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PubMed1987

Tests of gene order from three-locus linkage data.

Exact tests for gene order are derived and compared for three loci using linkage data from phase-known, completely informative marker loci (i.e. parents are heterozygotes with at most one allele identical at each locus), or from triple back-cross matings. A simulation method, based on resampling genotypes of children, is introduced to obtain approximations to the distribution of the test statistics for general mating types in families consisting of children and parents, with or without grandparents, as are used in many studies in human gene mapping. The method is illustrated by an application to linkage data on chromosome 13.

Chromosome Mapping↗
PubMed2004

Gene modifiers in pediatrics: application to cystic fibrosis.

Human disease is a result of interactions between each person's genetic program and the environment. Individual genes responsible for many pediatric diseases have been discovered, but there is still considerable variability in phenotype within a given disorder. While some of the variability is undoubtedly caused by environmental factors, genes other than the primary disease gene likely modify phenotypes. These gene modifiers alter the effects of the primary disease gene and therefore result in phenotypic variability. Studying gene modifiers will therefore likely lead to a better understanding of pathophysiology and to development of new treatments. Statistical and genetic methods used to identify gene modifiers range from simple association studies to complex family studies, each with its own strengths. The search for gene modifiers in cystic fibrosis (CF), a common mendelian disorder, provides a good example of an application of the latest approaches. Potential modifiers of CF are chosen to reflect the known pathophysiology of CF, including genes involved in the host response to infection and CF complications such as intestinal obstruction, diabetes, and liver disease. A region on chromosome 19 that modifies intestinal obstruction in CF has been identified based on a region of synteny in the mouse; however, the specific gene has not been completely characterized. While a number of other putative gene modifiers have been investigated in CF, none are clearly substantiated. To date, only a few gene modifiers in pediatric disease have been conclusively identified, but we believe that future research will open the doors for new knowledge and treatment.

Animals↗
PubMed1999

Genetically engineered polymers for drug delivery.

Genetic engineering methodology offers the ability to synthesize protein-based polymers with precisely controlled structures. Protein-based polymers synthesized by recombinant techniques have a well-defined monomer composition and sequence, stereochemistry, and a narrow molecular weight distribution. The structure of the polymeric carrier at the molecular level influences its biological disposition and drug release profile. Current methodologies of polymer synthesis (chemical polymerization) result in the production of polymers with heterogeneous molecular weights, and with monomer sequences and compositions defined in terms of statistical distributions. Genetic engineering methodologies can be used to design new polymeric drug carriers with improved properties, such as better-defined biorecognition, pharmacokinetic, biodegradation, and drug release profiles. In this review article the rationale and methodology of polymer synthesis using genetic engineering techniques, the status of such polymers in drug delivery to-date, and the potential of these polymers for the development of new systems in the future are discussed.

Drug Delivery Systems↗
PubMed1990

Base-pair specificity of protein-DNA recognition: a statistical-mechanical model.

The statistics of base-pair choice in individual recognition sites on DNA is shown to be determined by the functional binding requirements for recognition and a selection parameter. This selection parameter can be identified as a generalized external force required to deform a random-choice base-pair distribution into the observed specific-choice distribution. This external force is balanced by the randomization pressure which--driven by mutations--always tends to increase randomness in the base-pair choices. The model makes it possible to predict relative binding constants of particular recognition sequences based primarily on the statistics of base-pair usage. A further consequence of this formulation is that the randomization pressure appears explicitly as an important force shaping the evolutionary selection not only of DNA sites, but also of other properties involving macromolecular design.

Base Composition↗
PubMed1983

Displacement of chromosomes in mitosis: a technique for assessing differential chromosome error.

To assess whether displacement--the appearance of individual chromosomes inside of the ring of chromosomes attached to spindle fibers--is a valid method of analyzing chromosome misdivision, displacement data from six healthy female subjects were compared with data for mitotic and meiotic nondisjunction. Statistical analysis indicated that nondisjunction and displacement are equivalent methods of assessing differential chromosome error. Tests for homogeneity of the data sets showed no significant heterogeneity for the mitotic data, but chromosomes 1, 2, 11, 16, 17, 19, and 20 were responsible for significant heterogeneity in the meiotic data.

Adult↗
PubMed1990

Environmental index in genetic epidemiology: an investigation of its role, adequacy, and limitations.

The concept of environmental index is briefly reviewed. With a biologically plausible theoretical model, the consequences of indices being based on incomplete information about the familial environment are investigated. It is shown that using partial indices on all family members leads to both an underestimation of the familial environmental component of variance, also called cultural heritability, and, although to a possibly lesser extent, an overestimation of the genetic heritability. It is further shown that so long as complete indices are available on both parents, using identically partial indices on children will yield nearly undistorted parameter estimates. These conclusions were arrived at by using a special case of the model and may not apply in general.

Environment↗
PubMed2002

[Theoretical studies of QTL analysis of complex genetic diseases in humans].

Some genes controlling human diseases have been located on the regions less than 1 cM using linkage disequilibrium, and a few of them have been cloned. Z. W. Luo developed a method that can detect and estimate the coefficient of linkage disequilibrium between a marker locus and quantitative trait locus (QTL), and raised the theoretical strategies for high-resolution mapping of complex genetic disorders in humans. Based on the data mentioned above, a method for linkage test between a marker locus and QTL was set up, and a method for linkage test between two marker loci and epistatic QTL was suggested for the first time.

Chromosome Mapping↗
PubMed1999

Frequency of HLA-A and B alleles in early and late-onset Alzheimer's disease.

The frequency of various allele types of the class I Major Histocompatibility Complex (MHC) genes HLA-A and HLA-B were compared between pathologically confirmed groups of late and early-onset Alzheimer's disease (AD) and a control group. DNA was extracted from frozen brain tissue and the highly polymorphic second and third exons of the HLA-A and HLA-B genes were independently PCR amplified using specific primers. Individual allele types were identified using sequence-specific oligonucleotide probes. The results showed that the main frequency differences occurred between the late-onset AD and the control group however none of these reached statistical significance.

Adult↗
PubMed2006

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Genome-wide associations between hybrid sterility QTL and marker transmission ratio distortion.

Marker transmission ratio distortion (TRD) in genetic mapping populations is frequently ascribed to selection against allelic combinations that cause hybrid incompatibility. Accordingly, genomic regions of TRD should be nonrandomly associated (colocated) with loci that underlie hybrid incompatibility. To directly test this hypothesis, we evaluated the genome-wide qualitative and quantitative agreement between chromosomal regions exhibiting marker TRD and those known to contain hybrid incompatibility quantitative trait locus (QTL). Incompatibility data came from a near-isogenic line (NIL) analysis of pollen and seed sterility in a cross between two Solanum (formerly Lycopersicon) species. We assessed (1) whether these incompatibility loci are colocated with markers that show significant TRD in two earlier generations preceding these introgression lines and (2) whether the magnitude of marker distortion quantitatively matches the estimated strength of selection against each incompatibility locus. We found evidence that TRD regions are chromosomally colocated with hybrid incompatibility loci more frequently than is expected by chance: pollen sterility QTLs were most closely associated with distorted heterozygote frequencies in later-generation backcrosses. Nonetheless, there was no evidence for an association between TRD and seed sterility and little evidence of a quantitative association between the magnitude of marker TRD and the fitness effects of heterospecific alleles at each chromosomal location. We propose and test a model (the "dance partner" model) to explain several cases where regions of TRD are not associated with hybrid incompatibility loci. Under this model, some NILs containing greater than one heterospecific introgression may not express hybrid incompatibility phenotypes because they carry both appropriate genetic dance partners required for a fully functional interaction. Accordingly, negative interactions expressed in earlier backcross generations are masked in these double-introgression NILs. Based on this model, we identify the location of several new putative pairwise interactors underlying hybrid incompatibility in this species cross.

Chromosome Mapping↗
PubMed2001

Spatial structure of lemming populations (Dicrostonyx groenlandicus) fluctuating in density.

The pattern and scale of the genetic structure of populations provides valuable information for the understanding of the spatial ecology of populations, including the spatial aspects of density fluctuations. In the present paper, the genetic structure of periodically fluctuating lemmings (Dicrostonyx groenlandicus) in the Canadian Arctic was analysed using mitochondrial DNA (mtDNA) control region sequences and four nuclear microsatellite loci. Low genetic variability was found in mtDNA, while microsatellite loci were highly variable in all localities, including localities on isolated small islands. For both genetic markers the genetic differentiation was clear among geographical regions but weaker among localities within regions. Such a pattern implies gene flow within regions. Based on theoretical calculations and population census data from a snap-trapping survey, we argue that the observed genetic variability on small islands and the low level of differentiation among these islands cannot be explained without invoking long distance dispersal of lemmings over the sea ice. Such dispersal is unlikely to occur only during population density peaks.

Animals↗
PubMedDate not supplied

Frequency-dependent viability in mutant strains of Drosophila melanogaster.

We investigated the effects of genotypic frequencies on egg-to-adult viabilities in pairwise combinations of four strains of Drosophila melanogaster. The experiments involved mixture of a total of 42,000 eggs in varying proportions under controlled densities and observation of surviving adults. Viabilities were found to depend on frequencies in several genotypic combinations. In the most extreme case, the absolute viability of cn;bw females increased monotonically from 54% when common to 70% when rare. The results illustrate several statistical and methodological problems that might explain why some experiments have failed to detect frequency-dependent viabilities. These problems include heterogeneity between replications, sex differences in susceptibility to competition, and strong dependence of the experimental outcome on the choice of competitor genotypes.

Animals↗
PubMed2005

Hardy-Weinberg testing of a single homozygous genotype.

No proper statistical test is available for the evaluation of deviation of a single homozygous genotype from Hardy-Weinberg equilibrium (HWE) proportion. We propose a 1-d.f. chi2-test. The power of the proposed test is favorable compared to existing HWE testing procedures. The applications of this test are discussed.

Gene Frequency↗
PubMed1976

Order statistics of correlated variables and implications in genetic selection programmes.

Formulae are derived and examples given for the expected values of the order statistics from a sample of several groups or families of equal size where the group members have intra-class correlation t. As t increases from O the means of the highest ranking individuals are little reduced initially, but as t approaches 1 the change becomes more rapid, the total reduction depending on the number of groups. The effect on selection differentials of the intra-class correlation of family members is generally small for t less than 0.5, such as if selection is practised on individual performance. If, however, family mean performance is used in an index, the selection differentials may be substantially reduced.

Animals↗
PubMed2001

Statistical tests of selective neutrality in the age of genomics.

Examining genomic data for traces of selection provides a powerful tool for identifying genomic regions of functional importance. Many methods for identifying such regions have focused on conserved sites. However, positive selection may also be an indication of functional importance. This article provides a brief review of some of the statistical methods used to detect selection using DNA sequence data or other molecular data. Statistical tests based on allelic distributions or levels of variability often depend on strong assumptions regarding population demographics. In contrast, tests based on comparisons of the level of variability in nonsynonymous and synonymous sites can be constructed without demographic assumptions. Such tests appear to be useful for identifying specific regions or specific sites targeted by selection.

Alleles↗
PubMed1994

Design and analysis of chromosome physical mapping experiments.

Mathematical and statistical aspects of constructing ordered-clone physical maps of chromosomes are reviewed. Three broad problems are addressed: analysis of fingerprint data to identify configurations of overlapping clones, prediction of the rate of progress of a mapping strategy and optimal design of pooling schemes for screening large clone libraries.

Chromosome Mapping↗
PubMed1983

Nonideal statistics and positive correlation in phage recombination: studies with lambda tandem duplication phages.

The question of nonideality in phage recombination, that is, the extent to which recombinant frequencies differ from those expected from the proportions of the two parental types in the mass culture, was addressed by experiments with lambda tandem duplication phages. Isolation and genotypic analysis of triplication-phage progeny, all of which must be the result of intermolecular recombination, yielded a value of about 0.5 for the nonideality parameter h, i.e., the frequency of unlike-parent matings was only about 1/2 the "ideal" value. This value was independent of multiplicity and about the same for the Rec or Red recombination systems. Similar analysis of single-copy phage progeny yielded estimates of k, the ratio of intramolecular to intermolecular recombination of about 1/6 for the Rec system; no intramolecular events were detected in Red-mediated crosses. Consideration of known nonideality factors (finite input, limited number of intracellular sites for phage growth) suggests that the observed h values correspond to intracellular mixing efficiencies of 55 to 100%, depending on the number of intracellular phage growth sites assumed. Analysis of long-range positive correlation (negative interference) indicates that statistical effects caused unlike-parent double crossovers to be three to four times as frequent as an independent-event calculation would predict. In addition, Rec-mediated crosses showed a 1.3-fold positive correlation for unlike-parent crossovers (in a second interval) among the progeny of like-parent recombinations.

Bacteriophage lambda↗
PubMed2001

Weighting improves the "new Haseman-Elston" method.

Elston et al. [Genet Epidemiol, in press] apply the results of Wright [Am J Hum Genet 1997;60:740-742] and Drigalenko [Am J Hum Genet 1998;63:1242-1245] to extend the traditional Haseman-Elston regression scheme [Haseman and Elston, Behav Genet 1972;2:3-19] to include not only linkage information contained in the sib pair's squared difference, but also information in their mean-corrected squared sum. The new algorithm detects linkage to a quantitative trait locus by modelling sib pair trait covariance as a function of identity-by-descent status. We demonstrate why this new estimator is suboptimal and can in some cases be inferior to the original Haseman-Elston method. We also describe a simple approach to estimation which improves on this new Haseman-Elston method by incorporating variance-based weights into the test statistic while staying within the linear modelling framework. In support of our theoretical claim, we conduct both a sib pair simulation and an application to GAW 10 sib pair data showing that our new estimator is superior to both the old and new Haseman-Elston schemes currently implemented in the analysis package S.A.G.E. 4.0.

Algorithms↗
PubMed2005

Two major QTLs and several others relate to factors of metabolic syndrome in the family blood pressure program.

Genome-wide variance components linkage analysis was performed on 4 latent factors underlying metabolic syndrome derived from 10 risk factors. The latent factors represent obesity and insulin, blood pressure, lipids and insulin, and central obesity. The metabolic syndrome factor scores were derived in 4 ethnic groups recruited in 3 Networks of the Family Blood Pressure Program: GENOA (blacks, Hispanics, and whites), HyperGEN (blacks and whites), SAPPHIRe (Asians). Heritabilities of metabolic syndrome factors ranged from 66% for obesity and insulin to 11% for blood pressure factor. We observed higher heritabilities for obesity and insulin, and lipids and insulin, whereas those for blood pressure and central obesity were smaller. Linkage analysis detected two major quantitative trait loci. One of them linked to the obesity and insulin factor with a lod score of 3.94 (P=0.00001, marker GATA11A06, D18S53, 41.24 cM) at marker positions linkage (lod 4.71, at 46.84 cM at 1-cM-apart distances linkage), located on chromosome 18p11.21 in GENOA black. The other linked to the blood pressure factor with a lod score of 3.22 (P=0.000059, marker GATA49C09, D17S1290, 82 cM) at marker positions linkage (lod 3.56, at 84.63 cM for 1 cM apart distances linkage) located on chromosome 17q23.1 in Hispanics. These quantitative trait loci, together with 4 additional ones with lod scores >2.5, and 30 additional ones with lod score >1.7, offer hope for dissecting the genetic architecture of metabolic syndrome with beneficial implications for molecular diagnosis, prognosis, and in potential medical intervention.

Asian People↗