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PubMed1996

Phylogenetic analysis in molecular evolutionary genetics.

Recent developments of statistical methods in molecular phylogenetics are reviewed. It is shown that the mathematical foundations of these methods are not well established, but computer simulations and empirical data indicate that currently used methods such as neighbor joining, minimum evolution, likelihood, and parsimony methods produce reasonably good phylogenetic trees when a sufficiently large number of nucleotides or amino acids are used. However, when the rate of evolution varies extensively from branch to branch, many methods may fail to recover the true topology. Solid statistical tests for examining the accuracy of trees obtained by neighbor joining, minimum evolution, and least-squares method are available, but the methods for likelihood and parsimony trees are yet to be refined. Parsimony, likelihood, and distance methods can all be used for inferring amino acid sequences of the proteins of ancestral organisms that have become extinct.

DNA↗
PubMed2002

Comparison of genetic variability between Czech and foreign isolates of phytopathogenic bacteria Clavibacter michiganensis subsp. sepedonicus by Rep-PCR technique.

Repetitive-sequence-based polymerase chain reaction (Rep-PCR) method was used for analysis of genetic variability among bacterial populations from different world locations. Collection of 26 Czech and 13 foreign strains of Clavibacter michiganensis subsp. sepedonicus was amplified using BOX primer targeting to repetitive motif occurring in eubacterial genomes. Genetic fingerprints were visually compared and statistically evaluated by cluster analysis. Genetic similarity was estimated to be approximately 80% among all tested strains. Populations of these bacteria seem to be highly homogeneous; potential influence of geographic origin was not confirmed.

Actinomycetales↗
PubMed2004

Population genetic structure of an ectomycorrhizal fungus Amanita manginiana in a subtropical forest over two years.

The population genetic structure of the late-stage fungus Amanita manginiana in a natural forest in Dujiangyan, southwest China was examined over two years using inter-simple sequence repeat (ISSR) markers. Seven ISSR primers were used and 170 bands were obtained in this population: 134/160 and 135/153 bands were polymorphic for sporocarps of 2001 and 2002, respectively. Each sporocarp represented a single genet in 2001 and 2002, and no identical genets were found between the two years. The results of genetic similarity comparison, using unweighted pair group method with arithmetic means, and analysis of molecular variance, indicated that although genetic variances were mainly within individuals of the same year the genetic variance between years was statistically significant (P<0.001). Relationships between genetic similarity and spatial distance of pairwise sporocarps were also found to be different in the two years. The differences in genetic structure and genetic similarity between individuals of the two years implied that the sporocarps were not likely to be derived from continuous generations, i.e., the sporocarps collected in 2002 were not developed from sexual spores dispersed by sporocarps of 2001. We suggest that the life-cycle traits of ectomycorrhizal (ECM) fungi should be considered in genetic studies on ECM fungal populations.

Amanita↗
PubMed2005

New approaches to the genetic analysis of neuroticism and anxiety.

The completion of the human genome project and the complementary genome projects for other species has broadened the scope for novel bioinformatic approaches to quantitative trait locus (QTL) identification. A key issue for quantitative trait nucleotide (QTN) identification is progressing from a large QTL peak, spanning perhaps 50 cM and many hundreds of genes, to a gene or nucleotide variant which is responsible for that QTL effect. The complementary use of mouse models to dissect large syntenic loci in humans is a powerful method for reducing QTL intervals to the order of 1 Mb. This paper presents an overview of the approaches used in our laboratory to ultra-fine map QTLs for anxiety-related traits, and to identify quantitative trait genes (QTG). As new genetic techniques and statistical approaches arise, we are getting closer to identifying those long sought after QTNs.

Animals↗
PubMed2004

Genetic epidemiology: some special contributions of birth cohorts.

Birth cohorts that collect detailed phenotypic and environmental information, particularly if multigenerational, have an important contribution to make as we seek to understand the genetic and environmental determinants of common disease. Provided such multigenerational population cohorts are unselected by disease, trait or exposure, they can also contribute important information that is needed for optimal statistical analysis in genetic epidemiology generally. One example of this added value is an assessment, at specified loci, of whether or not there is distortion of the expected Mendelian 50 : 50 transmission of alleles to study subjects (e.g. due to differential loss of embryos of one genotype). Another example is to test for heterosis, i.e. whether heterozygotes have a greater or lesser effect than either homozygote. Finally, phenome scans (a fixed format analysis of the associations between a genotype of interest and thousands of outcome variables from the cohort database) could be used as a screening tool to test whether certain classes of genetic variation have more impact than others on human health and development, and so inform genotyping strategies generally.

Cohort Studies↗
PubMed2003

Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy.

To evaluate human immunodeficiency virus type 1 (HIV-1) replication and selection of drug-resistant viruses during seemingly effective highly active antiretroviral therapy (HAART), multiple HIV-1 env and pol sequences were analyzed and viral DNA levels were quantified from nucleoside analog-experienced children prior to and during a median of 5.1 (range, 1.8 to 6.4) years of HAART. Viral replication was detected at different rates, with apparently increasing sensitivity: 1 of 10 by phylogenetic analysis; 2 of 10 by viral evolution with increasing genetic distances from the most recent common ancestor (MRCA) of infection; 3 of 10 by selection of drug-resistant mutants; and 6 of 10 by maintenance of genetic distances from the MRCA. When four- or five-drug antiretroviral regimens were given to these children, persistent plasma viral rebound did not occur despite the accumulation of highly drug-resistant genotypes. Among the four children without genetic evidence of viral replication, a statistically significant decrease in the genetic distance to the MRCA was detected in three, indicating the persistence of a greater number of early compared to recent viruses, and their HIV-1 DNA decreased by > or =0.9 log(10), resulting in lower absolute DNA levels (P = 0.007). This study demonstrates the variable rates of viral replication when HAART has suppressed plasma HIV-1 RNA for years to a median of <50 copies/ml and that combinations of four or five antiretroviral drugs suppress viral replication even after short-term virologic failure of three-drug HAART and despite ongoing accumulation of drug-resistant mutants. Furthermore, the decrease of cellular HIV-1 DNA to low absolute levels in those without genetic evidence of viral replication suggests that monitoring viral DNA during HAART may gauge low-level replication.

Antiretroviral Therapy, Highly Active↗
PubMed1992

Population genetics in the forensic DNA debate.

The use of matching variable number of tandem repeat (VNTR) profiles to link suspects with crimes is potentially very powerful, but it has been quite controversial. Initial debate over laboratory procedures has largely given way to debate over the statistical and population genetic issues involved in calculating the frequency of a profile for a random member of a population. This frequency is used to weight the evidence of a match between suspect and crime scene material when the suspect denies responsibility for that material. A recent report from the National Research Council, intended to put to rest some of the issues, has instead raised further debate by advocating a procedure based on maximum frequencies of profile components over several different populations.

Alleles↗
PubMed2005

Population genetic structure of the Yangtze finless porpoise (Neophocaena phocaenoides asiaeorientalis): implications for management and conservation.

Understanding the population genetic structure is a prerequisite for conservation of a species. The degree of genetic variability characteristic of the mitochondrial DNA control region has been widely exploited in studies of population genetic structure and can be useful in identifying meaningful population subdivisions. To estimate the genetic profile of the Yangtze finless porpoise (Neophocaena phocaenoides asiaeorientalis), an endangered freshwater population endemic to China, the complete mtDNA control region was examined in 39 individuals belonging to seven different stocks inhabiting the middle and lower reaches of the Yangtze River. Very low genetic diversity was found (nucleotide diversity 0.0011 +/- 0.0002 and haplotypic diversity 0.65 +/- 0.05). The mtDNA genetic pattern of the Yangtze population appears to indicate a founder event in its evolutionary history and to support the marine origin for this population. Analyses by Fst and phi(st) yielded statistically significant population genetic structure (Fst = 0.44, P < 0.05; phi(st) = 0.36, P < 0.05). These results may have significant implications for the management and conservation of the Yangtze finless porpoise in the future.

Animals↗
PubMed1987

The interaction of statistical significance, biology of dose-response and test design in the assessment of genotoxicity data.

The most useful function of statistical significance in genetic toxicology is to separate weakly positive from negative data. To achieve this objective, the experimental system, design and analysis must be considered as a whole and not as separate entities. Assumptions underlying statistical methods should be checked for applicability to the biology of the test. The number and arrangement of samples and dose levels must be organized to suit the selected statistical method. The number of observations in the test and in each sample will depend on the smallest increase of biological importance which should be detected as significant (at a selected value for alpha error) and the maximum acceptable chance of failing to detect this increase as significant (beta error). Generally, a few dose levels and a high degree of replication are desirable with a repeat test if practical. In the analyses of data it is particularly important to adapt the statistics if there are multiple comparisons. Even after correct determination of significance, interpretation can be difficult because of possible experimental artefacts and chance errors plus the impossibility of proving a negative result.

Data Interpretation, Statistical↗
PubMed2006

GALGO: an R package for multivariate variable selection using genetic algorithms.

SUMMARY: The development of statistical models linking the molecular state of a cell to its physiology is one of the most important tasks in the analysis of Functional Genomics data. Because of the large number of variables measured a comprehensive evaluation of variable subsets cannot be performed with available computational resources. It follows that an efficient variable selection strategy is required. However, although software packages for performing univariate variable selection are available, a comprehensive software environment to develop and evaluate multivariate statistical models using a multivariate variable selection strategy is still needed. In order to address this issue, we developed GALGO, an R package based on a genetic algorithm variable selection strategy, primarily designed to develop statistical models from large-scale datasets.

Algorithms↗
PubMed1976

[The genetics of the protease inhibitor system and osteospongiosis. Statistical study in 199 patients].

Since the trypsin activity of the inner ear fluid appears to be essential in the evolution of otosclerosis towards a cochlear deafness it was obvious that the protease inhibitor system which is an excellent genetic marker ought to be studied during the onset and the evolution of otosclerosis. No differences with the statistical data from the normal population was found the origin of the trypsin that destroys the inner ear is to be found locally the histiocytes of the otosclerosis focus.

Ear, Middle↗
PubMed2005

Spatial genetic structure of two HIV-I-resistant polymorphisms (CCR2-64 I and SDF1-3'A) alleles in population of Shandong Province, China.

OBJECTIVE: To explore the spatial genetic structure of two HIV-I-resistant polymorphisms (CCR2-64 I and SDF1-3'A) alleles in the population of Shandong Province, China. METHODS: Using the techniques of spatial stratified sampling and spatial statistics, the spatial genetic structure of the locus (CCR2-64 I and SDF1-3'A), which was shown to be important co-receptor for HIV infection, was quantified from the populations of 36 sampled counties of Shandong Province, and a total of 3147 and 3172 samples were taken for testing CCR2-64I and SDF1-3'A respectively from individuals without known history of HIV-I infection and AIDS symptoms. RESULTS: There were significantly spatial genetic structures of the two alleles at different spatial distance classes on the scale of populations, but on the scale of individuals, no spatial structure was found in either the whole area of Shandong Province or the area of each sampled county. Although the change of frequencies of the two alleles with geographic locations in Shandong Province both showed gradual increase trends, their changing directions were inverse. The frequency of CCR2-64I allele gradually increased from the southwest to the northeast, while the frequency of SDF1-3'A allele gradually increased from the northeast to the southwest. However the RH to AIDS of combined types of their different genotypes did not represent obvious geographic diversity on the whole area of the Province. CONCLUSION: The frequency of allele usually has some spatial genetic structures or spatial autocorrelation with different spatial distance classes, but the genotypes of individuals have random distribution in the same geographic area. Evaluating spatial distribution of the genetic susceptibility of HIV (AIDS) to CCR2-64I and SDF1-3'A alleles, should focus on the frequencies of combined genotypes of CCR2 and SDF1 based on the two-locus genotypes of each individual rather than the frequencies of CCR2-64I and SDF1-3'A alleles.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Modeling clinically heterogeneous presenilin mutations with transgenic Drosophila.

To assess the potential of Drosophila to analyze clinically graded aspects of human disease, we developed a transgenic fly model to characterize Presenilin (PS) gene mutations that cause early-onset familial Alzheimer's disease (FAD). FAD exhibits a wide range in severity defined by ages of onset from 24 to 65 years . PS FAD mutants have been analyzed in mammalian cell culture, but conflicting data emerged concerning correlations between age of onset and PS biochemical activity . Choosing from over 130 FAD mutations in Presenilin-1, we introduced 14 corresponding mutations at conserved residues in Drosophila Presenilin (Psn) and assessed their biological activity in transgenic flies by using genetic, molecular, and statistical methods. Psn FAD mutant activities were tightly linked to their age-of-onset values, providing evidence that disease severity in humans primarily reflects differences in PS mutant lesions rather than contributions from unlinked genetic or environmental modifiers. Our study establishes a precedent for using transgenic Drosophila to study clinical heterogeneity in human disease.

Adult↗
PubMed2004

Identification of genetic networks.

In this report, we propose the use of structural equations as a tool for identifying and modeling genetic networks and genetic algorithms for searching the most likely genetic networks that best fit the data. After genetic networks are identified, it is fundamental to identify those networks influencing cell phenotypes. To accomplish this task we extend the concept of differential expression of the genes, widely used in gene expression data analysis, to genetic networks. We propose a definition for the differential expression of a genetic network and use the generalized T2 statistic to measure the ability of genetic networks to distinguish different phenotypes. However, describing the differential expression of genetic networks is not enough for understanding biological systems because differences in the expression of genetic networks do not directly reflect regulatory strength between gene activities. Therefore, in this report we also introduce the concept of differentially regulated genetic networks, which has the potential to assess changes of gene regulation in response to perturbation in the environment and may provide new insights into the mechanism of diseases and biological processes. We propose five novel statistics to measure the differences in regulation of genetic networks. To illustrate the concepts and methods for reconstruction of genetic networks and identification of association of genetic networks with function, we applied the proposed models and algorithms to three data sets.

Algorithms↗
PubMed2001

Unbiased discordant sib-pair tests when parental genotypes are missing.

Population admixture and stratification are potential sources of confounding in a variety of statistical analyses of genetic data. Many approaches to adjusting for such confounding have been developed in the context of association analyses. These approaches may generally be viewed as relying on nonparametric null hypotheses that specify certain, sometimes incompletely observed, conditional distributions; the conditional distributions are used to normalize test statistics to have expectation zero under the null hypothesis. Here, with a very simple example, it is shown that there is potentially information that is free of confounding, but that is not recovered by such normalized statistics. An approach presented here in the context of the simple example might be extended to methods for recovering information in more complex settings.

Bias↗
PubMed2005

Characterization of a likelihood based method and effects of markers informativeness in evaluation of admixture and population group assignment.

BACKGROUND: Detection and evaluation of population stratification are crucial issues in the conduct of genetic association studies. Statistical approaches useful for understanding these issues have been proposed; these methods rely on information gained from genotyping sets of markers that reflect population ancestry. Before using these methods, a set of markers informative for differentiating population genetic substructure (PGS) is necessary. We have previously evaluated the performance of a Bayesian clustering method implemented in the software STRUCTURE in detecting PGS with a particular informative marker set. In this study, we implemented a likelihood based method (LBM) in evaluating the informativeness of the same selected marker panel, with respect to assessing potential for stratification in samples of European Americans (EAs) and African Americans (AAs), that are known to be admixed. LBM calculates the probability of a set of genotypes based on observations in a reference population with known specific allele frequencies for each marker, assuming Hardy Weinberg equilibrium (HWE) for each marker and linkage equilibrium among markers. RESULTS: In EAs, the assignment accuracy by LBM exceeded 99% using the most efficient marker FY, and reached perfect assignment accuracy using the 10 most efficient markers excluding FY. In AAs, the assignment accuracy reached 96.4% using FY, and >95% when using at least the 9 most efficient markers. The comparison of the observed and reference allele frequencies (which were derived from previous publications and public databases) shows that allele frequencies observed in EAs matched the reference group more accurately than allele frequencies observed in AAs. As a result, the LBM performed better in EAs than AAs, as might be expected given the dependence of LBMs on prior knowledge of allele frequencies. Performance was not dependent on sample size. CONCLUSION: The performance of the LBM depends on the efficiency and number of markers, and depends greatly on how representative the available reference allele frequencies are for those of the population being assigned. This method is of value when the parental population is known and relevant allele frequencies are available.

Black or African American↗