Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population

An RNA virus population does not consist of a single genotype; rather, it is an ensemble of related sequences, termed quasispecies. Quasispecies arise from rapid genomic evolution powered by the high mutation rate of RNA viral replication. Although a high mutation rate is dangerous for a virus because it results in nonviable individuals, it has been hypothesized that high mutation rates create a 'cloud' of potentially beneficial mutations at the population level, which afford the viral quasispecies a greater probability to evolve and adapt to new environments and challenges during infection. Mathematical models predict that viral quasispecies are not simply a collection of diverse mutants but a group of interactive variants, which together contribute to the characteristics of the population. According to this view, viral populations, rather than individual variants, are the target of evolutionary selection. Here we test this hypothesis by examining the consequences of limiting genomic diversity on viral populations. We find that poliovirus carrying a high-fidelity polymerase replicates at wild-type levels but generates less genomic diversity and is unable to adapt to adverse growth conditions. In infected animals, the reduced viral diversity leads to loss of neurotropism and an attenuated pathogenic phenotype. Notably, using chemical mutagenesis to expand quasispecies diversity of the high-fidelity virus before infection restores neurotropism and pathogenesis. Analysis of viruses isolated from brain provides direct evidence for complementation between members in the quasispecies, indicating that selection indeed occurs at the population level rather than on individual variants. Our study provides direct evidence for a fundamental prediction of the quasispecies theory and establishes a link between mutation rate, population dynamics and pathogenesis.     

Global variation in copy number in the human genome

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.     

A phosphatase complex that dephosphorylates gammaH2AX regulates DNA damage checkpoint recovery

One of the earliest marks of a double-strand break (DSB) in eukaryotes is serine phosphorylation of the histone variant H2AX at the carboxy-terminal SQE motif to create gammaH2AX-containing nucleosomes. Budding-yeast histone H2A is phosphorylated in a similar manner by the checkpoint kinases Tel1 and Mec1 (ref. 2; orthologous to mammalian ATM and ATR, respectively) over a 50-kilobase region surrounding the DSB. This modification is important for recruiting numerous DSB-recognition and repair factors to the break site, including DNA damage checkpoint proteins, chromatin remodellers and cohesins. Multiple mechanisms for eliminating gammaH2AX as DNA repair completes are possible, including removal by histone exchange followed potentially by degradation, or, alternatively, dephosphorylation. Here we describe a three-protein complex (HTP-C, for histone H2A phosphatase complex) containing the phosphatase Pph3 that regulates the phosphorylation status of gammaH2AX in vivo and efficiently dephosphorylates gammaH2AX in vitro. gammaH2AX is lost from chromatin surrounding a DSB independently of the HTP-C, indicating that the phosphatase targets gammaH2AX after its displacement from DNA. The dephosphorylation of gammaH2AX by the HTP-C is necessary for efficient recovery from the DNA damage checkpoint.     

Variable Selection for Clustering and Classification

As data sets continue to grow in size and complexity, effective and efficient techniques are needed to target important features in the variable space. Many of the variable selection techniques that are commonly used alongside clustering algorithms are based upon determining the best variable subspace according to model fitting in a stepwise manner. These techniques are often computationally intensive and can require extended periods of time to run; in fact, some are prohibitively computationally expensive for high-dimensional data. In this paper, a novel variable selection technique is introduced for use in clustering and classification analyses that is both intuitive and computationally efficient. We focus largely on applications in mixture model-based learning, but the technique could be adapted for use with various other clustering/classification methods. Our approach is illustrated on both simulated and real data, highlighted by contrasting its performance with that of other comparable variable selection techniques on the real data sets.     

Functional connectivity in the retina at the resolution of photoreceptors

To understand a neural circuit requires knowledge of its connectivity. Here we report measurements of functional connectivity between the input and ouput layers of the macaque retina at single-cell resolution and the implications of these for colour vision. Multi-electrode technology was used to record simultaneously from complete populations of the retinal ganglion cell types (midget, parasol and small bistratified) that transmit high-resolution visual signals to the brain. Fine-grained visual stimulation was used to identify the location, type and strength of the functional input of each cone photoreceptor to each ganglion cell. The populations of ON and OFF midget and parasol cells each sampled the complete population of long- and middle-wavelength-sensitive cones. However, only OFF midget cells frequently received strong input from short-wavelength-sensitive cones. ON and OFF midget cells showed a small non-random tendency to selectively sample from either long- or middle-wavelength-sensitive cones to a degree not explained by clumping in the cone mosaic. These measurements reveal computations in a neural circuit at the elementary resolution of individual neurons.     

基于前景理论的多目标灰色局势决策方法

鉴于决策者风险态度对多目标决策的影响,提出一种基于前景理论的多目标灰色局势决策方法。该方法首先利用奖优罚劣的线性变换算子对原始决策信息进行规范化处理,进而确定正负理想方案。基于前景理论和多目标灰色局势决策方法确定前景价值函数,并利用方案综合前景值最大化的多目标优化模型求解最优权向量,进而求得综合效果测度矩阵,而后采用区间数的可能度对每个事件的局势进行排序,最后通过实例验证了该模型的有效性和实用性。     

Control of the carrier-envelope phases of a synchronously pumped femtosecond optical parametric oscillator and its applications

The intrinsic synchronization, multi-color outputs and related carrier-envelope phases （CEP） among pulses bring advantages to synchronously pumped femtosecond optical parametric oscillators and the pumping sources for broadband frequency comb generation and ultrashort waveform coherent syn-thesis. In this paper, we discuss our latest research results in this field, which cover the following as-pects： the phase relationship and energy conservation law in an OPO and related experimental verifi-cation; control of the pumping Ti-sapphire femtosecond laser＇s CEP by self-referencing technology, and its repetition-rate locking by piezoelectric transducer （PZT）; CEP locking of the pulses from the OPO by beating the non-phase-matched visible outputs against pump supercontinuum to obtain a driving signal for a fast PZT on the OPO end mirror; the generation of a broadband frequency comb spanning from 400 nm to 2.4 μm with 1.2 kHz bandwidth; and the realization of coherent interference between phase controlled pump pulses and signal second harmonic pulses.