Inventing an arsenal: adaptive evolution and neofunctionalization of snake venom phospholipase A(2 )genes

BACKGROUND: Gene duplication followed by functional divergence has long been hypothesized to be the main source of molecular novelty. Convincing examples of neofunctionalization, however, remain rare. Snake venom phospholipase A(2 )genes are members of large multigene families with many diverse functions, thus they are excellent models to study the emergence of novel functions after gene duplications. RESULTS: Here, I show that positive Darwinian selection and neofunctionalization is common in snake venom phospholipase A(2 )genes. The pattern of gene duplication and positive selection indicates that adaptive molecular evolution occurs immediately after duplication events as novel functions emerge and continues as gene families diversify and are refined. Surprisingly, adaptive evolution of group-I phospholipases in elapids is also associated with speciation events, suggesting adaptation of the phospholipase arsenal to novel prey species after niche shifts. Mapping the location of sites under positive selection onto the crystal structure of phospholipase A(2 )identified regions evolving under diversifying selection are located on the molecular surface and are likely protein-protein interactions sites essential for toxin functions. CONCLUSION: These data show that increases in genomic complexity (through gene duplications) can lead to phenotypic complexity (venom composition) and that positive Darwinian selection is a common evolutionary force in snake venoms. Finally, regions identified under selection on the surface of phospholipase A(2 )enzymes are potential candidate sites for structure based antivenin design

Cell-type phylogenetics and the origin of endometrial stromal cells

SummaryA challenge of genome annotation is the identification of genes performing specific biological functions. Here, we propose a phylogenetic approach that utilizes RNA-seq data to infer the historical relationships among cell types and to trace the pattern of gene-expression changes on the tree. The hypothesis is that gene-expression changes coincidental with the origin of a cell type will be important for the function of the derived cell type. We apply this approach to the endometrial stromal cells (ESCs), which are critical for the initiation and maintenance of pregnancy. Our approach identified well-known regulators of ESCs, PGR and FOXO1, as well as genes not yet implicated in female fertility, including GATA2 and TFAP2C. Knockdown analysis confirmed that they are essential for ESC differentiation. We conclude that phylogenetic analysis of cell transcriptomes is a powerful tool for discovery of genes performing cell-type-specific functions

Gas Sorption and Luminescence Properties of a Terbium(III)-Phosphine Oxide Coordination Material with Two-Dimensional Pore Topology

The structure, stability, gas sorption properties and luminescence behaviour of a new lanthanide-phosphine oxide coordination material are reported. The polymer PCM-15 is based on Tb(III) and tris(p-carboxylated) triphenylphosphine oxide and has a 5,5-connected net topology. It exhibits an infinite three-dimensional structure that incorporates an open, two-dimensional pore structure. The material is thermally robust and remains crystalline under high vacuum at 150 degrees C. When desolvated, the solid has a CO2 BET surface area of 1187 m(2) g(-1) and shows the highest reported uptake of both O-2 and H-2 at 77 K and 1 bar for a lanthanide-based coordination polymer. Isolated Tb(III) centres in the as-synthesized polymer exhibit moderate photoluminescence. However, upon removal of coordinated OH2 ligands, the luminescence intensity was found to approximately double; this process was reversible. Thus, the Tb(III) centre was used as a probe to detect directly the desolvation and resolvation of the polymer.Welch Foundation F-1738, F-1631National Science Foundation 0741973, CHE-0847763Chemistr

Adaptive evolution of Hox-gene homeodomains after cluster duplications

BACKGROUND: Hox genes code for homeodomain-containing transcription factors that function in cell fate determination and embryonic development. Hox genes are arranged in clusters with up to 14 genes. This archetypical chordate cluster has duplicated several times in vertebrates, once at the origin of vertebrates and once at the origin of gnathostoms, an additional duplication event is associated with the origin of teleosts and the agnanths, suggesting that duplicated Hox cluster genes are involved in the genetic mechanisms behind the diversification of vertebrate body plans, and the origin of morphological novelties. Preservation of duplicate genes is promoted by functional divergence of paralogs, either by subfunction partitioning among paralogs or the acquisition of a novel function by one paralog. But for Hox genes the mechanisms of paralog divergence is unknown, leaving open the role of Hox gene duplication in morphological evolution. RESULTS: Here, we use several complementary methods, including branch-specific d(N)/d(S )ratio tests, branch-site d(N)/d(S )ratio tests, clade level amino acid conservation/variation patterns, and relative rate ratio tests, to show that the homeodomain of Hox genes was under positive Darwinian selection after cluster duplications. CONCLUSION: Our results suggest that positive selection acted on the homeodomain immediately after Hox clusters duplications. The location of sites under positive selection in the homeodomain suggests that they are involved in protein-protein interactions. These results further suggest that adaptive evolution actively contributed to Hox-gene homeodomain functions

Conference on the Federal Sentencing Guidelines, Panel 3: The Allocation of Discretion Under the Guidelines

The guidelines have shifted the locus of discretion from the judge to the prosecutor. This transfer has drastically changed sentencing because the prosecutor\u27s role is very different from the judge\u27s role. Before the guidelines, the prosecutor\u27s role in sentencing was minimal. The prosecutor could put a cap on the sentence by accepting a plea to a charge with a low maximum, but there was virtually no instance in which the charge would put a floor under the judge\u27s sentence. The judge, on the other hand, could sentence however he liked. Not only was the judge\u27s decision correct because it was final – there was no appellate review of sentences within the statutory maximum – it was correct because there was no law by which it could be called incorrect. Absent a few factors that were statutorily excluded from consideration, the judge could take into account any factor he thought relevant, and weigh it to whatever degree he thought it counted. The judge could be harsh or lenient, a retributivist or a utilitarian, a believer in deterrence or rehabilitation

The transcriptomic evolution of mammalian pregnancy:gene expression innovations in endometrial stromal fibroblasts

The endometrial stromal fibroblast (ESF) is a cell type present in the uterine lining of therian mammals. In the stem lineage of eutherian mammals, ESF acquired the ability to differentiate into decidual cells in order to allow embryo implantation. We call the latter cell type “neo-ESF” in contrast to “paleo-ESF” which is homologous to eutherian ESF but is not able to decidualize. In this study, we compare the transcriptomes of ESF from six therian species: Opossum (Monodelphis domestica; paleo-ESF), mink, rat, rabbit, human (all neo-ESF), and cow (secondarily nondecidualizing neo-ESF). We find evidence for strong stabilizing selection on transcriptome composition suggesting that the expression of approximately 5,600 genes is maintained by natural selection. The evolution of neo-ESF from paleo-ESF involved the following gene expression changes: Loss of expression of genes related to inflammation and immune response, lower expression of genes opposing tissue invasion, increased markers for proliferation as well as the recruitment of FOXM1, a key gene transiently expressed during decidualization. Signaling pathways also evolve rapidly and continue to evolve within eutherian lineages. In the bovine lineage, where invasiveness and decidualization were secondarily lost, we see a re-expression of genes found in opossum, most prominently WISP2, and a loss of gene expression related to angiogenesis. The data from this and previous studies support a scenario, where the proinflammatory paleo-ESF was reprogrammed to express anti-inflammatory genes in response to the inflammatory stimulus coming from the implanting conceptus and thus paving the way for extended, trans-cyclic gestation

<i>TP53</i> copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants

A major constraint on the evolution of large body sizes in animals is an increased risk of developing cancer. There is no correlation, however, between body size and cancer risk. This lack of correlation is often referred to as ’Peto’s Paradox’. Here, we show that the elephant genome encodes 20 copies of the tumor suppressor gene TP53 and that the increase in TP53 copy number occurred coincident with the evolution of large body sizes, the evolution of extreme sensitivity to genotoxic stress, and a hyperactive TP53 signaling pathway in the elephant (Proboscidean) lineage. Furthermore, we show that several of the TP53 retrogenes (TP53RTGs) are transcribed and likely translated. While TP53RTGs do not appear to directly function as transcription factors, they do contribute to the enhanced sensitivity of elephant cells to DNA damage and the induction of apoptosis by regulating activity of the TP53 signaling pathway. These results suggest that an increase in the copy number of TP53 may have played a direct role in the evolution of very large body sizes and the resolution of Peto’s paradox in Proboscideans

“For a Long Time Our Voices have been Hushed”: Using Student Perspectives to Develop Supports for Neurodiverse College Students

Although the challenges that autistic students face adapting to college are often pronounced, they are similar to the challenges that students with other disabilities face (e.g., difficulties with social interaction, self-advocacy, and executive functioning). However, extant evaluations of services for autistic college students are very limited despite an emerging literature examining supports for college students with a range of other disabilities. Given that many autistic students do not self-identify as autistic in college, and consequently might avoid autism-specific services, autistic students might benefit from services that are designed to support a broad range of neurodiverse students, or services that are structured according to the principles of Universal Design. In order to develop such services, we assessed the self-reported needs of autistic college students and their peers with other disabilities. Guided by needs assessments and feedback from students, we developed and evaluated two semesters of mentor-led group programming for autistic college students and students with other disabilities. The first semester of the program focused on social skills; after receiving feedback from participants, the curriculum for the second semester focused on self-advocacy. Participation in social-skills groups was associated with decreased anxiety and autism symptoms. Participation in self-advocacy groups was associated with increased perceived social support from friends, academic self-efficacy, and more accurate definitions of self-advocacy. This research suggests that supports for neurodiverse college students should be developed with their input and should include opportunities to engage with diverse peers

Molecular Evolution of Duplicated Ray Finned Fish HoxA Clusters: Increased Synonymous Substitution Rate and Asymmetrical Co-divergence of Coding and Non-coding Sequences

In this study the molecular evolution of duplicated HoxA genes in zebrafish and fugu has been investigated. All 18 duplicated HoxA genes studied have a higher non-synonymous substitution rate than the corresponding genes in either bichir or paddlefish, where these genes are not duplicated. The higher rate of evolution is not due solely to a higher non-synonymous-to-synonymous rate ratio but to an increase in both the non-synonymous as well as the synonymous substitution rate. The synonymous rate increase can be explained by a change in base composition, codon usage, or mutation rate. We found no changes in nucleotide composition or codon bias. Thus, we suggest that the HoxA genes may experience an increased mutation rate following cluster duplication. In the non-Hox nuclear gene RAG1 only an increase in non-synonymous substitutions could be detected, suggesting that the increased mutation rate is specific to duplicated Hox clusters and might be related to the structural instability of Hox clusters following duplication. The divergence among paralog genes tends to be asymmetric, with one paralog diverging faster than the other. In fugu, all b-paralogs diverge faster than the a-paralogs, while in zebrafish Hoxa-13a diverges faster. This asymmetry corresponds to the asymmetry in the divergence rate of conserved non-coding sequences, i.e., putative cis-regulatory elements. These results suggest that the 5′ HoxA genes in the same cluster belong to a co-evolutionary unit in which genes have a tendency to diverge together