Evolutionary Rate and Genetic Heterogeneity of Human T-Cell Lymphotropic Virus Type II (HTLV-II) Using Isolates from European Injecting Drug Users

Seven new Italian and two new British HTLV-II isolates were obtained from injecting drug users and the entire long terminal repeat (LTR) region was sequenced. Restriction analysis showed that all the Italian isolates are of the IIb subtype, whereas the British isolates are of the IIa subtype. To understand whether the further differentiation of each two principal HTLV-II subtypes in several subgroups could be statistically supported by phylogenetic analysis, the neighbor-joining, parsimony, and maximum likelihood methods were used. The separation between IIa and IIb is very well supported by all three methods. At least two phylogenetic subgroups exist within the HTLV-IIa and at least three within the HTLV-IIb subtype. In the present analysis, no statistical support was obtained for additional phylogroups. Two particular subgroups seem interesting because they include all European and North American injecting drug user strains within the IIa and IIb subtypes, respectively. These data confirm that European HTLV-II infection among drug users is probably derived from North America. They also suggest that though a certain differentiation by restriction analysis in different subgroups is possible, carefully interpreted phylogenetic analyses remain necessary. Using the likelihood ratio test, a molecular clock for the drug user strains was calibrated. A fixation rate between 1.08 × 10⁻⁴ and 2.7 × 10⁻⁵ nucleotide substitutions per site per year was calculated for the IIa and IIb injecting drug user strains. This is the lowest fixation rate so far reported for RNA viruses, including for HIV, which typically range between 10⁻² and 10⁻⁴.     

Fitting genetic mapping functions based on sperm typing: results for three chromosomal segments in cattle

Genetic mapping functions translate the observed recombination rate between two loci into the corresponding map distance in Morgan units. Different mapping functions give different weights to multiple crossing overs and therefore lead to different results. This points out that not every function is best suited to fit a data set. The data used in this study originated from 2214 sperm from 37 Norwegian bulls, which were genotyped for 11 markers. The optimal functions for the chromosomes 6, 23 and the sex chromosome of cattle were derived using the maximum likelihood method, the likelihood ratio test and empirical discriminant analysis. It became apparent that for each chromosome a different function fitted the data best. These were the function of Rao et al. (Human Heredity 1977, 27, 99–104) with p = 0·63 for chromosome 6, the function of Goldgar & Fain (American Journal of Human Genetics 1988, 43, 38–45) with c₀ = 0·42, c₁ = 0·47, c₂ = 0·07 and c₃ = 0·04 for chromosome 23 and the function of Felsenstein (Genetics 1979, 91, 769–75) with K = 0·23 for the sex chromosome. The well known functions of Haldane (Journal of Genetics 1919, 8, 299–309) and Kosambi (Annals of Eugenics 1944, 12, 172–5) were shown to be suboptimal in most cases. A function is said to be multilocus feasible if the evaluation of the probability of all possible recombination events does not lead to negative values. The optimal function for chromosome 23 turned out to be multilocus feasible, whereas the functions for chromosome 6 and the sex chromosome were not. The choice of the correct mapping function is shown to have a considerable impact in mapping studies, when double recombinations have to be taken into account. Since there is no unique best mapping function, it is argued that it might be useful to use a simple parametric mapping function (like the one of Felsenstein 1979) and to estimate the respective parameter specifically for a given data set.     

Environmental change and the phenology of European aphids

Aphids, because of their short generation time and low developmental threshold temperatures, are an insect group expected to respond particularly strongly to environmental changes. Forty years of standardized, daily data on the abundance of flying aphids have been brought together from countries throughout Europe, through the EU Thematic Network 'EXAMINE'. Relationships between phenology, represented by date of first appearance in a year in a suction trap, of 29 aphid species and environmental data have been quantified using the residual maximum likelihood (REML) methodology. These relationships have been used with climate change scenario data to suggest plausible changes in aphid phenology. In general, the date of first record of aphid species in suction traps is expected to advance, the rate of advance varying with location and species, but averaging 8 days over the next 50 years. Strong relationships between aphid phenology and environmental variables have been found for many species, but they are notably weaker in species living all year on trees. Canonical variate analysis and principal coordinate analysis were used to determine ordinations of the 29 species on the basis of the presence/absence of explanatory variables in the REML models. There was strong discrimination between species with different life cycle strategies and between species feeding on herbs and trees, suggesting the possible value of trait-based groupings in predicting responses to environmental changes.     

肿瘤表达谱基因芯片数据的混合效应模型分析

目的:研究混合效应模型(Mixed Effects Model)在肿瘤表达谱基因芯片数据分析中的检验效能,并探讨其分析效果。方法:采用混合效应模型分析肿瘤实例基因芯片数据,并以基因集富集分析方法(GSEA)作为参照比较分析结果的有效性和科学性,探讨其检验效果。结果:通过混合效应模型和基因集富集分析(GSEA)两种方法对肿瘤基因芯片数据的分析和比较,两种方法筛选出共同的差异表达通路外,混合效应模型额外地筛选出来GSEA未能检验到的8条差异表达通路,且得到文献支持;混和效应模型筛选出的前10个差异表达通路中有6个已有生物学证明而基因集富集分析方法(GSEA)筛选出的前10个差异表达通路中仅有4个已有生物学证明。结论:混合效应模型作为top-down方法中的典型代表,其优势在于通过构建潜变量达到降维目的,可有效地减少多个复杂的变异来源从而保证了结果的准确性和科学性,其检验效能优于基因集富集分析方法(GSEA),是一种行之有效的筛选肿瘤基因芯片数据的分析方法。     

Gene-Flow in a Mosaic Hybrid Zone: Is Local Introgression Adaptive?

Genome-wide scans of genetic differentiation between hybridizing taxa can identify genome regions with unusual rates of introgression. Regions of high differentiation might represent barriers to gene flow, while regions of low differentiation might indicate adaptive introgression—the spread of selectively beneficial alleles between reproductively isolated genetic backgrounds. Here we conduct a scan for unusual patterns of differentiation in a mosaic hybrid zone between two mussel species, Mytilus edulis and M. galloprovincialis. One outlying locus, mac-1, showed a characteristic footprint of local introgression, with abnormally high frequency of edulis-derived alleles in a patch of M. galloprovincialis enclosed within the mosaic zone, but low frequencies outside of the zone. Further analysis of DNA sequences showed that almost all of the edulis allelic diversity had introgressed into the M. galloprovincialis background in this patch. We then used a variety of approaches to test the hypothesis that there had been adaptive introgression at mac-1. Simulations and model fitting with maximum-likelihood and approximate Bayesian computation approaches suggested that adaptive introgression could generate a “soft sweep,” which was qualitatively consistent with our data. Although the migration rate required was high, it was compatible with the functioning of an effective barrier to gene flow as revealed by demographic inferences. As such, adaptive introgression could explain both the reduced intraspecific differentiation around mac-1 and the high diversity of introgressed alleles, although a localized change in barrier strength may also be invoked. Together, our results emphasize the need to account for the complex history of secondary contacts in interpreting outlier loci.     

A Penalized-Likelihood Method to Estimate the Distribution of Selection Coefficients from Phylogenetic Data

We develop a maximum penalized-likelihood (MPL) method to estimate the fitnesses of amino acids and the distribution of selection coefficients (S = 2Ns) in protein-coding genes from phylogenetic data. This improves on a previous maximum-likelihood method. Various penalty functions are used to penalize extreme estimates of the fitnesses, thus correcting overfitting by the previous method. Using a combination of computer simulation and real data analysis, we evaluate the effect of the various penalties on the estimation of the fitnesses and the distribution of S. We show the new method regularizes the estimates of the fitnesses for small, relatively uninformative data sets, but it can still recover the large proportion of deleterious mutations when present in simulated data. Computer simulations indicate that as the number of taxa in the phylogeny or the level of sequence divergence increases, the distribution of S can be more accurately estimated. Furthermore, the strength of the penalty can be varied to study how informative a particular data set is about the distribution of S. We analyze three protein-coding genes (the chloroplast rubisco protein, mammal mitochondrial proteins, and an influenza virus polymerase) and show the new method recovers a large proportion of deleterious mutations in these data, even under strong penalties, confirming the distribution of S is bimodal in these real data. We recommend the use of the new MPL approach for the estimation of the distribution of S in species phylogenies of protein-coding genes.     

A phylogeny of Vetigastropoda and other “archaeogastropods”: re-organizing old gastropod clades

Abstract. The phylogenetic relationships among the “archaeogastropod” clades Patellogastropoda, Vetigastropoda, Neritimorpha, and Neomphalina are uncertain; the phylogenetic placement of these clades varies across different analyses, and particularly among those using morphological characteristics and those relying on molecular data. This study explores the relationships among these groups using a combined analysis with seven molecular loci (18S rRNA, 28S rRNA, histone H3, 16S rRNA, cytochrome c oxidase subunit I [COI], myosin heavy-chain type II, and elongation factor-1α [EF-1α]) sequenced for 31 ingroup taxa and eight outgroup taxa. The deep evolutionary splits among these groups have made resolution of stable relationships difficult, and so EF-1α and myosin are used in an attempt to re-examine these ancient radiation events. Three phylogenetic analyses were performed utilizing all seven genes: a single-step direct optimization analysis using parsimony, and two-step approaches using parsimony and maximum likelihood. A single-step direct optimization parsimony analysis was also performed using only five molecular loci (18S rRNA, 28S rRNA, histone H3, 16S rRNA, and COI) in order to determine the utility of EF-1α and myosin in resolving deep relationships. In the likelihood and POY optimal phylogenetic analyses, Gastropoda, Caenogastropoda, Neritimorpha, Neomphalina, and Patellogastropoda were monophyletic. Additionally, Neomphalina and Pleurotomariidae fell outside the remaining vetigastropods, indicating the need for further investigation into the relationship of these groups with other gastropods.     

Nonignorable Models for Intermittently Missing Categorical Longitudinal Responses

Summary A class of nonignorable models is presented for handling nonmonotone missingness in categorical longitudinal responses. This class of models includes the traditional selection models and shared parameter models. This allows us to perform a broader than usual sensitivity analysis. In particular, instead of considering variations to a chosen nonignorable model, we study sensitivity between different missing data frameworks. An appealing feature of the developed class is that parameters with a marginal interpretation are obtained, while algebraically simple models are considered. Specifically, marginalized mixed‐effects models ( Heagerty, 1999 , Biometrics 55, 688–698) are used for the longitudinal process that model separately the marginal mean and the correlation structure. For the correlation structure, random effects are introduced and their distribution is modeled either parametrically or non‐parametrically to avoid potential misspecifications.     

Saddlepoint Approximations to the Moments of Multitype Age‐Dependent Branching Processes,with Applications

Summary This article proposes saddlepoint approximations to the expectation and variance–covariance function of multitype age‐dependent branching processes. The proposed approximations are found accurate, easy to implement, and much faster to compute than by simulating the process. Multiple applications are presented, including the analyses of clonal data on the generation of oligodendrocytes from their immediate progenitor cells, and on the proliferation of Hela cells. New estimators are also constructed to analyze clonal data. The proposed methods are finally used to approximate the distribution of the generation, which has recently found several applications in cell biology.