No abstract

The human ␤-globin locus control region (LCR) harbors both strong chromatin opening and enhancer activity when assayed in transgenic mice. To understand the contribution of individual DNase I hypersensitive sites (HS) to the function of the human ␤-globin LCR, we have mutated the core elements within the context of a yeast artificial chromosome (YAC) carrying the entire locus and then analyzed the effect of these mutations on the formation of LCR HS elements and expression of the genes in transgenic mice. In the present study, we examined the consequences of two different HS2 mutations. We first generated seven YAC transgenic lines bearing a deletion of the 375-bp core enhancer of HS2. Single-copy HS2 deletion mutants exhibited severely depressed HS site formation and expression of all of the human ␤-globin genes at every developmental stage, confirming that HS2 is a vital, integral component of the LCR. We also analyzed four transgenic lines in which the core element of HS2 was replaced by that of HS3 and found that while HS3 is able to restore the chromatin-opening activity of the LCR, it is not able to functionally replace HS2 in mediating high-level globin gene transcription. These results continue to support the hypothesis that HS2, HS3, and HS4 act as a single, integral unit to regulate human globin gene transcription as a holocomplex, but they can also be interpreted to say that formation of a DNase I hypersensitive holocomplex alone is not sufficient for mediating high-level globin gene transcription. We therefore propose that the core elements must productively interact with one another to generate a unique subdomain within the nucleoprotein holocomplex that interacts in a stage-specific manner with individual globin gene promoters.Locus control regions (LCRs) are highly specialized tissuespecific DNA regulatory elements that are able to confer position-independent and copy number-dependent expression of cis-linked genes when examined in transgenic mice. Since the discovery of the human ␤-globin LCR (13, 20), a growing number of genes or loci have been found to be regulated by LCR-like activities. Most LCRs appear to be composite elements and, perhaps not coincidentally, contain several DNase I hypersensitive sites (HS). The examples of genes regulated by such elements include the human ␤-globin (45), the T-cellspecific CD2 (18), the T-cell receptor ␣/␦ (41), and the chicken lysozyme loci (2). Higgs et al. (23) and Montoliu et al. (35) have shown that single HS located upstream of the ␣-globin or tyrosinase genes also bear multiple activities normally attributed to an LCR.The human ␤-globin LCR, located from approximately 8 to 22 kbp upstream of the ε-globin gene (13, 14, 47, 48) is composed of four erythroid cell-specific (HS1 to HS4) and one ubiquitous (HS5) DNase I HS. This region mediates chromatin opening over the whole ␤-globin gene locus and also is responsible for stimulating high-level expression of the globin genes throughout erythroid cell development (12). Perhaps most remarkably, the LCR ...

Many rapid radiations, or bushes, throughout the Tree of Life remain unresolved. Here, we investigated how the shape of a bush interacts with two key processes -coalescence and mutation -that can lead to errors in phylogenetic inference under specific conditions. For this study, we focused on the tradeoff between sampling more individuals per species and sampling more loci as well as the utility of a species tree method based upon gene tree reconciliation and the concatenation of multiple loci for resolving bushes. We examined different bush shapes, varying both the speciation rate during the radiation and the depth of the radiation, to encompass a broad range of situations. Using simulations based upon parameters derived from empirical studies, we investigated the performance of phylogenetic analyses under different conditions to identify approaches with the greatest potential to resolve difficult phylogenies. Sampling a single individual for more loci outperformed sampling multiple individuals for one locus in all cases except the most recent radiations. We found that error due to homoplastic mutations increased with depth, while error due to the coalescent process remained unchanged. These simulations also revealed that, for certain ancient bushes, analyses of concatenated data matrices surprisingly resulted in more accurate phylogenies than gene tree reconciliation. The poor performance of gene tree reconciliation in this study appeared to reflect the poor estimation of gene trees, not the superiority of concatenation per se. Our results suggest concatenation remains a useful approximate method for species tree estimation, even for rapid evolutionary radiations. However, improved estimation of gene trees combined with use of gene tree reconciliation has the greatest potential for resolving the remaining bushes of the Tree of Life.

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This paper explores how predator evolution and the magnitude of predator genetic variation alter the population-level dynamics of predator-prey systems. We do this by analyzing a general eco-evolutionary predator-prey model using four methods: Method 1 identifies how eco-evolutionary feedbacks alter system stability in the fast and slow evolution limits; Method 2 identifies how the amount of standing predator genetic variation alters system stability; Method 3 identifies how the phase lags in predator-prey cycles depend on the amount of genetic variation; and Method 4 determines conditions for different cycle shapes in the fast and slow evolution limits using geometric singular perturbation theory. With these four methods, we identify the conditions under which predator evolution alters system stability and shapes of predator-prey cycles, and how those effect depend on the amount of genetic variation in the predator population. We discuss the advantages and disadvantages of each method and the relations between the four methods. This work shows how the four methods can be used in tandem to make general predictions about eco-evolutionary dynamics and feedbacks.

Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. In this randomized, double-blind, placebo-controlled study, patients with CRF ≥4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. Based on a pilot study, we randomized patients to receive either 400 mg of standardized PG twice daily or a matching placebo for 28 days. The primary end point was change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale from baseline to day 29. Of 127 patients, 112 (88.2%) were evaluable. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29 were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (<.001), and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 was not significantly different in the PG than in the placebo group (7.5 [12.7] vs 6.5 [9.9]; =.67). QoL, anxiety, depression, symptoms, and functional scores were not significantly different between the PG and placebo groups. Improvement in the FACIT-F subscale correlated with baseline scores (=.0005), Hospital Anxiety and Depression Scale results (=.032), and sex (=.023). There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64; =.024). Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF. Further studies are needed. ClinicalTrials.gov identifier: NCT01375114.

We use the small-bodied toucan genus Pteroglossus to test hypotheses about diversification in the lowland Neotropics. We sequenced three mitochondrial genes and one nuclear intron from all Pteroglossus species and used these data to reconstruct phylogenetic trees based on maximum parsimony, maximum likelihood, and Bayesian analyses. These phylogenetic trees were used to make inferences regarding both the pattern and timing of diversification for the group. We used the uplift of the Talamanca highlands of Costa Rica and western Panama as a geologic calibration for estimating divergence times on the Pteroglossus tree and compared these results with a standard molecular clock calibration. Then, we used likelihood methods to model the rate of diversification. Based on our analyses, the onset of the Pteroglossus radiation predates the Pleistocene, which has been predicted to have played a pivotal role in diversification in the Amazon rainforest biota. We found a constant rate of diversification in Pteroglossus evolutionary history, and thus no support that events during the Pleistocene caused an increase in diversification. We compare our data to other avian phylogenies to better understand major biogeographic events in the Neotropics. These comparisons support recurring forest connections between the Amazonian and Atlantic forests, and the splitting of cis/trans Andean species after the final uplift of the Andes. At the subspecies level, there is evidence for reciprocal monophyly and groups are often separated by major rivers, demonstrating the important role of rivers in causing or maintaining divergence. Because some of the results presented here conflict with current taxonomy of Pteroglossus, new taxonomic arrangements are suggested.

Recent studies investigating feedbacks between evolution and ecology suggest that microevolution may affect community structure. Motivated by this, we use a quantitative genetics and Lotka-Volterra framework to understand the impact of eco-evolutionary feedbacks on an intraguild predation community in which the intraguild predator evolves between a phenotype specialized for attacking its competitor (the intraguild prey) and a phenotype specialized for attacking a common resource. We show that evolution can drive both sudden and gradual shifts in community structure. Evolutionary rescue of the community, in which evolution prevents the loss of species, occurs in two ways: (i) selection to a particular phenotype that supports coexistence and (ii) continuous evolution between prey-and resource-specialist phenotypes that support communitylevel Red Queen dynamics in which the community fluctuates between prey-and predator-dominated states. Paradoxically, the predator can evolve to extirpate itself from the community provided that the ecological dynamics support bistability. Strong trade-offs between specialist phenotypes can lead to trait-based alternative states of the community resembling either a food chain or exploitative competition. Finally, we show that rapid evolution can stabilize equilibria that are unstable for the ecological dynamics, whereas slow evolution can stabilize equilibria that are unstable for the evolutionary dynamics. Our results demonstrate that eco-evolutionary feedbacks can drive shifts in community structure and that the overall dynamics depend on the trade-off strength and evolutionary rate.