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PubMed2006

Reduced splicing efficiency induced by synonymous substitutions may generate a substrate for natural selection of new splicing isoforms: the case of CFTR exon 12.

Alternative splicing has been associated with increased evolutionary changes and with recent exon creation or loss. The addition of a new exon can be explained by its inclusion in only a fraction of the transcripts leaving the original form intact and giving to the new form the possibility to evolve independently but the exon loss phenomenon is less clear. To explore the mechanism that could be involved in CFTR exon 12 lower splicing efficiency in primates, we have analyzed the effect of multiple synonymous variations. Random patterns of synonymous variations were created in CFTR exon12 and the majority of them induced exon inclusion, suggesting a suboptimal splicing efficiency of the human gene. In addition, the effect of each single synonymous substitution on splicing is strongly dependent on the exonic context and does not correlate with available in silico exon splicing prediction programs. We propose that casual synonymous substitutions may lead to a reduced splicing efficiency that can result in a variable proportion of exon loss. If this phenomenon happens in in-frame exons and to an extent tolerated by the cells it can have an important evolutionary effect since it may generate a substrate for natural selection of new splicing isoforms.

Alternative Splicing↗
PubMed2006

Quantitative analyses of circadian gene expression in mammalian cell cultures.

The central circadian pacemaker is located in the hypothalamus of mammals, but essentially the same oscillating system operates in peripheral tissues and even in immortalized cell lines. Using luciferase reporters that allow automated monitoring of circadian gene expression in mammalian fibroblasts, we report the collection and analysis of precise rhythmic data from these cells. We use these methods to analyze signaling pathways of peripheral tissues by studying the responses of Rat-1 fibroblasts to ten different compounds. To quantify these rhythms, which show significant variation and large non-stationarities (damping and baseline drifting), we developed a new fast Fourier transform-nonlinear least squares analysis procedure that specifically optimizes the quantification of amplitude for circadian rhythm data. This enhanced analysis method successfully distinguishes among the ten signaling compounds for their rhythm-inducing properties. We pursued detailed analyses of the responses to two of these compounds that induced the highest amplitude rhythms in fibroblasts, forskolin (an activator of adenylyl cyclase), and dexamethasone (an agonist of glucocorticoid receptors). Our quantitative analyses clearly indicate that the synchronization mechanisms by the cAMP and glucocorticoid pathways are different, implying that actions of different genes stimulated by these pathways lead to distinctive programs of circadian synchronization.

Animals↗
PubMed2005

Overview of marker vaccine and differential diagnostic test technology.

Recent advances in molecular biology, immunology, microbiology, genetics and microbial pathogenesis have lead to the development of a wide variety of new approaches for developing safer and more effective vaccines based on designs such as subunit vaccines, gene deleted vaccines, live vectored vaccines, and DNA mediated vaccines. Technology tools can be as basic as identifying naturally occurring strains with deletions that support differentiating infected from vaccinated animal (DIVA) needs or be based on higher technology developments such as improved protein expression and purification methods, transgenic plant- and plant virus-based antigen production, and novel adjuvants that target specific immune responses. These new approaches, when applied to the development of marker vaccines and companion diagnostic test kits hold tremendous potential for developing improved tools for eradication and control programs. Marker vaccines and companion diagnostic test kits must meet the established licensing requirements for purity, potency, safety and efficacy. Efficacy claims are based on evaluation of the level of protection demonstrated in host animal trials and may range from "prevents infection with (a specific agent)", to "for use as an aid in the reduction of disease due to (a specific agent)." The differences in claims and recommendations are a function of the variation in protection elicited by various vaccines. For designing effective eradication programs, vaccine efficacy characteristics such as for reducing susceptibility to infections and spread of infections must be well defined; similarly, diagnostic test performance characteristics (efficacy) must be determined. In addition to data to support efficacy claims, it is imperative that safety of production and use of vaccines be evaluated. During the design of marker vaccines and diagnostic tests, it is important to consider the application of appropriate technologies to improve the safety of these products. Use of recombinant technologies for production of vaccines and/or diagnostic test antigens can reduce the biosafety concerns during production and during use, including human exposure to zoonotic pathogens during production and use, and potential spread of foreign animal disease agents due to loss of biocontainment. In addition, vaccines may induce adverse reactions. It is important to determine the frequency of adverse events and to reduce the likelihood of induction of adverse reactions through proper design.

Animals↗
PubMed1979

Correlated characters in selection for aggressiveness in female mice. II. Maternal aggressiveness.

The present study investigated whether maternal aggression has shown a correlated response in a program of artificial selection for isolation-induced interfemale aggression in housemice. Females from the first replicate of lines (H1, C1, L1) and the second replicate of lines (H2, C2, L2) from generation S5 were given daily aggression tests for 20 consecutive days following the birth of their first litter. Evidence of a correlated response was found for replicate 2, but results for replicate 1 provided no evidence of a correlated response. In generation S10, when better separation of the lines on isolation-induced aggression had occurred, the study was repeated. In S10 there was clear evidence of a correlated response in both of the replicates.

Aggression↗
PubMed1994

Restricted maximum likelihood procedures for the estimation of additive and nonadditive genetic variances and covariances in multibreed populations.

Restricted maximum-likelihood procedures were developed to estimate additive and nonadditive genetic and environmental covariances for multiple traits in multibreed populations. The computational procedure follows the expectation-maximization (EM) algorithm, where the set of equations in the maximization step is solved by successive approximations. This computational procedure does not guarantee convergence to a symmetric positive-definite covariance matrix. Thus, computer programs will need to incorporate restrictions in the maximization step to ensure positive definiteness of each covariance matrix. Additive genetic and environmental covariances were modeled in subclass form (zeros and ones in the design matrices). Nonadditive genetic covariances were modeled in regression form (any value between and including zero and one in the design matrices). Computational requirements will be larger than for intrabreed analyses. Appropriate simplifying assumptions and numerical techniques (e.g., sparse and iterative numerical techniques) will be required for the implementation of these multibreed covariance estimation procedures. Number of iterations (5 to 12) and computing times (57 to 113 min) to achieve convergence when estimating 21 genetic and environmental covariances in five small simulated multibreed data sets (two breeds, 25,200 to 50,400 calves, 120 to 135 unrelated bulls) suggest that these procedures are computationally feasible.

Algorithms↗
PubMed2000

Exact multipoint quantitative-trait linkage analysis in pedigrees by variance components.

Methods based on variance components are powerful tools for linkage analysis of quantitative traits, because they allow simultaneous consideration of all pedigree members. The central idea is to identify loci making a significant contribution to the population variance of a trait, by use of allele-sharing probabilities derived from genotyped marker loci. The technique is only as powerful as the methods used to infer these probabilities, but, to date, no implementation has made full use of the inheritance information in mapping data. Here we present a new implementation that uses an exact multipoint algorithm to extract the full probability distribution of allele sharing at every point in a mapped region. At each locus in the region, the program fits a model that partitions total phenotypic variance into components due to environmental factors, a major gene at the locus, and other unlinked genes. Numerical methods are used to derive maximum-likelihood estimates of the variance components, under the assumption of multivariate normality. A likelihood-ratio test is then applied to detect any significant effect of the hypothesized major gene. Simulations show the method to have greater power than does traditional sib-pair analysis. The method is freely available in a new release of the software package GENEHUNTER.

Algorithms↗
PubMed2006

Inference about recombination from haplotype data: lower bounds and recombination hotspots.

Recombination is an important evolutionary mechanism responsible for creating the patterns of haplotype variation observable in human populations. Recently, there has been extensive research on understanding the fine-scale variation in recombination across the human genome using DNA polymorphism data. Historical recombination events leave signature patterns in haplotype data. A nonparametric approach for estimating the number of historical recombination events is to compute the minimum number of recombination events in the history of a set of haplotypes. In this paper, we provide new and improved methods for computing lower bounds on the minimum number of recombination events. These methods are shown to detect a higher number of recombination events for a haplotype dataset from a region in the lipoprotein lipase gene than previous lower bounds. We apply our methods to two datasets for which recombination hotspots have been experimentally determined and demonstrate a high density of detectable recombination events in the regions annotated as recombination hotspots. The programs implementing the methods in this paper are available at www.cs.ucsd.edu/users/vibansal/RecBounds/.

Chromosomes, Human↗
PubMed2005

Histone variant H2A.Z marks the 5' ends of both active and inactive genes in euchromatin.

In S. cerevisiae, histone variant H2A.Z is deposited in euchromatin at the flanks of silent heterochromatin to prevent its ectopic spread. We show that H2A.Z nucleosomes are found at promoter regions of nearly all genes in euchromatin. They generally occur as two positioned nucleosomes that flank a nucleosome-free region (NFR) that contains the transcription start site. Astonishingly, enrichment at 5' ends is observed not only at actively transcribed genes but also at inactive loci. Mutagenesis of a typical promoter revealed a 22 bp segment of DNA sufficient to program formation of a NFR flanked by two H2A.Z nucleosomes. This segment contains a binding site of the Myb-related protein Reb1 and an adjacent dT:dA tract. Efficient deposition of H2A.Z is further promoted by a specific pattern of histone H3 and H4 tail acetylation and the bromodomain protein Bdf1, a component of the Swr1 remodeling complex that deposits H2A.Z.

Acetylation↗
PubMed2004

SWAPSC: sliding window analysis procedure to detect selective constraints.

UNLABELLED: Sliding-window analysis procedure to detect selective constraints (SWAPSC) is a software system to dissect the constraints on the evolution of protein-coding genes. The program estimates rates of nucleotide substitutions at specific codon regions in each branch of a phylogenetic tree. The program uses several sets of simulated sequence alignments to estimate the probability of synonymous and non-synonymous nucleotide substitutions. Thereafter, a statistical analysis is conducted to determine the optimum window size to detect selective constraints. Finally, the optimum window size is slid along the real alignment and a test for significance of the estimated number of synonymous and non-synonymous nucleotide substitutions in each sliding step is conducted. A number of friendly useful output files is generated. AVAILABILITY: SWAPSC is available at http://www.may.ie/academic/biology/staff/mfmolecevolandbioinf.shtml distribution versions for both Linux and Windows operating systems are available, including manual and example files.

Algorithms↗
PubMed1998

Variations in the secondary metabolite camptothecin in relation to tissue age and season in Camptotheca acuminata.

We investigated variation in concentration of the secondary metabolite, camptothecin (CPT), in relation to leaf, branch and tree age, season, and leaf drying method in Camptotheca acuminata Decaisne saplings. Younger leaves contained higher CPT concentrations than older leaves. Within a branch, there was a linear decline in CPT concentration from leaves at the apex of the branch down to Leaf 7. Comparing leaves of similar age, those from younger trees had higher CPT concentrations than those from older trees. Over the course of the growing season, there was a steady decline of 11% per month in leaf CPT concentration. Branches showed a similar seasonal decline in CPT concentration to leaves; however, the rate of decline was threefold greater in leaves than in branches. Freeze-dried tissues had a 27% higher CPT concentration than oven- or air-dried tissues, suggesting that oven- and air-drying caused degradation of CPT. The decline in CPT concentration with tissue aging may reflect a genetically determined mechanism whereby, in young trees, chemicals serve as a first line of defense against attacks by herbivores and pathogenic microorganisms until other mechanisms are developed and deployed. We hypothesize that chemical defense mechanisms are programmed for early ontogenic stages, whereas they are induced by biotic and abiotic factors during later ontogenic stages.

Journal Article↗
PubMed2005

Development of genetic sexing strains in Lepidoptera: from traditional to transgenic approaches.

The sterile insect technique (SIT) is currently being used for the control of many agricultural pests, including some lepidopteran species. The SIT relies on the rearing and release of large numbers of genetically sterile insects into a wild population. The holokinetic chromosomes of Lepidoptera respond differently to radiation than do species where there is a localized centromere. This difference has enabled a variation of the SIT to be developed for Lepidoptera where a substerilizing dose of radiation is given to the insects before their release with the result that a certain level of sterility is inherited by the F1 offspring. The development of genetic sexing strains for fruit flies, enabling the release of males only, has resulted in enormous economic benefits in the mass rearing and has increased the efficiency of the field operations severalfold. This article outlines Mendelian approaches that are currently available to separate large numbers of males and females efficiently for different lepidopteran species and describes their difficulties and constraints. Successful transgenesis in several lepidopteran species opens up new possibilities to develop genetic sexing strains. The proposal to develop genetic sexing strains described in this article takes advantage of the fact that in Lepidoptera, the female is the heterogametic sex, with most species having aWZ sex chromosome pair, whereas the males are ZZ. This means that if a conditional lethal gene can be inserted into the W chromosome, then all females should die after the application of the restrictive condition. The assumptions made to accommodate this model are discussed, and the advantages to be gained for control programs are elucidated.

Animals↗
PubMed2004

Using the Mplus computer program to estimate models for continuous and categorical data from twins.

Historically, the focus of behavior genetic research was to obtain estimates of the sources of familial resemblance for a single phenotype. Current research strategies have moved beyond heritability estimates to the search for physiological and behavioral mechanisms by which genetic risk is translated into individual differences in behavior and disease liability. Such research questions often require multivariate designs and complex analytic models, including the analysis of continuous and categorical dependent variables within the same model. Recent advances in computer software for categorical data analysis have increased the tools available for researchers in behavior genetics. This paper describes how to use the Mplus software program (Muthén and Muthén, 1998, 2002) for the analysis of data obtained from twins. Example analyses include two- and five-group twin models for univariate and bivariate continuous and categorical variables. Data on alcoholism and age at first drink drawn from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders are used to illustrate how Mplus can be used to analyze multiple-category variables, recode and transform variables, select subgroups for analysis, handle subjects with incomplete data, include constraints to ensure non-negative loadings, include model covariates, model sex differences, and test alternative hypotheses about mediation of genetic risk by measured variables.

Adolescent↗
PubMed2006

Genotypic relatedness of yeasts in thrush and denture stomatitis.

BACKGROUND/AIM: Candida is an opportunistic pathogen. Understanding its genetic characters might increase our understanding of the pathogenesis of candidosis. We examined the genetic relationships of yeasts from the most common forms of oral candidosis: thrush and denture stomatitis. METHODS: Yeasts were sampled from palate, buccal mucosa, gingival sulci/periodontal pockets and/or denture fitting surface of 19 thrush patients and 22 denture stomatitis patients. Random amplified polymorphic DNA and the Dendron computer-assisted program were used to determine the genotypic relatedness of the yeasts. RESULTS: A dendrogram generated from 105 thrush isolates had similarity coefficients (S(AB)) ranging from 0.58 to 1 with four clusters derived at S(AB) 68%. Another dendrogram was generated from 91 isolates from denture stomatitis, with S(AB) ranging from 0.59 to 1. Three clusters were established at S(AB) 71%. In a composite dendrogram incorporating the thrush and denture stomatitis data and orally healthy data compiled from a previous study, five genotypic clusters were generated at S(AB) 68%. Cluster II, the most dominant, comprised isolates from thrush, denture stomatitis and healthy conditions, while clusters III and IV contained yeasts mainly from thrush. CONCLUSIONS: Palatal yeast carriage was significantly increased in thrush and denture stomatitis, also after radiation, chemotherapy and denture wearing. The buccal mucosa was favorable for yeast colonization regardless of oral condition. Yeasts in thrush were more diverse than in conditions of oral health. The common clone (II) of infecting yeasts and commensals suggested that commensals could induce thrush and denture stomatitis, whereas the unique clones in thrush (III, IV) might have been established through strain replacement or maintenance with minor genetic variation.

Adolescent↗
PubMed2004

Identifying uniformly mutated segments within repeats.

Given a long string of characters from a constant size alphabet we present an algorithm to determine whether its characters have been generated by a single i.i.d. random source. More specifically, consider all possible n-coin models for generating a binary string S, where each bit of S is generated via an independent toss of one of the n coins in the model. The choice of which coin to toss is decided by a random walk on the set of coins where the probability of a coin change is much lower than the probability of using the same coin repeatedly. We present a procedure to evaluate the likelihood of a n-coin model for given S, subject a uniform prior distribution over the parameters of the model (that represent mutation rates and probabilities of copying events). In the absence of detailed prior knowledge of these parameters, the algorithm can be used to determine whether the a posteriori probability for n=1 is higher than for any other n>1. Our algorithm runs in time O(l4logl), where l is the length of S, through a dynamic programming approach which exploits the assumed convexity of the a posteriori probability for n. Our test can be used in the analysis of long alignments between pairs of genomic sequences in a number of ways. For example, functional regions in genome sequences exhibit much lower mutation rates than non-functional regions. Because our test provides means for determining variations in the mutation rate, it may be used to distinguish functional regions from non-functional ones. Another application is in determining whether two highly similar, thus evolutionarily related, genome segments are the result of a single copy event or of a complex series of copy events. This is particularly an issue in evolutionary studies of genome regions rich with repeat segments (especially tandemly repeated segments).

Algorithms↗
PubMed1996

Genetic diversity among Mycobacterium avium complex AccuProbe-positive isolates.

The partial 32-kDa-protein gene sequences of 22 Mycobacterium avium complex (MAC) clinical isolates that were positive by the AccuProbe MAC probe only (not by the M. avium or M. intracellulare probe) were determined. The obtained nucleotide sequences were compared with the published sequences for M. tuberculosis, M. avium, and M. intracellulare by a sequence analysis program. There was a wide range of genetic diversity among the strains studied. Most of them (16 of 22) had sequences similar but not identical to those of M. avium and M. intracellulare. These strains were considered to be true MAC strains. Five strains had sequences in the category of the novel MAIX sequence, which was very different from the sequences of other mycobacteria analyzed thus far. In addition to these strains, one isolate had a sequence that differed greatly from the reference sequences. These results support previous findings showing that the MAC probably contains several additional species. Our results also suggest that the MAC AccuProbe may react with strains that do not belong to the MAC.

Bacterial Proteins↗
PubMed2004

Align-m--a new algorithm for multiple alignment of highly divergent sequences.

MOTIVATION: Multiple alignment of highly divergent sequences is a challenging problem for which available programs tend to show poor performance. Generally, this is due to a scoring function that does not describe biological reality accurately enough or a heuristic that cannot explore solution space efficiently enough. In this respect, we present a new program, Align-m, that uses a non-progressive local approach to guide a global alignment. RESULTS: Two large test sets were used that represent the entire SCOP classification and cover sequence similarities between 0 and 50% identity. Performance was compared with the publicly available algorithms ClustalW, T-Coffee and DiAlign. In general, Align-m has comparable or slightly higher accuracy in terms of correctly aligned residues, especially for distantly related sequences. Importantly, it aligns much fewer residues incorrectly, with average differences of over 15% compared with some of the other algorithms. AVAILABILITY: Align-m and the test sets are available at http://bioinformatics.vub.ac.be

Algorithms↗
PubMed2006

Comparative overview of current international strategies and guidelines for genetic toxicology testing for regulatory purposes.

National and international regulatory agencies historically have used genotoxicity information as part of a weight-of-evidence approach to evaluate potential human carcinogenicity. Additionally, some agencies consider heritable mutation a regulatory endpoint. Furthermore, genotoxicity has the potential to contribute to other adverse health conditions. This article provides a comparative overview of the testing strategies used by regulatory agencies throughout the world. Despite minor variations in details, the genotoxicity test schemes for most regulatory entities generally comprise three tests: a bacterial gene mutation assay, an in vitro mammalian cell assay for gene mutation and/or chromosome aberrations, and often an in vivo assay for chromosomal effects. In some cases, fewer than these three tests are required. In other cases, when exposure data, structure-activity considerations, or other factors warrant, even chemicals negative in the three baseline tests may be subject to additional testing. If genotoxicity is identified by the baseline screening tests, assessment of the ability of the chemical to interact with DNA in the gonad may be required. This may apply regardless of whether or not a cancer bioassay has been triggered. Mutagens positive in second stage gonadal assay(s) may be tested in third stage in vivo rodent tests to provide data for a quantitative risk assessment. In all testing, theutilization of internationally-recognized protocols, where they exist, is advisable, although not in all instances required. When testing for regulatory purposes, it is advisable to verify the testing program with the specific regulatory body or bodies responsible forregulatory oversight before beginning testing.

Government Regulation↗
PubMed2001

The Cooperative Familial Registry for Breast Cancer Studies: design and first year recruitment rates in Ontario.

The Ontario Familial Breast Cancer Registry (OFBCR) is one of six international sites of the Cooperative Familial Registry for Breast Cancer Studies collecting family history, epidemiologic information, and blood samples from families (with various patterns of familial risk) for the purpose of studying the etiology of breast cancer. To invite 2361 female breast cancer patients residing in Ontario to take part in the Registry, a package was sent that included a Family History Questionnaire. Several variations of mailing and follow-up strategies were employed. Overall, the response rate was 67%. The best response (74%) was achieved by following up our introductory package of information with a postcard 10 days later and a telephone call several weeks thereafter. Given the design of the project, which involves a considerable commitment on the part of both patients and their family members, we are impressed by the positive response of these women.

Breast Neoplasms↗