A comparison of mutation induction at the tk and hprt loci in human lymphoblastoid cells; quantitative differences are due to an additional class of mutations at the autosomal tk locus

X-Rays, ethyl methanesulfonate and ICR-191 induced 2 classes of trifluorothymidine-resistant mutants at the autosomal tk locus in human lymphoblastoid cells. These classes were differentiated by their growth rates; some mutants grew with a normal doubling time of 14-18 h (tk-NG), while others grew much more slowly, with doubling times of 21-44 h (tk-SG). Only mutants with normal growth rates were observed at the X-linked hprt locus; the frequencies of mutations induced at hprt were equal to those induced for tk-NG mutants. Thus, more mutations overall (by up to a factor of 6) were induced at tk than at hprt. These results are discussed in relation to recent studies in rodent cells, in which much greater mutation frequencies were observed at autosomal loci.     

Bias of maximum likelihood estimator of intraclass correlation

Summary A bias correction was derived for the maximum likelihood estimator (MLE) of the intraclass correlation. The bias consisted of two parts: a correction from MLE to the analysis of variance estimator (ANOVA) and the bias of ANOVA. The total possible bias was always negative and depended upon both the degree of correlation and the design size and balance. The first part of the bias was an exact algebraic expression from MLE to ANOVA, and the corrected estimator by this part was ANOVA. It was also shown that the first correction term was equivalent to Fisher's reciprocal bias correction on hisZ scores. The total possible bias of MLE was large for small and moderate samples. Relative biases were larger for small parametric values and vice versa. To ensure a relative bias less than 10% assuming an intraclass correlation of 0.025, which is not unusual in most of the animal genetic studies, the total number of observations (N) should be not less than 500. From a design point of view, minimum bias occurred atn = 2, the minimum family size possible, underN fixed.     

The cytologist and bacterioses of the vaginal-ectocervical area. Clues, commas and confusion

To evaluate the role of the cytologist in the diagnosis of bacterial vaginosis, the predominant bacterial patterns seen in 157 Papanicolaou-stained cervical smears were assessed and classified as large bacillus, anaerobic or scanty. A large bacillus pattern was found in 73 smears (46%), an anaerobic pattern in 77 (49%) and scanty bacteria in 7 (5%). Comma-shaped (curved) bacilli were found in 34 smears. The prevalence of clue cells in smears with anaerobic patterns was 73%. Gardnerella vaginalis was cultured from 89% of the cases with anaerobic-type smears containing clue cells and from 88% of those with anaerobic-type smears lacking clue cells. Mobiluncus sp. was cultured from 83% of the cases with anaerobic-type smears showing curved bacilli and 14% of those with anaerobic-type smears lacking curved bacilli. Papanicolaou-stained smears were found to be more sensitive and more specific for identifying clue cells than were wet preparations. A positive association was found between a positive KOH "whiff" test and the presence of curved bacilli on the Papanicolaou-stained smear. The clinical significance of these findings is discussed.     

Complete Genomic Sequence of the Human Retinoblastoma Susceptibility Gene

A 180,388-bp contig encompassing the human retinoblastoma gene was sequenced in its entirety. Partial analysis of the sequence revealed (1) a high (A + T)/(G + C) ratio and a high density of Line-1 (L1) repeat sequences, suggesting that the locus maps to G-bands 13q14.12 or 13q14.2; (2) Alu repeats that are asymmetrically oriented over a region extending 87 kb; (3) an overabundance of non-Alu-associated poly(A) tracts 10 bp or larger oriented in the antisense rather than the sense direction (36 vs 6); (4) an Alu sequence nested within an L1 repeat, indicating that the expansion of L1 repeats predates at least some of the Alu expansions; (5) at least three newly discovered microsatellite polymorphisms, one of which was subsequently found to be identical to a polymorphism in a microsatellite-based linkage map of the human genome published by another group; and (6) the basis of previously discovered intragenic RFLPs. This sequence should enhance studies of this locus and of the organization of the human genome.     

The dilemma of negative analysis of variance estimators of intraclass correlation

Summary At least two common practices exist when a negative variance component estimate is obtained, either setting it to zero or not reporting the estimate. The consequences of these practices are investigated in the context of the intraclass correlation estimation in terms of bias, variance and mean squared error (MSE). For the one-way analysis of variance random effects model and its extension to the common correlation model, we compare five estimators: analysis of variance (ANOVA), concentrated ANOVA, truncated ANOVA and two maximum likelihood-like (ML) estimators. For the balanced case, the exact bias and MSE are calculated via numerical integration of the exact sample distributions, while a Monte Carlo simulation study is conducted for the unbalanced case. The results indicate that the ANOVA estimator performs well except for designs with family size n = 2. The two ML estimators are generally poor, and the concentrated and truncated ANOVA estimators have some advantages over the ANOVA in terms of MSE. However, the large biases may make the concentrated and truncated ANOVA estimators objectionable when intraclass correlation () is small. Bias should be a concern when a pooled estimate is obtained from the literature since <0.05 in many genetic studies.     

Antimicrobial Functions of Lactoferrin Promote Genetic Conflicts in Ancient Primates and Modern Humans

Lactoferrin is a multifunctional mammalian immunity protein that limits microbial growth through sequestration of nutrient iron. Additionally, lactoferrin possesses cationic protein domains that directly bind and inhibit diverse microbes. The implications for these dual functions on lactoferrin evolution and genetic conflicts with microbes remain unclear. Here we show that lactoferrin has been subject to recurrent episodes of positive selection during primate divergence predominately at antimicrobial peptide surfaces consistent with long-term antagonism by bacteria. An abundant lactoferrin polymorphism in human populations and Neanderthals also exhibits signatures of positive selection across primates, linking ancient host-microbe conflicts to modern human genetic variation. Rapidly evolving sites in lactoferrin further correspond to molecular interfaces with opportunistic bacterial pathogens causing meningitis, pneumonia, and sepsis. Because microbes actively target lactoferrin to acquire iron, we propose that the emergence of antimicrobial activity provided a pivotal mechanism of adaptation sparking evolutionary conflicts via acquisition of new protein functions.     

Bayesian mapping of genomewide interacting quantitative trait loci for ordinal traits

Development of statistical methods and software for mapping interacting QTL has been the focus of much recent research. We previously developed a Bayesian model selection framework, based on the composite model space approach, for mapping multiple epistatic QTL affecting continuous traits. In this study we extend the composite model space approach to complex ordinal traits in experimental crosses. We jointly model main and epistatic effects of QTL and environmental factors on the basis of the ordinal probit model (also called threshold model) that assumes a latent continuous trait underlies the generation of the ordinal phenotypes through a set of unknown thresholds. A data augmentation approach is developed to jointly generate the latent data and the thresholds. The proposed ordinal probit model, combined with the composite model space framework for continuous traits, offers a convenient way for genomewide interacting QTL analysis of ordinal traits. We illustrate the proposed method by detecting new QTL and epistatic effects for an ordinal trait, dead fetuses, in a F(2) intercross of mice. Utility and flexibility of the method are also demonstrated using a simulated data set. Our method has been implemented in the freely available package R/qtlbim, which greatly facilitates the general usage of the Bayesian methodology for genomewide interacting QTL analysis for continuous, binary, and ordinal traits in experimental crosses.     

Nonparametric estimation of the effects of quantitative trait loci

Interval mapping of quantitative trait loci from breeding experiments plays an important role in understanding the mechanisms of disease, both in humans and other organisms. Standard approaches to estimation involve parametric assumptions for the component distributions and may be sensitive to model misspecification. Some nonparametric tests have been studied. However, nonparametric estimation of the phenotypic distributions has not been considered in the genetics literature, even though such methods might provide essential nonparametric summaries for comparing different loci. We develop a sufficient condition for identifiability of the phenotypic distributions. Simple nonparametric estimators for the distributions are proposed for uncensored and right censored data. They have a closed form and their small and large sample properties are readily established. Their practical utility as numerical summaries which complement nonparametric tests is demonstrated on two recent genetics examples.     

Identification of key concepts in biomedical literature using a modified Markov heuristic

MOTIVATION: The recent explosion of interest in mining the biomedical literature for associations between defined entities such as genes, diseases and drugs has made apparent the need for robust methods of identifying occurrences of these entities in biomedical text. Such concept-based indexing is strongly dependent on the availability of a comprehensive ontology or lexicon of biomedical terms. However, such ontologies are very difficult and expensive to construct, and often require extensive manual curation to render them suitable for use by automatic indexing programs. Furthermore, the use of statistically salient noun phrases as surrogates for curated terminology is not without difficulties, due to the lack of high-quality part-of-speech taggers specific to medical nomenclature. RESULTS: We describe a method of improving the quality of automatically extracted noun phrases by employing prior knowledge during the HMM training procedure for the tagger. This enhancement, when combined with appropriate training data, can greatly improve the quality and relevance of the extracted phrases, thereby enabling greater accuracy in downstream literature mining tasks.