Additions, Losses, and Rearrangements on the Evolutionary Route from a Reconstructed Ancestor to the Modern Saccharomyces cerevisiae Genome

Comparative genomics can be used to infer the history of genomic rearrangements that occurred during the evolution of a species. We used the principle of parsimony, applied to aligned synteny blocks from 11 yeast species, to infer the gene content and gene order that existed in the genome of an extinct ancestral yeast about 100 Mya, immediately before it underwent whole-genome duplication (WGD). The reconstructed ancestral genome contains 4,703 ordered loci on eight chromosomes. The reconstruction is complete except for the subtelomeric regions. We then inferred the series of rearrangement steps that led from this ancestor to the current Saccharomyces cerevisiae genome; relative to the ancestral genome we observe 73 inversions, 66 reciprocal translocations, and five translocations involving telomeres. Some fragile chromosomal sites were reused as evolutionary breakpoints multiple times. We identified 124 genes that have been gained by S. cerevisiae in the time since the WGD, including one that is derived from a hAT family transposon, and 88 ancestral loci at which S. cerevisiae did not retain either of the gene copies that were formed by WGD. Sites of gene gain and evolutionary breakpoints both tend to be associated with tRNA genes and, to a lesser extent, with origins of replication. Many of the gained genes in S. cerevisiae have functions associated with ethanol production, growth in hypoxic environments, or the uptake of alternative nutrient sources

Mechanisms of Chromosome Number Evolution in Yeast

The whole-genome duplication (WGD) that occurred during yeast evolution changed the basal number of chromosomes from 8 to 16. However, the number of chromosomes in post-WGD species now ranges between 10 and 16, and the number in non-WGD species (Zygosaccharomyces, Kluyveromyces, Lachancea, and Ashbya) ranges between 6 and 8. To study the mechanism by which chromosome number changes, we traced the ancestry of centromeres and telomeres in each species. We observe only two mechanisms by which the number of chromosomes has decreased, as indicated by the loss of a centromere. The most frequent mechanism, seen 8 times, is telomere-to-telomere fusion between two chromosomes with the concomitant death of one centromere. The other mechanism, seen once, involves the breakage of a chromosome at its centromere, followed by the fusion of the two arms to the telomeres of two other chromosomes. The only mechanism by which chromosome number has increased in these species is WGD. Translocations and inversions have cycled telomere locations, internalizing some previously telomeric genes and creating novel telomeric locations. Comparison of centromere structures shows that the length of the CDEII region is variable between species but uniform within species. We trace the complete rearrangement history of the Lachancea kluyveri genome since its common ancestor with Saccharomyces and propose that its exceptionally low level of rearrangement is a consequence of the loss of the non-homologous end joining (NHEJ) DNA repair pathway in this species

Evolutionary context improves regulatory network predictions

A novel algorithm harnesses phylogenetic information and facilitates a better understanding of the evolutionary divergence of gene regulation between species

Moving the Needle on Justice Reform: A Report on the American Justice Summit 2014

Executive Summary: Taking place over 5 hours during the afternoon of November 10th, 2014, in John Jay College’s Gerald W. Lynch Theater, the American Justice Summit was an unprecedented public meeting of some of the most important individuals working in contemporary criminal justice reform. The event placed these individuals in front of an audience of six hundred-odd practitioners, activists, students, elected officials, and policy professionals, in conversation with leading journalists and each other, to describe the scope and contours of the problems posed by the country’s dysfunctional and interlocking systems of criminal justice – mass incarceration, police-community relations, the system’s disproportionate criminalization of young people, people of color, and the mentally ill, its contributions to urban poverty, violence, and alienation – and to grapple with potential solutions. This report synthesizes data gathered from the event itself and its publicly available video record with dozens of participant and audience interviews in order to describe points of consensus and divergence among the gathered experts, to detail the full range of their proposed solutions, to evaluate the event’s impact on the gathered participants and the audience bearing witness, and to consider potentially fruitful directions for future efforts on a similar template. Having established the mold for large-scale, high-profile public events addressing criminal justice policy and advocating reform, Tina Brown Live Media and John Jay College have provided a powerful model for moving this essential conversation forward. In addition to providing a snapshot of the event and its immediate impact, this report attempts to address the context of a fast-moving reform conversation and an ideologically inclusive movement, the shape and focus of which is in constant flux as it takes place across academic institutions, policy forums, and media platforms. More voices join this conversation every day; it is the job of events like the American Justice Summit to curate these voices, and amplify those with the most meaningful ideas to contribute. Please note: Featured quotations throughout the document (shaded text boxes) contain hyperlinks to clips of the video and audio interviews from which they were drawn

Use of the complete basis set limit for computing highly accurate ab initio dipole moments

Calculating dipole moments with high-order basis sets is generally only possible for the light molecules, such as water. A simple, yet highly effective strategy of obtaining high-order dipoles with small, computationally less expensive basis sets is described. Using the finite field method for computing dipoles, energies calculated with small basis sets can be extrapolated to produce dipoles that are comparable to those obtained in high order calculations. The method reduces computational resources by approximately 50% (allowing the calculation of reliable dipole moments for larger molecules) and simultaneously improves the agreement with experimentally measured infrared transition intensities. For atmospherically important molecules which are typically too large to consider the use of large basis sets, this procedure will provide the necessary means of improving calculated spectral intensities by several percent

Origins, evolution, domestication and diversity of Saccharomyces beer yeasts

Yeasts have been used for food and beverage fermentations for thousands of years. Today, numerous different strains are available for each specific fermentation process. However, the nature and extent of the phenotypic and genetic diversity and specific adaptations to industrial niches have only begun to be elucidated recently. In Saccharomyces, domestication is most pronounced in beer strains, likely because they continuously live in their industrial niche, allowing only limited genetic admixture with wild stocks and minimal contact with natural environments. As a result, beer yeast genomes show complex patterns of domestication and divergence, making both ale (S. cerevisiae) and lager (S. pastorianus) producing strains ideal models to study domestication and, more generally, genetic mechanisms underlying swift adaptation to new niches

The solubility–permeability interplay in using cyclodextrins as pharmaceutical solubilizers: Mechanistic modeling and application to progesterone

A quasi-equilibrium mass transport analysis has been developed to quantitatively explain the solubility–permeability interplay that exists when using cyclodextrins as pharmaceutical solubilizers. The model considers the effects of cyclodextrins on the membrane permeability ( P m ) as well as the unstirred water layer (UWL) permeability ( P aq ), to predict the overall effective permeability ( P eff ) dependence on cyclodextrin concentration ( C CD ). The analysis reveals that: (1) UWL permeability markedly increases with increasing C CD since the effective UWL thickness quickly decreases with increasing C CD ; (2) membrane permeability decreases with increasing C CD , as a result of the decrease in the free fraction of drug; and (3) since P aq increases and P m decreases with increasing C CD , the UWL is effectively eliminated and the overall P eff tends toward membrane control, that is, P eff  ≈  P m above a critical C CD . Application of this transport model enabled excellent quantitative prediction of progesterone P eff as a function of HPΒCD concentrations in PAMPA assay, Caco-2 transepithelial studies, and in situ rat jejunal-perfusion model. This work demonstrates that when using cyclodextrins as pharmaceutical solubilizers, a trade-off exists between solubility increase and permeability decrease that must not be overlooked; the transport model presented here can aid in striking the appropriate solubility–permeability balance in order to achieve optimal overall absorption. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2739–2749, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71376/1/22033_ftp.pd

Practically Useful: What the Rosetta Protein Modeling Suite Can Do for You

The objective of this review is to enable researchers to use the software package ROSETTA for biochemical and biomedicinal studies. We provide a brief review of the six most frequent research problems tackled with ROSETTA. For each of these six tasks, we provide a tutorial that illustrates a basic ROSETTA protocol. The ROSETTA method was originally developed for de novo protein structure prediction and is regularly one of the best performers in the community-wide biennial Critical Assessment of Structure Prediction. Predictions for protein domains with fewer than 125 amino acids regularly have a backbone root-mean-square deviation of better than 5.0 A ˚. More impressively, there are several cases in which ROSETTA has been used to predict structures with atomic level accuracy better than 2.5 A ˚. In addition to de novo structure prediction, ROSETTA also has methods for molecular docking, homology modeling, determining protein structures from sparse experimental NMR or EPR data, and protein design. ROSETTA has been used to accurately design a novel protein structure, predict the structure of protein-protein complexes, design altered specificity protein-protein and protein-DNA interactions, and stabilize proteins and protein complexes. Most recently, ROSETTA has been used to solve the X-ray crystallographic phase problem. ROSETTA is a unified software package for protein structure prediction and functional design. It has been used to predic

VISIT-TS: A multimedia tool for population studies on tic disorder

Population-based assessment of Tourette syndrome (TS) and other tic disorders produces a paradox. On one hand, ideally diagnosis of tic disorders requires expert observation. In fact, diagnostic criteria for TS explicitly require expert assessment of tics for a definite diagnosis. On the other hand, large-scale population surveys with expert assessment of every subject are impracticable. True, several published studies have successfully used expert assessment to find tic prevalence in a representative population (e.g. all students in a school district). However, extending these studies to larger populations is daunting. We created a multimedia tool to demonstrate tics to a lay audience, discuss their defining and common attributes, and address features that differentiate tics from other movements and vocalizations. A first version was modified to improve clarity and to include a more diverse group in terms of age and ethnicity. The result is a tool intended for epidemiological research. It may also provide additional benefits, such as more representative minority recruitment for other TS studies and increased community awareness of TS