抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, upstream, downstream, splice site, or intergenic regions. Coding effects such as synonymous or non-synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frame shifts can be predicted. Here the use of SnpEff is illustrated by annotating ~356,660 candidate SNPs in ~117 Mb unique sequences, representing a substitution rate of ~1/305 nucleotides, between the Drosophila melanogaster w1118; iso-2; iso-3 strain and the reference y1; cn1 bw1 sp1 strain. We show that ~15,842 SNPs are synonymous and ~4,467 SNPs are non-synonymous (N/S ~0.28). The remaining SNPs are in other categories, such as stop codon gains (38 SNPs), stop codon losses (8 SNPs), and start codon gains (297 SNPs) in...

A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3

The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.

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The Ensembl Variant Effect Predictor.

Geneticists study the gene; however, for epigeneticists, there is no obvious 'epigene'. Nevertheless, during the past year, more than 2,500 articles, numerous scientific meetings and a new journal were devoted to the subject of epigenetics. It encompasses some of the most exciting contemporary biology and is portrayed by the popular press as a revolutionary new science--an antidote to the idea that we are hard-wired by our genes. So what is epigenetics?

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Perceptions of epigenetics

Summary
1The role of phenotypic plasticity in evolution has historically been a contentious issue because of debate over whether plasticity shields genotypes from selection or generates novel opportunities for selection to act. Because plasticity encompasses diverse adaptive and non-adaptive responses to environmental variation, no single conceptual framework adequately predicts the diverse roles of plasticity in evolutionary change.
2Different types of phenotypic plasticity can uniquely contribute to adaptive evolution when populations are faced with new or altered environments. Adaptive plasticity should promote establishment and persistence in a new environment, but depending on how close the plastic response is to the new favoured phenotypic optimum dictates whether directional selection will cause adaptive divergence between populations. Further, non-adaptive plasticity in response to stressful environments can result in a mean phenotypic response being further away from the favoured optimum or alternatively increase the variance around the mean due to the expression of cryptic genetic variation. The expression of cryptic genetic variation can facilitate adaptive evolution if by chance it results in a fitter phenotype.
3We conclude that adaptive plasticity that places populations close enough to a new phenotypic optimum for directional selection to act is the only plasticity that predictably enhances fitness and is most likely to facilitate adaptive evolution on ecological time-scales in new environments. However, this type of plasticity is likely to be the product of past selection on variation that may have been initially non-adaptive.
4We end with suggestions on how future empirical studies can be designed to better test the importance of different kinds of plasticity to adaptive evolution.

/pdf/adaptive-versus-non-adaptive-phenotypic-plasticity-and-the-55680hih4y.pdf

Adaptive versus non‐adaptive phenotypic plasticity and the potential for contemporary adaptation in new environments

This paper describes a new program SnpSift for filtering differential DNA sequence variants between two or more experimental genomes after genotoxic chemical exposure. Here, we illustrate how SnpSift can be used to identify candidate phenotype-relevant variants including single nucleotide polymorphisms, multiple nucleotide polymorphisms, insertions, and deletions (InDels) in mutant strains isolated from genome-wide chemical mutagenesis of Drosophila melanogaster. First, the genomes of two independently isolated mutant fly strains that are allelic for a novel recessive male-sterile locus generated by genotoxic chemical exposure were sequenced using the Illumina next-generation DNA sequencer to obtain 20- to 29-fold coverage of the euchromatic sequences. The sequencing reads were processed and variants were called using standard bioinformatic tools. Next, SnpEff was used to annotate all sequence variants and their potential mutational effects on associated genes. Then, SnpSift was used to filter and select differential variants that potentially disrupt a common gene in the two allelic mutant strains. The potential causative DNA lesions were partially validated by capillary sequencing of polymerase chain reaction-amplified DNA in the genetic interval as defined by meiotic mapping and deletions that remove defined regions of the chromosome. Of the five candidate genes located in the genetic interval, the Pka-like gene CG12069 was found to carry a separate pre-mature stop codon mutation in each of the two allelic mutants whereas the other four candidate genes within the interval have wild-type sequences. The Pka-like gene is therefore a strong candidate gene for the male-sterile locus. These results demonstrate that combining SnpEff and SnpSift can expedite the identification of candidate phenotype-causative mutations in chemically mutagenized Drosophila strains. This technique can also be used to characterize the variety of mutations generated by genotoxic chemicals.

/pdf/using-drosophila-melanogaster-as-a-model-for-genotoxic-32vffc70sa.pdf

Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift

Morphological alterations have been shown to occur in Drosophila melanogaster when function of Hsp90 (heat shock 90-kDa protein 1α , encoded by Hsp83) is compromised during development 1 . Genetic selection maintains the altered phenotypes in subsequent generations1. Recent experiments have shown, however, that phenotypic variation still occurs in nearly isogenic recombinant inbred strains of Arabidopsis thaliana2. Using a sensitized isogenic D. melanogaster strain, iso-Kr If-1 , we confirm this finding and present evidence supporting an epigenetic mechanism for Hsp90’s capacitor function, whereby reduced activity of Hsp90 induces a heritably altered chromatin state. The altered chromatin state is evidenced by ectopic expression of the morphogen wingless in eye imaginal discs and a corresponding abnormal eye phenotype, both of which are epigenetically heritable in subsequent generations, even when function of Hsp90 is restored. Mutations in nine different genes of the trithorax group that encode chromatin-remodeling proteins also induce the abnormal phenotype. These findings suggest that Hsp90 acts as a capacitor for morphological evolution through epigenetic and genetic mechanisms. The D. melanogaster segmentation gene Kruppel (Kr) encodes a zinc-finger transcription factor that is required for the development of several thoracic and abdominal segments 3 . The dominant Kr Irregular facets (Kr If-1 ) allele causes ectopic expression of Kr protein mostly in the ventral region of the eye imaginal disc, which causes a reduction in the size of the eye (refs. 4,5; Fig. 1a,b). In a deficiency (Df) chromosome screen, the details of which will be presented elsewhere, we found that deficiency for ten chromosomal regions caused ectopic outgrowth in eyes of Kr If-1 flies. When we mated females with any of these deficiencies (Df/+) to Kr If-1 homozygous males, a considerable percentage of the Kr If-1/+ offspring had ectopic outgrowth (data not shown). But the reciprocal cross (Kr If-1 homozygous females × Df/+ males) produced at least an order of magnitude fewer offspring with ectopic outgrowth, suggesting that the phenotype is induced primarily by dosage-sensitive maternal-effect loci. Consistent with this genetic designation, ectopic outgrowth was independent of inheritance of the Df chromosome. Thorough testing of previously identified mutations uncovered by these Df lines identified 15 mutations in ten maternal-effect genes, dubbed Me(Kr If-1 ), that cause ectopic outgrowth. Although we tested mutations in multiple genes that were uncovered by the deficiencies, we identified only one Me(Kr If-1 ) gene in each Df region (Table 1). letter

/pdf/evidence-for-an-epigenetic-mechanism-by-which-hsp90-acts-as-1wdb8nwpdh.pdf

Evidence for an Epigenetic Mechanism by which Hsp90 Acts as a Capacitor for Morphological Evolution

Many environmental toxins, such as heavy metals, air particles, and ozone, induce oxidative stress and decrease the levels of NADH and NADPH, cofactors that drive anabolic biochemical reactions and provide reducing capacity to combat oxidative stress. Recently, it was found that the Ten-eleven translocation (TET) protein family members, which oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in the DNA, is activated under high oxygen conditions by alpha ketoglutarate (-KG), a cofactor produced by aerobic metabolism in the citric acid cycle. TET, Jumonji-family histone demethylases, and prolyl hydroxylase, a repressor of HIF1a under high oxygen conditions, all require alpha ketoglutarate (a-KG) as cofactors for their activation. The impact of the HIF1a and TET proteins, which appear to have opposing functions, reaches several aspects of human life-including cell growth regulation, embryonic stem cell maintenance, cell differentiation, and tumorigenesis. The role of metabolism on regulating ...

Hypothesis: Environmental regulation of 5-hydroxymethylcytosine by oxidative stress

Hsp90 is a chaperone for over 100 'client proteins' in the cell, most of which are involved in signaling pathways. For example, Hsp90 maintains several nuclear hormone receptors, such as the estrogen receptor (ER), as agonist-receptive monomers in the cytoplasm. In the presence of agonist, Hsp90 dissociates and the receptors dimerize, enter the nucleus and ultimately activate transcription of the target genes. Increasing evidence suggests that Hsp90 also has a role in modifying the chromatin conformation of many genes. For example, Hsp90 has recently been shown to increase the activity of the histone H3 lysine-4 methyltransferase SMYD3, which activates the chromatin of target genes. Further evidence for chromatin-remodeling functions is that Hsp90 acts as a capacitor for morphological evolution by masking epigenetic variation. Release of the capacitor function of Hsp90, such as by environmental stress or by drugs that inhibit the ATP-binding activity of Hsp90, exposes previously hidden morphological phenotypes in the next generation and for several generations thereafter. The chromatin-modifying phenotypes of Hsp90 have striking similarities to the trans-generational effects of the ER agonist diethylstilbesterol (DES). Prenatal and perinatal exposure to DES increases the predisposition to uterine developmental abnormalities and cancer in the daughters and granddaughters of exposed pregnant mice. In this review, we propose that trans-generational epigenetic phenomena involving Hsp90 and DES are related and that chromatin-mediated WNT signaling modifications are required. This model suggests that inhibitors of Hsp90, WNT signaling and chromatin-remodeling enzymes might function as anticancer agents by interfering with epigenetic reprogramming and canalization in cancer stem cells.

/pdf/hsp90-and-environmental-impacts-on-epigenetic-states-a-model-xneyv6bkms.pdf

Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer

Xiangyi Lu

Papers

A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3

Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift

Evidence for an Epigenetic Mechanism by which Hsp90 Acts as a Capacitor for Morphological Evolution

Hypothesis: Environmental regulation of 5-hydroxymethylcytosine by oxidative stress

Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer