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At least 1,225 records · Page 68Linked to original sources
PubMed1999

A Bayesian approach to replication of linkage findings.

A novel Bayesian approach to replication studies, allowing for locus heterogeneity, is introduced. Compared with currently used approaches to replication, it offers a natural way to accumulate evidence across independently collected data sets and yields more interpretable results. Using for replicates (one as initial study and the other three as replication studies) from Problem 2 of the Genetic Analysis Workshop 11 data, we show the performance of this method. All four disease susceptibility loci (D1G009, D1G024, D3G045, D5G035) are identified and accurately mapped, with no false positive signals.

Bayes Theorem↗
PubMed2006

Simultaneous estimation of gene-gene and gene-environment interactions for numerous loci using double penalized log-likelihood.

Many common human diseases are considered to be caused by complex multifactorial processes. For these diseases, it is expected that numerous genetic and environmental factors and, possibly, their interactions play a role. Therefore, simultaneously analyzing the effects of numerous genes and environmental factors is a more realistic approach compared to single gene analyses, but the large number of genes and environmental factors pose a challenge, not in the least due to the limitations created by the tools available for analyzing such high-dimensional models. In the present manuscript we propose a method that is capable of identifying "true" interactions in a setting where the number of effects to be estimated is very large and can even surpass the number of observations. Basically, all possible (interaction) effects are entered in a double penalized model, where main effects are ridge penalized, whereas the interactions are subjected to a least absolute shrinkage and selection operator (lasso) penalty. Results from the simulations and real data show that the proposed method is capable of detecting interactions even with relative small effect sizes.

Alleles↗
PubMed2006

Family-based association tests for ordinal traits adjusting for covariates.

We present a class of family-based association tests (FBATs) for ordinal traits that adjust for the effects of covariates. For complex diseases, especially mental health conditions including nicotine dependence and substance use, the outcome variables are often recorded in an ordinal rather than quantitative scale. The naturally recorded ordinal traits are commonly analyzed either as quantitative traits or are dichotomized. It has been demonstrated repeatedly in recent studies that these commonly used approaches to dealing with ordinal traits are inadequate and result in loss of power. In this report, we make use of conditional likelihood to derive score test statistics that belong to a general class of FBATs. We conducted simulation studies to compare the type I error and power of our proposed test with existing tests. The empirical result suggests that our test produces reasonable type I errors and has power far exceeding (often doubling) those of existing tests. We applied our proposed test to a data set on alcohol dependence and found that six single nucleotide polymorphisms (SNPs) are significantly associated (P-values < or =0.001) with alcohol dependence after adjusting for gender and age. Three of the SNPs (rs619, rs1972373, and rs1571423) or their tightly linked regions have been suggested in the literature from the analysis of the same data, demonstrating the consistent findings between various methods. The other three SNPs (rs485874, rs718251, and rs1869907) are identified for the first time using this data set, underscoring the potential power of our proposed test.

Alcoholism↗
PubMed2006

Prioritizing regions of candidate genes for efficient mutation screening.

The availability of the complete sequence of the human genome has dramatically facilitated the search for disease-causing sequence variations. In fact, the rate-limiting step has shifted from the discovery and characterization of candidate genes to the actual screening of human populations and the subsequent interpretation of observed variations. In this study we tested the hypothesis that some segments of candidate genes are more likely than others to contain disease-causing variations and that these segments can be predicted bioinformatically. A bioinformatic technique, prioritization of annotated regions (PAR), was developed to predict the likelihood that a specific coding region of a gene will harbor a disease-causing mutation based on conserved protein functional domains and protein secondary structures. This method was evaluated by using it to analyze 710 genes that collectively harbor 4,498 previously identified mutations. Nearly 50% of the genes were recognized as disease-associated after screening only 9% of the complete coding sequence. The PAR technique identified 90% of the genes as containing at least one mutation, with less than 40% of the screening resources that traditional approaches would require. These results suggest that prioritization strategies such as PAR can accelerate disease-gene identification through more efficient use of screening resources.

Computational Biology↗
PubMed1991

Which locus has the oldest allele?

This paper studies aspects of the distribution of non-mutant ancestors of a sample of gametes in a two-locus infinitely-many-alleles model. The ancestral process of two gametes is considered in detail. Included are algorithms for calculating the probability that the oldest allele is from the first locus, and the expected age of the oldest allele. Extensions to an r-locus model in the cases of complete linkage and independence are also studied.

Alleles↗
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↗
PubMed1991

Spontaneous generation of selectable variation in the brain.

Selection models of behavior presuppose "selectable variation", diversity in the brain that is stable over time. Diversity can arise spontaneously through the mutual interactions of cell assemblies, which are postulated to align or disalign their neighbors into processing modes conforming to or opposite from their own. These processes are similar to magnetization and crystallization. If aligning and disaligning influences are distributed at random, a state resembling a spin glass can arise, where processing modes are highly varied in space but stable in time. If disalignment occurs regularly at the points of a two-dimensional lattice, and elsewhere the interactions are aligning, a pattern emerges with properties remarkably similar to visual orientation columns. These patterns are maintained dynamically, and emerge statistically without detailed genetic specification.

Animals↗
PubMed1999

The evolution of codon preferences in Drosophila: a maximum-likelihood approach to parameter estimation and hypothesis testing.

Synonymous codon usage in related species may differ as a result of variation in mutation biases, differences in the overall strength and efficiency of selection, and shifts in codon preference-the selective hierarchy of codons within and between amino acids. We have developed a maximum-likelihood method to employ explicit population genetic models to analyze the evolution of parameters determining codon usage. The method is applied to twofold degenerate amino acids in 50 orthologous genes from D. melanogaster and D. virilis. We find that D. virilis has significantly reduced selection on codon usage for all amino acids, but the data are incompatible with a simple model in which there is a single difference in the long-term Ne, or overall strength of selection, between the two species, indicating shifts in codon preference. The strength of selection acting on codon usage in D. melanogaster is estimated to be |Nes| approximately 0.4 for most CT-ending twofold degenerate amino acids, but 1.7 times greater for cysteine and 1.4 times greater for AG-ending codons. In D. virilis, the strength of selection acting on codon usage for most amino acids is only half that acting in D. melanogaster but is considerably greater than half for cysteine, perhaps indicating the dual selection pressures of translational efficiency and accuracy. Selection coefficients in orthologues are highly correlated (rho = 0.46), but a number of genes deviate significantly from this relationship.

Amino Acids↗
PubMed2003

Transient dynamics in multilocus invasions by transgenic organisms.

With recent advances in molecular genetics, it is likely that releases of genetically modified organisms will be used for a variety of purposes. In many cases, such systems would utilize organisms that have been modified on multiple genetic loci. Predicting the effect of such releases will require an understanding of the transient dynamics in the system. However, theoretical understanding of transient dynamics in multilocus systems is limited, particularly for early generations when gametic disequilibrium is still high. I derive approximate expressions for marginal allele frequency and marginal two-locus disequilibrium that are applicable in this initial period, assuming infinite population size, two alleles per locus, and weak viability selection. I then apply these results to exploring the effect of parameters on the frequency of the resident gamete type in a release of organisms carrying an autocidal allele on multiple loci. This leads to simple approximate expressions for the optimal number of loci carrying the autocidal allele (as a function of release size and the degree of natural selection against the alleles) and the size of release needed to overcome a given level of selection against the released alleles.

Alleles↗
PubMed2003

Evolutionarily stable sets in the single-locus frequency-dependent model of natural selection.

Recent developments in the static theory of evolutionarily stable sets (ESSets) are applied to the single-locus frequency-dependent model of natural selection. Particular emphasis is paid to the ESSet properties of the preimage of an ESS (or ESSet) under the genotype-phenotype map. When an ESS is realized in genetic equilibrium with redundancy in a diploid sexual population, the basic problem in biological terms is whether the corresponding set of allele frequencies is an evolutionarily stable set. The interesting question of the dynamic stability of this preimage is also discussed and a geometric condition developed which implies its evolutionary and dynamic stability.

Alleles↗
PubMed2000

Strategies to optimize marker-assisted introgression of multiple unlinked QTL.

To optimize designs to implement marker-assisted introgression programs aiming to introgress three unlinked quantitative trait loci (QTL), the present paper studies different alternatives versus a traditional backcross or intercross phase. Four alternative backcross strategies appear to be more advantageous by having 50% less genotyping load than a traditional backcross strategy tracking all three QTL at a time through a single line. A multiplication phase following the selection of homozygous animals at the three QTL as an intercross alternative allows doubling of the number of homozygous animals in a mouse model compared with the first intercross generation. Within the same model, a second intercross alternative with individuals carrying all three QTL at the first intercross results in a 12-fold increase in the number of homozygous animals obtained in the first intercross generation. The same ranges of decrease are observed in the number of animals to be genotyped and the number of genotypings when targeting a fixed number of homozygous animals. An option, with two lines each carrying two QTL through the backcross phase and coupled with the second intercross alternative, appears to be the best introgression alternative. This option requires 76% fewer genotypings, 68% fewer animals to be genotyped, and costs 75% less than an option in which all three QTL are introgressed through a single line.

Animals↗
PubMed2006

Quantitative structure analysis of genetic diversity among spring bread wheats (Triticum aestivum L.) from different geographical regions.

Genetic diversity in spring bread wheat (T. aestivum L.) was studied in a total of 69 accessions. For this purpose, 52 microsatellite (SSR) markers were used and a total of 406 alleles were detected, of which 182 (44.8%) occurred at a frequency of <5% (rare alleles). The number of alleles per locus ranged from 2 to 14 with an average of 7.81. The largest number of alleles per locus occurred in the B genome (8.65) as compared to the A (8.43) and D (5.93) genomes, respectively. The polymorphism index content (PIC) value varied from 0.24 to 0.89 with an average of 0.68. The highest PIC for all accessions was found in the B genome (0.71) as compared to the A (0.68) and D genomes (0.63). Genetic distance-based method (standard UPGMA clustering) and a model-based method (structure analysis) were used for cluster analysis. The two methods led to analogical results. Analysis of molecular variance (AMOVA) showed that 80.6% of the total variation could be explained by the variance within the geographical groups. In comparison to the diversity detected for all accessions (H ( e ) = 0.68), genetic diversity among European spring bread wheats was H ( e ) = 0.65. A comparatively higher diversity was observed between wheat varieties from Southern European countries (Austria/Switzerland, Portugal/Spain) corresponding to those from other regions.

Alleles↗
PubMed1989

Structural instability of models of sexual selection.

Models for sexual selection by the coevolution of female preference and a male trait have as a generic feature the existence of a neutrally stable line of equilibria up and down which the system can drift at random. However, this feature is structurally unstable since it is destroyed by introducing either mutation or weak direct selection on female preference into the model, to be replaced by a single equilibrium (or a finite set of disconnected equilibria). This process is investigated in detail under a simple but general population genetic model. It is concluded that the level of female preference is determined by mutation, selection, and genetic drift acting directly on it, and drags the male trait along with it along the line of equilibria. More attention should be paid to selective forces acting directly on female preference.

Biological Evolution↗
PubMed1992

The exact values of the probability of fixation of underdominant chromosomal rearrangements.

A numerical analysis of the probability of fixation of a chromosomal mutation with partial sterility of the heterozygote in a single population is performed. Three different genetic models are considered: the first model entails constant selection against the heterozygote and is the model almost universally used in previous works; in the other two models selection against the heterozygote depends on its frequency. The exact values of the fixation probability are found by iterating transition matrices with genotype specification. Differences in results among models are small. The exact values found in the first model are compared to estimates obtained from approximations. Solutions based on diffusion models give good approximations when selection against the heterozygote is low, especially if the population is very small. For the higher values of the selection coefficient against the heterozygote, the estimates are rather imprecise, especially when the populations are not very small.

Animals↗
PubMed2006

An investigation of genomic base distribution.

While veritable oceans of ink have been spilled over the base distributions within genes, the literature is virtually silent on large scale intra genomic base distribution. To address this issue, we have examined approximately 3400 chromosomal sequences from approximately 2000 entire genomes-including DNA and RNA, single- and double-stranded, coding and non-coding genomes. For each sequence the mean, variance, skewness, and kurtosis for each base were computed along with the genome base composition. The main findings are: (1) there is no simple relationship between these statistics and the base composition of the genome, (2) in non-viral genomes, base distribution is non-uniform, (3) base distribution in non-eukaryotic genomes obeys a number of simple rules, (4) these rules are not dependent on the presence of coding sequences, (5) bacterial genomes in particular are unusually compliant with these rules, and (6) eukaryotes have a unique pattern of base distribution.

Base Composition↗
PubMed2005

Equilibrium, observability and controllability in selection-mutation models.

In this paper we shortly discuss the problem of the equilibrium in the well-known Fisher type selection-mutation model, also providing a formula for particular three-allele models. The considered continuous-time dynamics is a known extension of the classical model of natural selection given by Fisher. We also extend the existing investigation of the observability of Fisher's model to the case when another evolutionary factor, mutation is also present. Moreover, we prove a result of technical character, which makes it possible to apply the methodology of nonlinear systems with invariant manifold, to models of artificial selection. For an illustration, a class of three-allele systems is presented in which the controllability into equilibrium is guaranteed without any condition on the biological parameters.

Algorithms↗
PubMed2005

Support versus corroboration.

Numerous metrics have been developed that attempt to assess the reliability of phylogenetic trees. Several of these commonly used measures of tree and tree branch support are described and discussed in the context of their relationship to Popperian corroboration. Claims that measures of support indicate the accuracy of phylogenetic trees or provide information for tree choice are rebutted. Measures of support are viewed as being of heuristic value within a given phylogenetic framework for describing the precision of the data based on perturbations to the data. However, no direct link is observed between the calculation of measures of support and corroboration. Direct measures of support, but not re-sampling or randomization methods, may play a more specific role in phylogenetic inference by providing the tools to search for falsifiers that could be the subject of future rounds of hypothesis testing.

Algorithms↗