基于结构域组合信息预测蛋白质相互作用

基于多个结构域联合作用导致蛋白质间相互作用的假设,提出了一种预测蛋白质间相互作用的新方法。使用支持向量机分析结构域组合对序列的氨基酸理化性质得到其序列特征值,同时采用统计分析的方法获取其频率特征值,最后通过融合上述两种特征估计该结构域组合间发生相互作用的可能性,并以此预测蛋白质间相互作用关系。该方法能够预测所有结构域组合间相互作用关系,且对于蛋白质相互作用关系有着较好的预测效果。     

DNA进化马尔可夫过程模型的评价与推广

本文对ＤＮＡ序列进化过程中核苷酸替代的随机模型进行了评价,对替代速率在时间和空间上不恒定的情形进行了考察和推广。Ｌａｎａｖｅ等（１９８４）曾提出一个模型,宣称对替代的模式未做任何假定,但事实上我们证明它假定替代过程是可逆的。运用２－ｐ、４－ｐ和６－ｐ模型进行的计算表明替代速度在位点间的差异会造成估计的替代数严重偏低,并且替代数越大,偏差也越大。替代模式在位点间的差异也会造成估计值偏低,但偏差不严重     

氨基酸的表面特性和溶剂化自由能

我们计算了氨基酸的溶剂可接近面积,局域偶极矩及表面电场.结果显示了亲、疏水基团与水相互作用具有不同的微观本质,由此提出了新的估计氨基酸溶剂化能的方法.     

遗传参数估计原理探讨——亲本间亲缘相关时的参数估计方法

本文通过对方差分析模型和相应的期望均方组成的分析,提出了用同胞资料估计遗传参数,当父本间、母本间及父母本间存在亲缘相关时的参数估计方法,并以实例阐明其应用方法。采用本文方法估计的遗传参数高于采用假定亲本间不相关时的常规估计方法的结果,亲本间相关越大,这种偏差也越大。计算机程序PARESTH、PARESTF为本方法推广应用提供了方便。此外,本文结论对一般的方差分析,在因素水平间相关程度能确定的情况下也是适用的。     

DNA序列进化过程中核苷酸替代的非独立性研究

本文评述了DNA序列间核苷酸替代数的估计方法,并通过对七个物种中组蛋白基因的比较对DNA进化的模型进行了考察。发现H2A基因第三位点上的碱基组成在物种间变异很大,并且跟H2A基因第一位点、H4基因第一、三位点及H2A上游,下游序列中的碱基组成有强正相关,提示DNA序列进化过程中存在着物种特异的区域性约束力。可能的原因是高等真核生物中GC含量升高,或者是染色体重组使这些同源序列位于不同的等质区段,从而受到不同的选择突变压。密码内各位点上核苷酸替代的相关性分析表明不同位点的替代是非独立的,其原因可能是一次替代事件引起多个位点的变化。文中讨论了这些结果对进化树推断的意义。     

前瞻研究中多因素人群归因危险度的Poisson回归模型估计

本文提出多因素前瞻研究中利用Poisson回归发病率预测模型和相对危险度估计调整和综合人群归因危险度的方法,与Bruzzi等和Deubner等提出的多因素人群归因危险度估计方法进行了比较,强调在前瞻资料的人群归因危险度的估计中利用poisson回归模型考虑失访病例和随访时间效应,并能直接估计相对危险度的优势.应用所建立的方法对启东县肝病人群14年前瞻观察资料进行肝癌危险因素的人群归因危险度的估计。     

利用单元内方差分析法估计遗传参数的探讨

在遗传力的估计过程中,需将多种非遗传因素的影响从公畜间方差或者母畜间方差中剔除。在我国常使用的是盛志廉教授提出的单元内同胞相关法。本文对该法从理论上进行了更详细的证明,并将其推广到两层分类方差分析时的情况。同时还给出了当公母畜彼此间有亲缘关系时,利用单元内方差分析估计遗传力的方法。这些方法既可使遗传力的估计简便,又具有多因方差分析的功用。     

一种基于数学期望的亲子与同胞相关系数的估计方法

本文在对亲本平方和、子代同胞间平方和、同胞内平方和与亲子间乘积和求数学期望的基础上,估计亲子与同胞相关系数,导出了两套不同的亲子与同胞相关系数的估计公式,其中之一与Srivastava（1984）提出的完全一致,但估计方法较之具有直接性,推导过程得到了简化．     

安徽省茶树品种与茶叶氨基酸遗传差异的对应分析

本文运用对应分析的方法对皖西和皖南种植的地方茶树品种与茶叶氨基酸遗传差异进行了研究,结果表明皖西品种必须氨基酸含量高于皖南品种.茶叶中17种游离氨基酸可用非必须氨基酸和必须氨基酸两个主因子来描述．对应分析可有效地同时揭示氨基酸间、品种间以及氨基酸与品种间的关系,茶叶氨基酸遗传差异与品种产地无必然联系．     

删失数据下的非参数分位回归

本文结合分位回归方法与非参数模型,对删失数据下的非参数分位回归模型的估计方法以及算法进行研究,运用质量再分配加权思想(Redistribution-of-Mass)将删失参数模型的估计方法推广到非参数领域,同时,出于充分利用数据信息的考虑,本文综合逆概率加权和质量再分配加权思想,在估计过程中采用这两类权数,提出了一种新的局部综合加权估计.通过蒙特卡洛模拟可知,在固定删失情形下,无论有无异方差存在,质量再分配加权估计有显著的优势;而在随机删失情形下,逆概率与质量再分配综合加权估计效果最好,进而验证了本文提出的估计方法的有效性和合理性.最后本文将各估计方法应用于实际数据中,实证分析的结果进一步展示了所提出估计方法的合理性.     

Freeing phylogenies from artifacts of alignment.

Widely used methods for phylogenetic inference, both those that require and those that produce alignments, share certain weaknesses. These weaknesses are discussed, and a method that lacks them is introduced. For each pair of sequences in the data set, the method utilizes both insertion-deletion and amino acid replacement information to estimate a pairwise evolutionary distance. It is also possible to allow regional heterogeneity of replacement rates. Because a likelihood framework is adopted, the standard deviation of each pairwise distance can be estimated. The distance matrix and standard error estimates are used to infer a phylogenetic tree. As an example, this method is used on 10 widely diverged sequences of the second largest RNA polymerase subunit. A pseudo-bootstrap technique is devised to assess the validity of the inferred phylogenetic tree.     

Models of amino acid substitution and applications to mitochondrial protein evolution

Models of amino acid substitution were developed and compared using maximum likelihood. Two kinds of models are considered. "Empirical" models do not explicitly consider factors that shape protein evolution, but attempt to summarize the substitution pattern from large quantities of real data. "Mechanistic" models are formulated at the codon level and separate mutational biases at the nucleotide level from selective constraints at the amino acid level. They account for features of sequence evolution, such as transition-transversion bias and base or codon frequency biases, and make use of physicochemical distances between amino acids to specify nonsynonymous substitution rates. A general approach is presented that transforms a Markov model of codon substitution into a model of amino acid replacement. Protein sequences from the entire mitochondrial genomes of 20 mammalian species were analyzed using different models. The mechanistic models were found to fit the data better than empirical models derived from large databases. Both the mutational distance between amino acids (determined by the genetic code and mutational biases such as the transition-transversion bias) and the physicochemical distance are found to have strong effects on amino acid substitution rates. A significant proportion of amino acid substitutions appeared to have involved more than one codon position, indicating that nucleotide substitutions at neighboring sites may be correlated. Rates of amino acid substitution were found to be highly variable among sites.      

Improved dating of the human/chimpanzee separation in the mitochondrial DNA tree: Heterogeneity among amino acid sites

The internal branch lengths estimated by distance methods such as neighbor joining are shown to be biased to be short when the evolutionary rate differs among sites. The variable-invariable model for site heterogeneity fits the amino acid sequence data encoded by the mitochondrial DNA from Hominoidea remarkably well. By assuming the orangutan separation to be 13 or 16 Myr old, a maximum-likelihood analysis estimates a young date of 3.6 ± 0.6 or 4.4 ± 0.7 Myr (±1 SE) for the human/chimpanzee separation, and these estimates turn out to be robust against differences in the assumed model for amino acid substitutions. Although some uncertainties still exist in our estimates, this analysis suggests that humans separated from chimpanzees some 4–5 Myr ago.Correspondence to: M. Hasewaga     

Structure-Activity relationship in mutated pyrazinamidases from Mycobacterium tuberculosis

The pncA gene codes the pyrazinamidase of Mycobacterium tuberculosis, which converts pyrazinamide to ammonia and pyrazinoic-acid, the active antituberculous compound. Pyrazinamidase mutations are associated to pyrazinamide-resistant phenotype, however how mutations affect the structure of the pyrazinamidase, and how structural changes affect the enzymatic function and the level of pyrazinamide-resistance is unknown. The structures of mutated pyrazinamidases from twelve Mycobacterium tuberculosis strains and the pyrazinamide-susceptible H37Rv reference strain were modelled using homology modelling and single amino acid replacement. Physical-chemical and structural parameters of each pyrazinamidase were calculated. These parameters were: The change of electrical charge of the mutated amino acid, the change of volume of the mutated amino acid, the change of a special amino acid, the distance of the mutated amino acid to the active site, the distance of the mutated amino acid to the metal-coordination site, and the orientation of the side-chain of the mutated amino acid. The variability of the enzymatic activity of the recombinant pyrazinamidases, and the microbiological susceptibility to pyrazinamide determined by BACTEC 460TB, were modelled in multiple linear regressions. Physical-chemical and structural parameters of the mutated pyrazinamidases were tested as predictors. Structural and physical-chemical variations of the pyrazinamidase explained 75% of the variability of the enzymatic activity, 87% of the variability of the kinetic constant and 40% of the variability of the pyrazinamide-resistance level. Based on computer models of mutated pyrazinamidases, the structural parameters explained a high variability of the enzymatic function, and to a lesser extent the resistance level.     

Disentangling the perturbational effects of amino acid substitutions in the DNA-binding domain of p53

The spectrum of somatic cancer-associated missense mutations in the human TP53 gene was studied in order to assess the potential structural and functional importance of various intra-molecular properties associated with these substitutions. Relating the observed frequency of particular amino acid substitutions in the p53 DNA-binding domain to their expected frequency, as calculated from DNA sequence-dependent mutation rates, yielded estimates of their relative clinical observation likelihood (RCOL). Several biophysical properties were found to display significant covariation with RCOL values. Thus RCOL values were observed to decrease with increasing solvent accessibility of the substituted residue and with increasing distance from the p53 DNA-binding and Zn²⁺-binding sites. The number of adverse steric interactions introduced by an amino acid replacement was found to be positively correlated with its RCOL value, irrespective of the magnitude of the interactions. A gain in hydrogen bond number was found to be only half as likely to come to clinical attention as mutations involving either a reduction or no change in hydrogen bond number. When the difference in potential energy between the wild-type and mutant DNA-binding domains was considered, RCOL values exhibited a minimum around changes of zero. Finally, classification of mutated residues in terms of their protein/solvent environment yielded, for somatic p53 mutations, RCOL values that resembled those previously determined for inherited mutations of human factor IX causing haemophilia B, suggesting that similar mechanisms may be responsible for the mutation-related perturbation of biological function in different protein folds. Received: 31 August 1998 / Accepted: 26 October 1998     

A covarion-based method for detecting molecular adaptation: application to the evolution of primate mitochondrial genomes

A new method for detecting site-specific variation of evolutionary rate (the so-called covarion process) from protein sequence data is proposed. It involves comparing the maximum-likelihood estimates of the replacement rate of an amino acid site in distinct subtrees of a large tree. This approach allows detection of covarion at the gene or the amino acid levels. The method is applied to mammalian-mitochondrial-protein sequences. Significant covarion-like evolution is found in the (simian) primate lineage: some amino acid positions are fast-evolving (i.e. unconstrained) in non-primate mammals but slow-evolving (i.e. highly constrained) in primates, and some show the opposite pattern. Our results indicate that the mitochondrial genome of primates reached a new peak of the adaptive landscape through positive selection.     

A Field Evaluation of Distance Measurement Error in Auditory Avian Point Count Surveys

ABSTRACT Detection distance is an important and common auxiliary variable measured during avian point count surveys. Distance data are used to determine the area sampled and to model the detection process using distance sampling theory. In densely forested habitats, visual detections of birds are rare, and most estimates of detection distance are based on auditory cues. Distance sampling theory assumes detection distances are measured accurately, but empirical validation of this assumption for auditory detections is lacking. We used a song playback system to simulate avian point counts with known distances in a forested habitat to determine the error structure of distance estimates based on auditory detections. We conducted field evaluations with 6 experienced observers both before and after distance estimation training. We conducted additional studies to determine the effect of height and speaker orientation (toward or away from observers) on distance estimation error. Distance estimation errors for all evaluations were substantial, although training reduced errors and bias in distance estimates by approximately 15%. Measurement errors showed a nonlinear relationship to distance. Our results suggest observers were not able to differentiate distances beyond 65 m. The height from which we played songs had no effect on distance estimation errors in this habitat. The orientation of the song source did have a large effect on distance estimation errors; observers generally doubled their distance estimates for songs played away from them compared with distance estimates for songs played directly toward them. These findings, which we based on realistic field conditions, suggest measures of uncertainty in distance estimates to auditory detections are substantially higher than assumed by most researchers. This means aural point count estimates of avian abundance based on distance methods deserve careful scrutiny because they are likely biased.     

A common channel-forming motif in evolutionarily distant porins.

Four new crystal packings of Escherichia coli porins are presented (phosphoporin, maltoporin, and two crystal forms of matrix porin). These were determined by molecular replacement methods using a polyalanine trial model acquired from the refined coordinates of porin from Rhodobacter capsulatus. The successful molecular replacement shows that the dominant motif found in R. capsulatus porin (a 16-stranded antiparallel beta-barrel) also applies to the E. coli porins, despite the lack of significant amino acid sequence homology. A 30 degrees-40 degrees tilt of the beta-strands with respect to the membrane normal was derived from the intensity distributions in the X-ray diffraction patterns for each porin studied, stressing their similarity. In view of the evolutionary distance between enteric and photosynthetic bacteria, the antiparallel beta-barrel may have significance as a basic structural motif for the formation of bacterial membrane channel structures.     

Effects of ambient noise on detectability and localization of avian songs and tones by observers in grasslands

Probability of detection and accuracy of distance estimates in aural avian surveys may be affected by the presence of anthropogenic noise, and this may lead to inaccurate evaluations of the effects of noisy infrastructure on wildlife. We used arrays of speakers broadcasting recordings of grassland bird songs and pure tones to assess the probability of detection, and localization accuracy, by observers at sites with and without noisy oil and gas infrastructure in south‐central Alberta from 2012 to 2014. Probability of detection varied with species and with speaker distance from transect line, but there were few effects of noisy infrastructure. Accuracy of distance estimates for songs and tones decreased as distance to observer increased, and distance estimation error was higher for tones at sites with infrastructure noise. Our results suggest that quiet to moderately loud anthropogenic noise may not mask detection of bird songs; however, errors in distance estimates during aural surveys may lead to inaccurate estimates of avian densities calculated using distance sampling. We recommend caution when applying distance sampling if most birds are unseen, and where ambient noise varies among treatments.