Selection for Increased Mutation Rates with Fertility Differences between Matings

Previous studies of mutation modification have considered models in which selection is a result of viability differences that are sex symmetric. The results of a numerical study of a model in which selection is a result of fertility differences between mated pairs demonstrate that the type of selection to which a population is subject can have a significant impact on the evolution of various parameters of the genetic system. When the fertility of matings between individuals with different genotypes exceeds the fertility of at least some of the matings between individuals with the same genotype, selection may favor increased rates of mutation, in contrast to the results from all existing constant viability models with random mating and infinite population size. Increased mutation rates are most frequently favored when forward and back mutation occur at approximately equal rates and when the modifying locus is loosely linked to the selected locus. We present one example in which selection favors increased rates of mutation even though the selection scheme is reducible to one of differential viability between the sexes.     

Selection for High Mutation Rates in Chemostats

Complementation and polarity suppression data are interpreted in terms of the genetic structure of the maltose B region. It is proposed that this region comprises two divergent operons. One operon includes malK, a cistron involved in maltose permeation, and lamB the only known cistron specifically involved in lambda receptor synthesis. The other operon includes malJ(1) and malJ(2) which are most probably two different cistrons, both involved in maltose permeation*. It is further assumed that expression of the two operons is controlled by malT, the positive regulatory gene of the maltose system, located in the malA region. The target(s) for the action of the malT product is (are) most likely to be located between malJ(1) and malK. There is an indication that the two operons might overlap in the region of their promoters. The structure of such an overlap as well as the possible function of the products of the different cistrons in malB are briefly discussed.     

An Eighteen Serum Cytokine Signature for Discriminating Glioma from Normal Healthy Individuals

Glioblastomas (GBM) are largely incurable as they diffusely infiltrate adjacent brain tissues and are difficult to diagnose at early stages. Biomarkers derived from serum, which can be obtained by minimally invasive procedures, may help in early diagnosis, prognosis and treatment monitoring. To develop a serum cytokine signature, we profiled 48 cytokines in sera derived from normal healthy individuals (n = 26) and different grades of glioma patients (n = 194). We divided the normal and grade IV glioma/GBM serum samples randomly into equal sized training and test sets. In the training set, the Prediction Analysis for Microarrays (PAM) identified a panel of 18 cytokines that could discriminate GBM sera from normal sera with maximum accuracy (95.40%) and minimum error (4.60%). The 18-cytokine signature obtained in the training set discriminated GBM sera from normal sera in the test set as well (accuracy 96.55%; error 3.45%). Interestingly, the 18-cytokine signature also differentiated grade II/Diffuse Astrocytoma (DA) and grade III/Anaplastic Astrocytoma (AA) sera from normal sera very efficiently (DA vs. normal–accuracy 96.00%, error 4.00%; AA vs. normal–accuracy 95.83%, error 4.17%). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using 18 cytokines resulted in the enrichment of two pathways, cytokine-cytokine receptor interaction and JAK-STAT pathways with high significance. Thus our study identified an 18-cytokine signature for distinguishing glioma sera from normal healthy individual sera and also demonstrated the importance of their differential abundance in glioma biology.     

Comparison of Substitution Rates in ZFX and ZFY Introns of Sheep and Goat Related Species Supports the Hypothesis of Male-Biased Mutation Rates

There is a growing body of evidence that males serve as the major generators of mutations, due to the larger number of cell divisions involved in sperm compared to egg production. In mammals, this hypothesis (referred to as ``male-driven evolution') has been tested by comparison of nucleotide substitution rates on the X and Y sex chromosomes in a limited number of taxa, predominantly primates and rodents. This study asks whether male-driven evolution is a more general phenomenon among mammals, by comparison of paralogous ZFX and ZFY intron sequences in sheep and goat species (the tribe Caprini). The male-to-female mutation ratio, α_m, was estimated to be between 2.93 (95% CI, 1.51–8.61) and 3.94 (95% CI, 1.25–32.29) when calculated using pairwise distance and branch length, respectively, suggesting that the Caprini are subject to weak, male-driven evolution. Comparison to published values for primates, felids, and rodents implies that there may be some correlation with reproductive life span. However, this is difficult to test with current data because confidence intervals are large and overlapping. Nonindependent evolution of paralogous sequences and/or the presence of selective constraints could lead to inaccurate estimates of α_m. No evidence for gene conversion between the ZFX and the ZFY introns was found, and this suggests that they have evolved independently during the radiation of the Caprini. Finally, there was no apparent evidence that these introns are subject to selective constraints, although low levels of intraspecific polymorphism reduce the power of neutrality tests. Received: 13 February 2001 / Accepted: 23 May 2001     

Statistical Methods for Analyzing Drosophila Germline Mutation Rates

Most studies of mutation rates implicitly assume that they remain constant throughout development of the germline. However, researchers recently used a novel statistical framework to reveal that mutation rates differ dramatically during sperm development in Drosophila melanogaster. Here a general framework is described for the inference of germline mutation patterns, generated from either mutation screening experiments or DNA sequence polymorphism data, that enables analysis of more than two mutations per family. The inference is made more rigorous and flexible by providing a better approximation of the probabilities of patterns of mutations and an improved coalescent algorithm within a single host with realistic assumptions. The properties of the inference framework, both the estimation and the hypothesis testing, were investigated by simulation. The refined inference framework is shown to provide (1) nearly unbiased maximum-likelihood estimates of mutation rates and (2) robust hypothesis testing using the standard asymptotic distribution of the likelihood-ratio tests. It is readily applicable to data sets in which multiple mutations in the same family are common.     

Equilibrium between Genetic Drift and Migration at Various Mutation Rates: Simulation Analysis

Rates of approach to equilibrium values of F _ST /R _ST at various mutation rates and using different mutation models (K-allele model KAM and stepwise model SMM) were analyzed numerically for the finite island model and the one-dimensional stepping stone models of migration, using simulation. In the island model of migration and the KAM mutation model, the rate of approach to the equilibrium F _ST value was appreciably higher and the equilibrium value was almost twofold lower at μ (mutation rate) = m (migration rate) than at μ ≪ m. In the one-dimensional stepping stone model of migration and the KAM model of mutation, the mutation rate significantly affected both the rate of approaching F _ST equilibrium and the equilibrium value. In both island and one-dimensional stepping stone models and SMM, R _ST was not influenced by various mutation rates. The rate of approach to the equilibrium values of both F _ST and R _ST was lower for the stepping stone model than to the island model. R _ST was rather resistant to deviations from the SMM mutation model. __________ Translated from Genetika, Vol. 41, No. 9, 2005, pp. 1283–1288. Original Russian Text Copyright ? 2005 by Efremov.     

线粒体DNA突变相关疾病的基因治疗

mtDNA是动物细胞染色体外唯一存在的遗传物质,mtDNA突变相关疾病正越来越为人们所认识,但目前尚无有效的治疗手段。应用亲脂质阳离子,构建靶向线粒体PNA,转线粒体移植手段。以及构建mtDNA样质粒,都可能是今后的研究方向。     

Variation in Heterozygosity Predicts Variation in Human Substitution Rates between Populations,Individuals and Genomic Regions

The “heterozygote instability” (HI) hypothesis suggests that gene conversion events focused on heterozygous sites during meiosis locally increase the mutation rate, but this hypothesis remains largely untested. As humans left Africa they lost variability, which, if HI operates, should have reduced the mutation rate in non-Africans. Relative substitution rates were quantified in diverse humans using aligned whole genome sequences from the 1,000 genomes project. Substitution rate is consistently greater in Africans than in non-Africans, but only in diploid regions of the genome, consistent with a role for heterozygosity. Analysing the same data partitioned into a series of non-overlapping 2 Mb windows reveals a strong, non-linear correlation between the amount of heterozygosity lost “out of Africa” and the difference in substitution rate between Africans and non-Africans. Putative recent mutations, derived variants that occur only once among the 80 human chromosomes sampled, occur preferentially at the centre of 2 Kb windows that have elevated heterozygosity compared both with the same region in a closely related population and with an immediately adjacent region in the same population. More than half of all substitutions appear attributable to variation in heterozygosity. This observation provides strong support for HI with implications for many branches of evolutionary biology.     

Purifying Selection,Drift, and Reversible Mutation with Arbitrarily High Mutation Rates

Some species exhibit very high levels of DNA sequence variability; there is also evidence for the existence of heritable epigenetic variants that experience state changes at a much higher rate than sequence variants. In both cases, the resulting high diversity levels within a population (hyperdiversity) mean that standard population genetics methods are not trustworthy. We analyze a population genetics model that incorporates purifying selection, reversible mutations, and genetic drift, assuming a stationary population size. We derive analytical results for both population parameters and sample statistics and discuss their implications for studies of natural genetic and epigenetic variation. In particular, we find that (1) many more intermediate-frequency variants are expected than under standard models, even with moderately strong purifying selection, and (2) rates of evolution under purifying selection may be close to, or even exceed, neutral rates. These findings are related to empirical studies of sequence and epigenetic variation.     

A Unified Approach to Genotype Imputation and Haplotype-Phase Inference for Large Data Sets of Trios and Unrelated Individuals

We present methods for imputing data for ungenotyped markers and for inferring haplotype phase in large data sets of unrelated individuals and parent-offspring trios. Our methods make use of known haplotype phase when it is available, and our methods are computationally efficient so that the full information in large reference panels with thousands of individuals is utilized. We demonstrate that substantial gains in imputation accuracy accrue with increasingly large reference panel sizes, particularly when imputing low-frequency variants, and that unphased reference panels can provide highly accurate genotype imputation. We place our methodology in a unified framework that enables the simultaneous use of unphased and phased data from trios and unrelated individuals in a single analysis. For unrelated individuals, our imputation methods produce well-calibrated posterior genotype probabilities and highly accurate allele-frequency estimates. For trios, our haplotype-inference method is four orders of magnitude faster than the gold-standard PHASE program and has excellent accuracy. Our methods enable genotype imputation to be performed with unphased trio or unrelated reference panels, thus accounting for haplotype-phase uncertainty in the reference panel. We present a useful measure of imputation accuracy, allelic R², and show that this measure can be estimated accurately from posterior genotype probabilities. Our methods are implemented in version 3.0 of the BEAGLE software package.     

An Evolutionary Reduction Principle for Mutation Rates at Multiple Loci

A model of mutation rate evolution for multiple loci under arbitrary selection is analyzed. Results are obtained using techniques from Karlin (Evolutionary Biology, vol. 14, pp. 61–204, 1982) that overcome the weak selection constraints needed for tractability in prior studies of multilocus event models.     

Using USP I and USP IV for Discriminating Dissolution Rates of Nano- and Microparticle-Loaded Pharmaceutical Strip-Films

Recent interest in the development of drug particle-laden strip-films suggests the need for establishing standard regulatory tests for their dissolution. In this work, we consider the dissolution testing of griseofulvin (GF) particles, a poorly water-soluble compound, incorporated into a strip-film dosage form. The basket apparatus (USP I) and the flow-through cell dissolution apparatus (USP IV) were employed using 0.54% sodium dodecyl sulfate as the dissolution medium as per USP standard. Different rotational speeds and dissolution volumes were tested for the basket method while different cell patterns/strip-film position and dissolution media flow rate were tested using the flow-through cell dissolution method. The USP I was not able to discriminate dissolution of GF particles with respect to particle size. On the other hand, in the USP IV, GF nanoparticles incorporated in strip-films exhibited enhancement in dissolution rates and dissolution extent compared with GF microparticles incorporated in strip-films. Within the range of patterns and flow rates used, the optimal discrimination behavior was obtained when the strip-film was layered between glass beads and a flow rate of 16 ml/min was used. These results demonstrate the superior discriminatory power of the USP IV and suggest that it could be employed as a testing device in the development of strip-films containing drug nanoparticles.Key Words: BCS class II, dissolution, drug nanoparticles, flow-through cell, pharmaceutical strip-films     

The Association between Aids Related Stigma and Major Depressive Disorder among HIV-Positive Individuals in Uganda

Background

Major depressive disorder in people living with HIV/AIDS (PLWHA) is common and may be associated with a number of factors, including AIDS-related stigma, decreased CD4 levels, increased opportunistic infections and sociodemographic variables. The extent to which AIDS-related stigma is associated with major depressive disorder among PLWHA has not been well studied in sub-Saharan Africa. The objective of this study was to examine the associations between major depressive disorder, AIDS-related stigma, immune status, and sociodemographic variables with the aim of making recommendations that can guide clinicians.

Methods

We assessed 368 PLWHA for major depressive disorder, as well as for potentially associated factors, including AIDS-related stigma, CD4 levels, presence of opportunistic infections, and sociodemographic variables.

Results

The prevalence of major depressive disorder was 17.4%, while 7.9% of the participants had AIDS related stigma. At multivariable analysis, major depressive disorder was significantly associated with AIDS-related stigma [OR = 1.65, CI (1.20–2.26)], a CD4 count of ≥200 [OR 0.52 CI (0.27–0.99)], and being of younger age [0.95, CI (0.92–0.98).

Conclusions

Due to the high burden of major depressive disorder, and its association with AIDS related stigma, routine screening of PLWHA for both conditions is recommended. However, more research is required to understand this association.     

Genome-Wide Copy Number Variation Analysis in Extended Families and Unrelated Individuals Characterized for Musical Aptitude and Creativity in Music

Music perception and practice represent complex cognitive functions of the human brain. Recently, evidence for the molecular genetic background of music related phenotypes has been obtained. In order to further elucidate the molecular background of musical phenotypes we analyzed genome wide copy number variations (CNVs) in five extended pedigrees and in 172 unrelated subjects characterized for musical aptitude and creative functions in music. Musical aptitude was defined by combination of the scores of three music tests (COMB scores): auditory structuring ability, Seashores test for pitch and for time. Data on creativity in music (herein composing, improvising and/or arranging music) was surveyed using a web-based questionnaire.Several CNVRs containing genes that affect neurodevelopment, learning and memory were detected. A deletion at 5q31.1 covering the protocadherin-α gene cluster (Pcdha 1-9) was found co-segregating with low music test scores (COMB) in both sample sets. Pcdha is involved in neural migration, differentiation and synaptogenesis. Creativity in music was found to co-segregate with a duplication covering glucose mutarotase gene (GALM) at 2p22. GALM has influence on serotonin release and membrane trafficking of the human serotonin transporter. Interestingly, genes related to serotonergic systems have been shown to associate not only with psychiatric disorders but also with creativity and music perception. Both, Pcdha and GALM, are related to the serotonergic systems influencing cognitive and motor functions, important for music perception and practice. Finally, a 1.3 Mb duplication was identified in a subject with low COMB scores in the region previously linked with absolute pitch (AP) at 8q24. No differences in the CNV burden was detected among the high/low music test scores or creative/non-creative groups. In summary, CNVs and genes found in this study are related to cognitive functions. Our result suggests new candidate genes for music perception related traits and supports the previous results from AP study.     

Bayesian Procedures for the Estimation of Mutation Rates from Fluctuation Experiments

Bayesian procedures are developed for estimating mutation rates from fluctuation experiments. Three Bayesian point estimators are compared with four traditional ones using the results of 10,000 simulated experiments. The Bayesian estimators were found to be at least as efficient as the best of the previously known estimators. The best Bayesian estimator is one that uses (1/m(2)) as the prior probability density function and a quadratic loss function. The advantage of using these estimators is most pronounced when the number of fluctuation test tubes is small. Bayesian estimation allows the incorporation of prior knowledge about the estimated parameter, in which case the resulting estimators are the most efficient. It enables the straightforward construction of confidence intervals for the estimated parameter. The increase of efficiency with prior information and the narrowing of the confidence intervals with additional experimental results are investigated. The results of the simulations show that any potential inaccuracy of estimation arising from lumping together all cultures with more than n mutants (the jackpots) almost disappears at n = 70 (provided that the number of mutations in a culture is low). These methods are applied to a set of experimental data to illustrate their use.     

The MBLOSUM: A Server for Deriving Mutation Targets and Position-specific Substitution Rates

Abstract

To facilitate mutagenesis study, it is necessary to be able to derive mutation targets and associated substitution rates in the sequence of interest regardless of the availability of corresponding structure. It is also important to obtain these data depending on the specific aims of the mutation process. The MBLOSUM server determines candidate positions for mutations and derives position-specific substitution rates given only a protein sequence. Different sets of complete genomes collected according to their phylogeny or specificity of environments along with compete set of non-redundant sequences can be used in calculations depending on the experimental task. MBLOSUM server is available at: http://apps.cbu.uib.no/mblosum     

Spontaneous Mutation Rates in Mammalian Cells: Effect of Differential Growth Rates and Phenotypic Lag

We calculated a spontaneous rate of 26-37 x 10(-6) mutations per cell division for L5178Y MOLY (mouse lymphoma) cells at the thymidine kinase locus (tk+/(-)----tk-/-) using a procedure that isolated and segregated cells during expression. This rate was 50 times higher than when cells expressed the mutant phenotype in suspension. The higher mutation rates obtained with the in situ procedure suggest that many of the mutants, whether expressed or unexpressed, grew more slowly than wild-type cells prior to selection with trifluorothymidine (TFT), implying that the slow growth phenotype is expressed earlier than the TFTr (TFT-resistant) phenotype. The loss of mutants was not restricted to cells forming small colonies; the mutation rate for cells forming large colonies was more than ten times higher using the in situ procedure. In this new procedure, the cells expressed spontaneous mutations while growing in semisolid medium for up to 3 days without TFT. Mutants were then selected in situ by adding an overlay of TFT and the visible colonies were analyzed after 11 days. Cells with spontaneous mutations at the tk locus required approximately 30 hr for the more rapidly expressing cells with new mutations to be detected. Most of the TFTr colonies selected after 60 hr of growth in semisolid medium represented independent mutations that had accumulated during the first 30 hr.(ABSTRACT TRUNCATED AT 250 WORDS)