Complex coordination of cell plasticity by a PGC-1α-controlled transcriptional network in skeletal muscle

Skeletal muscle cells exhibit an enormous plastic capacity in order to adapt to external stimuli. Even though our overall understanding of the molecular mechanisms that underlie phenotypic changes in skeletal muscle cells remains poor, several factors involved in the regulation and coordination of relevant transcriptional programs have been identified in recent years. For example, the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a central regulatory nexus in the adaptation of muscle to endurance training. Intriguingly, PGC-1α integrates numerous signaling pathways and translates their activity into various transcriptional programs. This selectivity is in part controlled by differential expression of PGC-1α variants and post-translational modifications of the PGC-1α protein. PGC-1α-controlled activation of transcriptional networks subsequently enables a spatio-temporal specification and hence allows a complex coordination of changes in metabolic and contractile properties, protein synthesis and degradation rates and other features of trained muscle. In this review, we discuss recent advances in our understanding of PGC-1α-regulated skeletal muscle cell plasticity in health and disease

An Integrative Alternative For America\u27s Privacy Torts

Rugg and Smith encapsulate a transition between two approaches to tort protection of privacy. Rugg reflects the unitary-tort theory, which recognizes a single tort and seeks only to determine if the plaintiff\u27s interest in privacy has been breached by the defendant\u27s behavior. Smith reflects the multiple-tort approach that recognizes four torts, encompassing four ways in which privacy is breached, that have in common only an interference with a loosely defined understanding of privacy. This understanding of the privacy tort was lifted from the Restatement (Second) of Torts (1977), which adopted a construct first proffered by Dean William Prosser in a 1960 law review article. This Comment argues that the flexibility envisioned by the Restatement can best be achieved through an alternative offered by the Government of Ireland in the summer of 2006. The Irish proposal recognizes a single tort for invasion of privacy, defining the degree of privacy that an individual may expect as that which is reasonable under all the circumstances. It lists a series of factors to consider when evaluating all the circumstances, as well as defenses and recognized violations. The Irish integrative approach seeks to incorporate the elasticity of the unitary-tort approach with the clarity of the multiple-tort approach in a single statute. Adoption of the Irish approach would allow American jurisdictions to more clearly articulate the privacy tort and to better channel the adaptive powers of American common law. Part I of this Comment explains that modern American privacy-tort law is the result of the tension between two conflicting viewpoints on invasion-of-privacy torts. Part II shows how the widespread acceptance of the four tort structure in the United States has stunted the development of the privacy tort. Part III surveys the provisions of the Irish proposal, while Part IV analyzes the benefits offered by the Irish integrative approach. Part V explores how an American jurisdiction can utilize a structure like that in the Irish bill to take advantage of these benefits. Finally, Part VI concludes that the Irish proposal offers an opportunity for American privacy-tort jurisprudence to embrace the adaptive and evolutionary power of the common law

An Integrative Alternative For America\u27s Privacy Torts

Rugg and Smith encapsulate a transition between two approaches to tort protection of privacy. Rugg reflects the unitary-tort theory, which recognizes a single tort and seeks only to determine if the plaintiff\u27s interest in privacy has been breached by the defendant\u27s behavior. Smith reflects the multiple-tort approach that recognizes four torts, encompassing four ways in which privacy is breached, that have in common only an interference with a loosely defined understanding of privacy. This understanding of the privacy tort was lifted from the Restatement (Second) of Torts (1977), which adopted a construct first proffered by Dean William Prosser in a 1960 law review article. This Comment argues that the flexibility envisioned by the Restatement can best be achieved through an alternative offered by the Government of Ireland in the summer of 2006. The Irish proposal recognizes a single tort for invasion of privacy, defining the degree of privacy that an individual may expect as that which is reasonable under all the circumstances. It lists a series of factors to consider when evaluating all the circumstances, as well as defenses and recognized violations. The Irish integrative approach seeks to incorporate the elasticity of the unitary-tort approach with the clarity of the multiple-tort approach in a single statute. Adoption of the Irish approach would allow American jurisdictions to more clearly articulate the privacy tort and to better channel the adaptive powers of American common law. Part I of this Comment explains that modern American privacy-tort law is the result of the tension between two conflicting viewpoints on invasion-of-privacy torts. Part II shows how the widespread acceptance of the four tort structure in the United States has stunted the development of the privacy tort. Part III surveys the provisions of the Irish proposal, while Part IV analyzes the benefits offered by the Irish integrative approach. Part V explores how an American jurisdiction can utilize a structure like that in the Irish bill to take advantage of these benefits. Finally, Part VI concludes that the Irish proposal offers an opportunity for American privacy-tort jurisprudence to embrace the adaptive and evolutionary power of the common law

Recombination rate and protein evolution in yeast

<p>Abstract</p> <p>Background</p> <p>Theory and artificial selection experiments show that recombination can promote adaptation by enhancing the efficacy of natural selection, but the extent to which recombination affects levels of adaptation across the genome is still an open question. Because patterns of molecular evolution reflect long-term processes of mutation and selection in nature, interactions between recombination rate and genetic differentiation between species can be used to test the benefits of recombination. However, this approach faces a major difficulty: different evolutionary processes (i.e. negative versus positive selection) produce opposing relationships between recombination rate and genetic divergence, and obscure patterns predicted by individual benefits of recombination.</p> <p>Results</p> <p>We use a combination of polymorphism and genomic data from the yeast <it>Saccharomyces cerevisiae </it>to infer the relative importance of nearly-neutral (i.e. slightly deleterious) evolution in different gene categories. For genes with high opportunities for slightly deleterious substitution, recombination substantially reduces the rate of molecular evolution, whereas divergence in genes with little opportunity for slightly deleterious substitution is not strongly affected by recombination.</p> <p>Conclusion</p> <p>These patterns indicate that adaptation throughout the genome can be strongly influenced by each gene's recombinational environment, and suggest substantial long-term fitness benefits of enhanced purifying selection associated with sexual recombination.</p

Sex differences in deleterious mutational effects in Drosophila melanogaster: combining quantitative and population genetic insights

Fitness effects of deleterious mutations can differ between females and males due to: (i) sex differences in the strength of purifying selection; and (ii) sex differences in ploidy. Although sex differences in fitness effects have important broader implications (e.g., for the evolution of sex and lifespan), few studies have quantified their scope. Those that have belong to one of two distinct empirical traditions: (i) quantitative genetics, which focusses on multi-locus genetic variances in each sex, but is largely agnostic about their genetic basis; and (ii) molecular population genetics, which focusses on comparing autosomal and X-linked polymorphism, but is poorly suited for inferring contemporary sex differences. Here, we combine both traditions to present a comprehensive analysis of female and male adult reproductive fitness among 202 outbred, laboratory-adapted, hemiclonal genomes of Drosophila melanogaster. While we find no clear evidence for sex differences in the strength of purifying selection, sex differences in ploidy generate multiple signals of enhanced purifying selection for X-linked loci. These signals are present in quantitative genetic metrics—i.e., a disproportionate contribution of the X to male (but not female) fitness variation—and population genetic metrics—i.e., steeper regressions of an allele’s average fitness effect on its frequency, and proportionally less nonsynonymous polymorphism on the X than autosomes. Fitting our data to models for both sets of metrics, we infer that deleterious alleles are partially recessive. Given the often-large gap between quantitative and population genetic estimates of evolutionary parameters, our study showcases the benefits of combining genomic and fitness data when estimating such parameters

Recombination dynamics of a human Y-chromosomal palindrome:rapid GC-biased gene conversion, multi-kilobase conversion tracts, and rare inversions

The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten paralogous sequence variants (PSVs) within the arms of P6 in 378 Y chromosomes whose evolutionary relationships within the SNP-defined Y phylogeny are known. This allowed the identification of 146 historical gene conversion events involving individual PSVs, occurring at a rate of 2.9-8.4×10(-4) events per generation. A consideration of the nature of nucleotide change and the ancestral state of each PSV showed that the conversion process was significantly biased towards the fixation of G or C nucleotides (GC-biased), and also towards the ancestral state. Determination of haplotypes by long-PCR allowed likely co-conversion of PSVs to be identified, and suggested that conversion tract lengths are large, with a mean of 2068 bp, and a maximum in excess of 9 kb. Despite the frequent formation of recombination intermediates implied by the rapid observed gene conversion activity, resolution via crossover is rare: only three inversions within P6 were detected in the sample. An analysis of chimpanzee and gorilla P6 orthologs showed that the ancestral state bias has existed in all three species, and comparison of human and chimpanzee sequences with the gorilla outgroup confirmed that GC bias of the conversion process has apparently been active in both the human and chimpanzee lineages

Determinants of the efficacy of natural selection on coding and noncoding variability in two passerine species

Population genetic theory predicts that selection should be more effective when the effective population size (Ne) is larger, and that the efficacy of selection should correlate positively with recombination rate. Here, we analyzed the genomes of ten great tits and ten zebra finches. Nucleotide diversity at 4-fold degenerate sites indicates that zebra finches have a 2.83-fold larger Ne. We obtained clear evidence that purifying selection is more effective in zebra finches. The proportion of substitutions at 0-fold degenerate sites fixed by positive selection (α) is high in both species (great tit 48%; zebra finch 64%) and is significantly higher in zebra finches. When α was estimated on GC-conservative changes (i.e., between A and T and between G and C), the estimates reduced in both species (great tit 22%; zebra finch 53%). A theoretical model presented herein suggests that failing to control for the effects of GC-biased gene conversion (gBGC) is potentially a contributor to the overestimation of α, and that this effect cannot be alleviated by first fitting a demographic model to neutral variants. We present the first estimates in birds for α in the untranslated regions, and found evidence for substantial adaptive changes. Finally, although purifying selection is stronger in high-recombination regions, we obtained mixed evidence for α increasing with recombination rate, especially after accounting for gBGC. These results highlight that it is important to consider the potential confounding effects of gBGC when quantifying selection and that our understanding of what determines the efficacy of selection is incomplete

Sex-specific Trans-regulatory Variation on the Drosophila melanogaster X Chromosome

The X chromosome constitutes a unique genomic environment because it is present in one copy in males, but two copies in females. This simple fact has motivated several theoretical predictions with respect to how standing genetic variation on the X chromosome should differ from the autosomes. Unmasked expression of deleterious mutations in males and a lower census size are expected to reduce variation, while allelic variants with sexually antagonistic effects, and potentially those with a sex-specific effect, could accumulate on the X chromosome and contribute to increased genetic variation. In addition, incomplete dosage compensation of the X chromosome could potentially dampen the male-specific effects of random mutations, and promote the accumulation of X-linked alleles with sexually dimorphic phenotypic effects. Here we test both the amount and the type of genetic variation on the X chromosome within a population of Drosophila melanogaster, by comparing the proportion of X linked and autosomal trans-regulatory SNPs with a sexually concordant and discordant effect on gene expression. We find that the X chromosome is depleted for SNPs with a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordant effect. Interestingly, the contrasting results for SNPs with sexually concordant and discordant effects are driven by SNPs with a larger influence on expression in females than expression in males. Furthermore, the distribution of these SNPs is shifted towards regions where dosage compensation is predicted to be less complete. These results suggest that intrinsic properties of dosage compensation influence either the accumulation of different types of trans-factors and/or their propensity to accumulate mutations. Our findings document a potential mechanistic basis for sex-specific genetic variation, and identify the X as a reservoir for sexually dimorphic phenotypic variation. These results have general implications for X chromosome evolution, as well as the genetic basis of sex-specific evolutionary change

Evolutionary Consequences of Sex Linkage and Sex-Specific Selection.

Males and females make equal genetic contributions to each generation, yet each sex is exposed to different, sometimes opposing forces of natural and sexual selection. Because males and females are part of a common gene pool, “sex-specific selection” – selection differing between males and females in strength and/or direction – can potentially have major population genetic and adaptive consequences for sexually reproducing species. When selection follows the same trajectory in both sexes and acts more strongly in males, sex-specific selection facilitates adaptation. However, opposing selection between the sexes can also generate genomic conflict over the outcome of evolution. Such “sexually antagonistic selection” represents an adaptive constraint for sexually reproducing species. Despite its potential importance, theoretical and empirical studies in evolutionary genetics often overlook sex-specific selection. Though this neglect is beginning to be remedied, a thorough understanding of the adaptive consequences of sex-specific selection is currently lacking. This dissertation represents an attempt to better understand the evolutionary genetic consequences of sex-specific selection, and specifically focuses on three related questions: (A) Is adaptation enhanced or constrained by sex-linked inheritance, which theory predicts should enhance opportunities for sex-specific selection? (B) How do sex linkage and processes of sex-specific selection interact to influence patterns of fitness heritability between parents and offspring? (C) What are the long-term adaptive consequences of sexual reproduction on population fitness and the genetic load of deleterious mutations? These questions are addressed using a combination of mathematical theory, bioinformatics and comparative genomics techniques, and quantitative genetic experiments using the fruit fly Drosophila melanogaster. The theoretical and empirical aspects of the dissertation confirm that sex-specific selection is an important evolutionary consideration and that it generates both adaptive benefits and adaptive costs for sexually reproducing species.Ph.D.Ecology and Evolutionary BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64677/1/tconnal_3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/64677/2/tconnal_1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/64677/3/tconnal_2.pd

Slow evolution of sex-biased genes in the reproductive tissue of the dioecious plant Salix viminalis

The relative rate of evolution for sex-biased genes has often been used as a measure of the strength of sex-specific selection. In contrast to studies in a wide variety of animals, far less is known about the molecular evolution of sex-biased genes in plants, particularly in dioecious angiosperms. Here, we investigate the gene expression patterns and evolution of sex-biased genes in the dioecious plant Salix viminalis. We observe lower rates of sequence evolution for male-biased genes expressed in the reproductive tissue compared to unbiased and female-biased genes. These results could be partially explained by the lower codon usage bias for sex-biased genes leading to elevated rates of synonymous substitutions compared to unbiased genes. However, the stronger haploid selection in the reproductive tissue of plants, together with pollen competition, would also lead to higher levels of purifying selection acting to remove deleterious variation. Future work should focus on the differential evolution of haploid- and diploid-specific genes in order to understand the selective dynamics acting on these loci