Genetic and Evolutionary Correlates of Fine-Scale Recombination Rate Variation in Drosophila persimilis

Recombination is fundamental to meiosis in many species and generates variation on which natural selection can act, yet fine-scale linkage maps are cumbersome to construct. We generated a fine-scale map of recombination rates across two major chromosomes in Drosophila persimilis using 181 SNP markers spanning two of five major chromosome arms. Using this map, we report significant fine-scale heterogeneity of local recombination rates. However, we also observed “recombinational neighborhoods,” where adjacent intervals had similar recombination rates after excluding regions near the centromere and telomere. We further found significant positive associations of fine-scale recombination rate with repetitive element abundance and a 13-bp sequence motif known to associate with human recombination rates. We noted strong crossover interference extending 5–7 Mb from the initial crossover event. Further, we observed that fine-scale recombination rates in D. persimilis are strongly correlated with those obtained from a comparable study of its sister species, D. pseudoobscura. We documented a significant relationship between recombination rates and intron nucleotide sequence diversity within species, but no relationship between recombination rate and intron divergence between species. These results are consistent with selection models (hitchhiking and background selection) rather than mutagenic recombination models for explaining the relationship of recombination with nucleotide diversity within species. Finally, we found significant correlations between recombination rate and GC content, supporting both GC-biased gene conversion (BGC) models and selection-driven codon bias models. Overall, this genome-enabled map of fine-scale recombination rates allowed us to confirm findings of broader-scale studies and identify multiple novel features that merit further investigation.     

癌症与可变剪接

可变剪接在发育、分化和癌症等过程中发挥着非常重要的作用。近年来,越来越多的研究表明可变剪接与癌症有着密切的关系,许多癌症相关基因受可变剪接调控。由于癌症特异性的剪接变体具有明显的诊断价值,使得对癌症与可变剪接的研究成为热点。简要概述了癌症相关基因的可变剪接、可变剪接变体的鉴定方法、可变剪接与癌症治疗等研究进展。     

Mechano-Regulation of Alternative Splicing

Alternative splicing contributes to the complexity of proteome by producing multiple mRNAs from a single gene. Affymetrix exon arrays and experiments in vivo or in vitro demonstrated that alternative splicing was regulated by mechanical stress. Expression of mechano-growth factor (MGF) which is the splicing isoform of insulin-like growth factor 1(IGF-1) and vascular endothelial growth factor (VEGF) splicing variants such as VEGF₁₂₁, VEGF_165, VEGF₂₀₆, VEGF₁₈₉, VEGF₁₆₅ and VEGF₁₄₅ are regulated by mechanical stress. However, the mechanism of this process is not yet clear. Increasing evidences showed that the possible mechanism is related to Ca²⁺ signal pathway and phosphorylation signal pathway. This review proposes possible mechanisms of mechanical splicing regulation. This will contribute to the biomechanical study of alternative splicing.     

Tissue-Specific Effects of Genetic and Epigenetic Variation on Gene Regulation and Splicing

Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans’ lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.     

Patterns and Determinants of Floristic Variation across Lowland Forests of Bolivia

Floristic variation is high in the Neotropics, but little is known about the factors shaping this variation at the mesoscale. We examined floristic composition and its relationship with environmental factors across 220 1‐ha permanent plots in tropical lowland Bolivia. For each plot, abundance of 100 species (93 tree and 7 palm species ≥10 cm diam) was obtained. Climatic data, related to rainfall seasonality and temperature, were interpolated from all available weather stations in the region, and soil properties, related to texture and fertility, were obtained for each plot. Floristic variation was strongly associated with differences in water availability and temperature, and therefore the climatic gradient shaped floristic variation more strongly than the edaphic gradient. Detrended correspondence analysis ordination divided lowland Bolivia primarily into two major groups (Southern Chiquitano region vs. the Amazon region) and a multiple response permutation procedure distinguished five floristic regions. Overall, the tested environmental variables differed significantly among the five regions. Using indicator species analysis, we distinguished 82 strong indicator species, which had significant environmental preferences for one floristic region. These species can be used as indicators of environmental conditions or to determine which floristic region a certain forest belongs. Given the predicted decreases in rainfall and increases in temperature for tropical lowland forests, our gradient approach suggests that species composition may shift drastically with climate change. Abstract in Spanish is available at http://www.blackwell‐synergy.com/loi/btp .     

可变剪接与细胞凋亡调控

细胞凋亡(apoptosis)是多细胞生物的一种基本生命活动,在机体的生长发育、免疫调节及维持内环境稳定等各方面扮演着重要的角色.遗传和生化研究表明,细胞凋亡受到复杂而精细的调控.转录水平、翻译后水平等各种层次的调控,构成了一个复杂的凋亡调控网络.     

Integration of Experiments across Diverse Environments Identifies the Genetic Determinants of Variation in Sorghum bicolor Seed Element Composition

Seedling establishment and seed nutritional quality require the sequestration of sufficient element nutrients. The identification of genes and alleles that modify element content in the grains of cereals, including sorghum (Sorghum bicolor), is fundamental to developing breeding and selection methods aimed at increasing bioavailable element content and improving crop growth. We have developed a high-throughput work flow for the simultaneous measurement of multiple elements in sorghum seeds. We measured seed element levels in the genotyped Sorghum Association Panel, representing all major cultivated sorghum races from diverse geographic and climatic regions, and mapped alleles contributing to seed element variation across three environments by genome-wide association. We observed significant phenotypic and genetic correlation between several elements across multiple years and diverse environments. The power of combining high-precision measurements with genome-wide association was demonstrated by implementing rank transformation and a multilocus mixed model to map alleles controlling 20 element traits, identifying 255 loci affecting the sorghum seed ionome. Sequence similarity to genes characterized in previous studies identified likely causative genes for the accumulation of zinc, manganese, nickel, calcium, and cadmium in sorghum seeds. In addition to strong candidates for these five elements, we provide a list of candidate loci for several other elements. Our approach enabled the identification of single-nucleotide polymorphisms in strong linkage disequilibrium with causative polymorphisms that can be evaluated in targeted selection strategies for plant breeding and improvement.Sorghum (Sorghum bicolor) is a globally cultivated source of food, feed, and fiber. Contrasting needs for elemental nutrient accumulation limit crop yield and quality for sorghum marketed to different sectors. The seed-bearing reproductive organs, or panicles, in sorghum represent up to 30% of the total dry matter yield (Amaducci et al., 2004). Plant-based diets, in which grains compose the major food source, require the accumulation of bioavailable essential elements in the plant seeds. Currently, iron (Fe) and zinc (Zn) deficiencies negatively affect the health of over two billion people worldwide (World Health Organization, 2002). Increased bioavailable elemental nutrient content in the edible portions of sorghum for human and animal nutrition could ameliorate this nutritional crisis (Graham et al., 1999; World Health Organization, 2002). Additional global health benefits could be achieved by increasing magnesium (Mg), selenium (Se), calcium (Ca), and copper (Cu; White and Broadley, 2005) while reducing the concentration of toxic elements, including arsenic (As) and cadmium (Cd; Ma et al., 2008).Seed element accumulation results from interconnected biological processes, including element uptake by the roots, translocation and remobilization within the plant, and ultimately import, deposition, and assimilation/storage in the seeds. Element availability is further affected by the accumulation of metabolites in seeds (Vreugdenhil et al., 2004). High-throughput ionomic analysis, or concurrent measurement of multiple elements, allows for the quantitative and simultaneous measurement of an organism’s elemental composition, providing a snapshot of the functional state of an organism under different experimental conditions (Salt et al., 2008). Most studies of the plant ionome utilize inductively coupled plasma mass spectroscopy (ICP-MS). Briefly, inductively coupled plasma (ICP) functions to ionize the analyte into atoms, which are then detected by mass spectroscopy. Reference standards are used to identify and quantitate each element of interest in the sample. ICP-MS analysis can be accomplished in as little as 1 min per sample, which allows for high-throughput processing of thousands of samples (Salt et al., 2008). Previous studies have demonstrated that several elements, including Fe, manganese (Mn), Zn, cobalt (Co), and Cd, share mechanisms of accumulation (Yi and Guerinot, 1996; Vert et al., 2002; Connolly et al., 2003). Ionomic signatures derived from multiple elements also have been shown to better predict plant physiological status for some elements than the measure of the element’s concentration, including essential nutrients like Fe (Baxter et al., 2008). Holistically examining the ionome provides significant insights into the networks underlying ion homeostasis beyond single-element studies (Baxter and Dilkes, 2012).There are over 45,000 catalogued lines of sorghum at the U.S. Department of Agriculture Germplasm Resource Information Network. This diverse collection of sorghum germplasm contains genetic variation with undiscovered impact on seed element composition (Das et al., 1997). Mapping quantitative trait loci for seed element concentration has been successful in a number of species, including Arabidopsis (Arabidopsis thaliana; Vreugdenhil et al., 2004; Waters and Grusak, 2008; Buescher et al., 2010), rice (Oryza sativa; Norton et al., 2010; Zhang et al., 2014), wheat (Triticum aestivum; Shi et al., 2008; Peleg et al., 2009), and maize (Zea mays; Simić et al., 2012; Baxter et al., 2013, 2014). Genome-wide association (GWA) mapping is well suited for uncovering the genetic basis for complex traits, including seed element accumulation. One of the key strengths of association mapping is that a priori knowledge is not necessary to identify new loci associated with the trait of interest. Furthermore, a GWA mapping population is composed of lines that have undergone numerous recombination events, allowing for a narrower mapping interval. Previous GWA studies in maize (Tian et al., 2011), rice (Huang et al., 2010), and sorghum (Morris et al., 2013) have been successful in identifying the genetic basis for various agronomic traits. Here, we analyzed the seed ionome from a community-generated association panel to identify potential loci underlying seed element accumulation in sorghum.     

Pre-mRNA选择性剪接的调控及选择性剪接数据库

Pre-mRNA选择性剪接是真核生物转录组和蛋白质组多样性的主要来源,也是细胞分化、发育等过程中重要的基因表达调控方式。约95%的人类多外显子基因存在RNA选择性剪接|很多人类基因疾病的发生与RNA剪接错误相关。随着共转录现象的发现,RNA选择性剪接调控机制研究也取得了很大进展。本文分别从序列层面和核小体定位、组蛋白修饰、DNA甲基化及非编码RNA等表观遗传层面,系统地阐述了RNA选择性剪接的调控机制。为便于搜索,本文介绍了近10年来RNA选择性剪接相关的数据库。     

Origin of Spliceosomal Introns and Alternative Splicing

In this work we review the current knowledge on the prehistory, origins, and evolution of spliceosomal introns. First, we briefly outline the major features of the different types of introns, with particular emphasis on the nonspliceosomal self-splicing group II introns, which are widely thought to be the ancestors of spliceosomal introns. Next, we discuss the main scenarios proposed for the origin and proliferation of spliceosomal introns, an event intimately linked to eukaryogenesis. We then summarize the evidence that suggests that the last eukaryotic common ancestor (LECA) had remarkably high intron densities and many associated characteristics resembling modern intron-rich genomes. From this intron-rich LECA, the different eukaryotic lineages have taken very distinct evolutionary paths leading to profoundly diverged modern genome structures. Finally, we discuss the origins of alternative splicing and the qualitative differences in alternative splicing forms and functions across lineages.     

Genome-Wide Patterns of Genetic Variation within and among Alternative Selective Regimes

Environmental heterogeneity has been hypothesized to influence levels of genetic variation but the effect of heterogeneity depends on (i) the form of heterogeneity, (ii) whether ecologically relevant or neutral loci are being considered, and (iii) the genetic basis of ecological adaptation. We surveyed genome-wide SNP diversity in replicate experimental Drosophila melanogaster populations with equal census sizes that evolved for 42 generations under one of four selection regimes: (i) salt-enriched environment (Salt), (ii) cadmium-enriched environment (Cad), (iii) temporally (Temp) or (iv) spatially (Spatial) variable environments. There was significant differentiation between all pairs of treatments but the greatest differentiation occurred between the two homogenous treatments (Cad and Salt). For sites likely under differential ecological selection (and those closely linked to them), the pattern of within-population diversity π followed the expectation from classic antagonistic selection theory: Spatial>Temp>Salt≈Cad. However, neutral diversity unlinked to selected sites followed a different pattern: Spatial>Salt≈Cad>Temp. As implicated by the latter result, measures of F_ST among replicate populations within treatments are consistent with differences in effective population sizes among selective regimes despite equal census sizes. Though there are clear changes in the rank order of treatments when contrasting selected and neutral sites with respect to π, the rank ordering of treatments with respect to F_ST appears reasonably consistent between site categories. These results demonstrate that alternative selective regimes affect within- and among-population diversity differently for different site types.     

Multipotent Genetic Suppression of Retrotransposon-Induced Mutations by Nxf1 through Fine-Tuning of Alternative Splicing

Cellular gene expression machinery has coevolved with molecular parasites, such as viruses and transposons, which rely on host cells for their expression and reproduction. We previously reported that a wild-derived allele of mouse Nxf1 (Tap), a key component of the host mRNA nuclear export machinery, suppresses two endogenous retrovirus-induced mutations and shows suggestive evidence of positive selection. Here we show that Nxf1^CAST suppresses a specific and frequent class of intracisternal A particle (IAP)-induced mutations, including Ap3d1^mh2J, a model for Hermansky-Pudlak syndrome, and Atcay^hes, an orthologous gene model for Cayman ataxia, among others. The molecular phenotype of suppression includes ∼two-fold increase in the level of correctly-spliced mRNA and a decrease in mutant-specific, alternatively-processed RNA accumulating from the inserted allele. Insertional mutations involving ETn and LINE elements are not suppressed, demonstrating a high degree of specificity to this suppression mechanism. These results implicate Nxf1 in some instances of pre-mRNA processing, demonstrate the useful range of Nxf1^CAST alleles for manipulating existing mouse models of disease, and specifically imply a low functional threshold for therapeutic benefit in Cayman ataxia.     

mRNA选择性剪接的分子机制

真核细胞mRNA前体经过剪接成为成熟的mRNA,而mRNA前体的选择性剪接极大地增加了蛋白质的多样性和基因表达的复杂程度,剪接位点的识别可以以跨越内含子的机制(内含子限定)或跨越外显子的机制(外显子限定)进行。选择性剪接有多种剪接形式：选择不同的剪接位点,选择不同的剪接末端,外显子的不同组合及内含子的剪接与否等。选择性剪接过程受到许多顺式元件和反式因子的调控,并与基本剪接过程紧密联系,剪接体中的一些剪接因子也参与了对选择性剪接的调控。选择性剪接也是1个伴随转录发生的过程,不同的启动子可调控产生不同的剪接产物。mRNA的选择性剪接机制多种多样,已发现RNA编辑和反式剪接也可参与选择性剪接过程。     

Alternative Splicing and Control of Apoptotic DNA Fragmentation

It has long been suggested that alternative splicing is involved in regulation of apoptosis by producing mRNA isoforms that encode proteins with distinct and even opposite functions in apoptotic pathways. However, the physiological functions and regulatory mechanisms of such alternative splicing events have been unclear. Recently, it was demonstrated that inactivation of a single SR protein, ASF/SF2, can modulate a specific step in the apoptotic pathway, internucleosomal DNA fragmentation, by regulating ICAD pre-mRNA alternative splicing. These studies have provided new evidence supporting the important role of regulated splicing and SR proteins in the process of apoptosis.