minor influences on tumor development to complete tumor resistance. The gender specificity is reflected by the fact that male (BDIX x BDIV) F2 rats exhibit a 2-fold higher incidence of EtNU-induced schwannomas than females as well as a shorter survival time. A number of human nervous system tumors too arise with a marked gender bias. Genes mediating gender-specific predisposition of developing malignant schwannomas in the rat may be relevant for the human individual risk of developing nervous system tumors.

Alkylating Agents↗
PubMed1989

Treatment of diet-resistant polygenic hypercholesterolaemic patients with a new nicotinate derivative; in vivo and in vitro low density lipoprotein metabolic studies.

Six patients (four women and two men) with mild to moderate hypercholesterolemia, but with no clinical evidence of the disease being monogenic familial hypercholesterolaemia and who, over the previous 3 months on a rigidly controlled hypolipidaemic diet therapy, showed no reduction in plasma cholesterol levels, were recruited into a study to assess the metabolic effects of Pirozadil, a new nicotinic acid derivative. After a 3 month treatment period, a significant reduction in plasma cholesterol from 299.8 +/- 31.2 mg/dl (mean +/- SD) to 256.8 +/- 18.1 mg/dl (P less than 0.02) and Low Density Lipoprotein (LDL) cholesterol from 211.7 +/- 44.9 mg/dl to 168.8 +/- 19.0 mg/dl (P less than 0.05) was observed. Although there was a trend toward decreased plasma and Very Low Density Lipoprotein (VLDL) triglyceride, the differences did not reach statistical significant. High Density Lipoprotein (HDL) cholesterol was unchanged. The drug was well tolerated with no side effects noted. To assess the mode of action, autologous125I-labelled LDL was injected and apoprotein B (apo B) kinetic parameters were measured; production rate (PR) and fractional catabolic rate (FCR). An in vitro measurement of the in vivo catabolism (LDL-apo B receptor activity in freshly isolated lymphocytes) was also measured pre- and post-treatment. The pharmacological intervention resulted in a significant decrease of 19.9% in PR from 10.5 +/- 1.81 mg/kg/d to 8.41 +/- 1.13 mg/kg/d (P less than 0.05) while the FCR remained relatively unchanged (0.260 +/- 0.042 vs 0.248 +/- 0.040 pools/d) as did the LDL receptor activity (78.2 +/- 20.9 vs 69.3 +/- 21.4 ng LDL/mg cell protein/hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins B↗
PubMed1993

Predictions of the dynamics of a polygenic character under directional selection.

A quantitative genetic model for the response of the distribution of a single metric trait to directional selection is investigated. Particular attention is paid to the performance of approximations that use only limited information on the initial state of the population, such as the mean, the variance, the skewness and the kurtosis. Selection is imposed according to an exponentially increasing fitness function, populations mate at random, have discrete generations, and all genetic effects are supposed to be additive. Neglecting random drift, qualitatively different predictions for the initial response of a large population that has previously been at a mutation-stabilizing selection balance are derived. These depend on different assumptions about the initial distribution and are compared to the exact dynamics of that model. Linkage disequilibrium can be ignored as long as linkage is not too tight. The mathematical analysis rests on the method of cumulants and of cumulant-generating functions and produces exact equations for the evolution of cumulants in this model. Small populations subject to random drift are shown to respond in a qualitatively different way. The case of small populations is treated, primarily, by Monte Carlo simulations. The consequences of qualitatively different assumptions about maintenance of variation through mutation for the initial response to exponential directional selection are discussed. It is concluded that a significant initial increase in variance is unlikely to be observed in selection experiments if the effective population size is not larger than 500 and if response is caused by additive genes. The present results also apply to weak truncation selection.

Mathematics↗
PubMed2000

The stability of symmetric solutions to polygenic models.

Analysis of multilocus evolution is usually intractable for more than n approximately 10 genes, because the frequencies of very large numbers of genotypes must be followed. An exact analysis of up to n approximately 100 loci is feasible for a symmetrical model, in which a set of unlinked loci segregate for two alleles (labeled "0" and "1") with interchangeable effects on fitness. All haploid genotypes with the same number of 1 alleles can then remain equally frequent. However, such a symmetrical solution may be unstable: for example, under stabilizing selection, populations tend to fix any one genotype which approaches the optimum. Here, we show how the 2(n)x2(n) stability matrix can be decomposed into a set of matrices, each no larger than nxn. This allows the stability of symmetrical solutions to be determined. We apply the method to stabilizing and disruptive selection in a single deme and to selection against heterozygotes in a linear cline.

Emigration and Immigration↗
PubMed1990

Inconsistencies in standard approximations for selection coefficients at loci affecting a polygenic character.

Inconsistencies exist in the standard expansions used to approximate selection coefficients for alleles at a locus underlying a quantitative character. Allelic (marginal) fitnesses obtained from expansions based on average excesses differ from allelic fitnesses obtained from expansions based on genotypic values. Similarly, W, the mean population fitness based on summing over either allelic or genotypic fitnesses usually differs mean population fitness obtained by averaging over the unrestricted phenotypic distribution. A consistent value of W requires no variation in genotypic values. If, as suggested by Nagylaki (1984), expansions are corrected for the decrease in phenotypic variance resulting from conditioning on the presence of a particular allele or genotype, inconsistencies still exist. Unless integral of W(z)[Vzp"(z) + zp'(z) + p(z)] dz = 0, where p(z) is the phenotypic probability density function, Vz the phenotypic variance, W(z) the fitness of phenotypic value z, the primes denote differentiation with respect to z, allelic fitnesses based on average effects differ from allelic fitnesses based on genotypic values. This condition must also be satisfied in order for either expansion to give a consistent W, as first shown by Nagylaki. For arbitrary W(z), this is satisfied if and only if phenotypes are normally distributed.

Alleles↗
PubMed1992

Second-order approximations for selection coefficients at polygenic loci. II. Pleiotropy.

I determine the second-order approximation for the phenotypic distribution of an arbitrary number of quantitative traits, ignoring the effects of epistasis and linkage disequilibrium, conditioned on the presence of a specified genotype at one underlying locus of small effect. Using this approximation, I determine formulae for the effects of selection at a single locus with random mating under either Gaussian stabilizing selection, or correlated selection with truncation selection for one character. These formulae apply for arbitrary phenotypic distributions, yet even with multivariate Gaussian distributions of phenotypic effects the formula for correlated selection includes a correction to the standard formula in Falconer (1989). I demonstrate that this approximation has an error that is third order in the allelic or genotypic effects, independent of the form of the phenotypic distribution. I show also that the approximation of analogous form for the phenotypic distribution conditioned on the presence of a specified allele at a single locus is also correct to second order. Both approximations allow for dominance and are consistent in the sense that computing marginal fitnesses from approximations based on genotypic deviations and those based on average allelic effect yield the same answers.

Genotype↗
PubMed1990

Second-order approximations for selection coefficients at polygenic loci.

I determine the second-order approximation for the phenotypic distribution of a quantitative trait, ignoring the effects of epistasis and linkage disequilibrium, conditioned on the presence of a specified genotype at one underlying locus of small effect. I demonstrate that this approximation has an error that is third order in the allelic or genotypic effects, independent of the form of the phenotypic distribution. I also show that the approximation of analogous form for the phenotypic distribution conditioned on the presence of a specified allele at a single locus is also correct to second order. Both approximations allow for dominance and are consistent in the sense that computing marginal fitnesses from approximations based on genotypic deviations and those based on average allelic effect yield the same answers. Surprisingly, the second-order approximations derived here yield the same approximation for dynamics at a single locus as first-order approximations used earlier thus justifying earlier stability computations based on these first-order approximations.

Alleles↗
PubMed1990

Maintenance of polygenic variation through mutation-selection balance: bifurcation analysis of a biallelic model.

Biallelic models which ignore linkage disequilibrium have been used to study variability maintained by mutation in the presence of Gaussian stabilizing selection. Recent work of Barton (1986) showed that these models have stable equilibria at which the mean phenotype differed from the optimum, and that the variability maintained at such equilibria would be higher than at the symmetric equilibria calculated by Bulmer (1980) and others. Here I determine the bifurcation structure of this model, and confirm and extend Barton's results. The form of the bifurcations gives information about the domains of attraction of various equilibria, and shows why the nonsymmetric equilibria may not be observed. The techniques may prove useful in the analysis of other population genetic models.

Alleles↗
PubMed1989

Genetic analysis of obesity-induced diabetes associated with a limited capacity to synthesize insulin in C57BL/KS mice: evidence for polygenic control.

Expression of obesity-induced diabetes associated with the diabetes or db mutation in mice varies in inbred strains. This study utilized a genetic analysis to evaluate the number of genes responsible for the difference in diabetes responses between mice of the susceptible C57BL/KsJ (BL/Ks) and resistant 129/J inbred strains. BL/Ks (db/+) males and 129/J (+/+) females were bred to generate F1 hybrids, and the F1 females (db/+ and +/+, distinguished by progeny testing) were backcrossed to BL/Ks (db/+) males. A total of 252 backcrossed males were obtained, of which 31 were db/db and obese. While the plasma glucose of all the fed backcrossed mice was greater than 22 mmol/l, the expression of diabetes varied considerably, as measured by fasting plasma glucose, fed plasma insulin, and pancreatic insulin and proinsulin mRNA content. That proinsulin mRNA content was a good indicator of diabetes severity and islet dysfunction was seen in the inverse correlation between proinsulin mRNA content and fasting plasma glucose (r = 0.69, p less than 0.001), and a direct correlation between proinsulin mRNA and plasma insulin (r = 0.86, p less than 0.001), and pancreatic insulin content (r = 0.61, p less than 0.01). If a single gene were responsible for severe islet dysfunction, one-half of the backcrossed mice would develop low proinsulin mRNA levels like the BL/Ks parent, and one-half would be resistant to islet destruction. Statistical evaluation (SKUMIX) of the distribution of these parameters in backcrossed mice rejected with a high degree of probability a bimodal distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗