Diffusion Approximations for Demographic Inference: DaDi

Models of demographic history (population sizes, migration rates, and divergence times) inferred from genetic data complement archeology and serve as null models in genome scans for selection. Most current inference methods are computationally limited to considering simple models or non-recombining data. We introduce a method based on a diffusion approximation to the joint frequency spectrum of genetic variation between populations. Our implementation, DaDi, can model up to three interacting populations and scales well to genome-wide data. We have applied DaDi to human data from Africa, Europe, and East Asia, building the most complex statistically well-characterized model of human migration out of Africa to date

Simulations and Modelling for Biological Invasions

Biological invasions are characterized by the movement of organisms from their native geographic region to new, distinct regions in which they may have significant impacts. Biological invasions pose one of the most serious threats to global biodiversity, and hence significant resources are invested in predicting, preventing, and managing them. Biological systems and processes are typically large, complex, and inherently difficult to study naturally because of their immense scale and complexity. Hence, computational modelling and simulation approaches can be taken to study them. In this dissertation, I applied computer simulations to address two important problems in invasion biology. First, in invasion biology, the impact of genetic diversity of introduced populations on their establishment success is unknown. We took an individual-based modelling approach to explore this, leveraging an ecosystem simulation called EcoSim to simulate biological invasions. We conducted reciprocal transplants of prey individuals across two simulated environments, over a gradient of genetic diversity. Our simulation results demonstrated that a harsh environment with low and spatially-varying resource abundance mediated a relationship between genetic diversity and short-term establishment success of introduced populations rather than the degree of difference between native and introduced ranges. We also found that reducing Allee effects by maintaining compactness, a measure of spatial density, was key to the establishment success of prey individuals in EcoSim, which were sexually reproducing. Further, we found evidence of a more complex relationship between genetic diversity and long-term establishment success, assuming multiple introductions were occurring. Low-diversity populations seemed to benefit more strongly from multiple introductions than high-diversity populations. Our results also corroborated the evolutionary imbalance hypothesis: the environment that yielded greater diversity produced better invaders and itself was less invasible. Finally, our study corroborated a mechanical explanation for the evolutionary imbalance hypothesis – the populations evolved in a more intense competitive environment produced better invaders. Secondly, an important advancement in invasion biology is the use of genetic barcoding or metabarcoding, in conjunction with next-generation sequencing, as a potential means of early detection of aquatic introduced species. Barcoding and metabarcoding invariably requires some amount of computational DNA sequence processing. Unfortunately, optimal processing parameters are not known in advance and the consequences of suboptimal parameter selection are poorly understood. We aimed to determine the optimal parameterization of a common sequence processing pipeline for both early detection of aquatic nonindigenous species and conducting species richness assessments. We then aimed to determine the performance of optimized pipelines in a simulated inoculation of sequences into community samples. We found that early detection requires relatively lenient processing parameters. Further, optimality depended on the research goal – what was optimal for early detection was suboptimal for estimating species richness and vice-versa. Finally, with optimal parameter selection, fewer than 11 target sequences were required in order to detect 90% of nonindigenous species

Inferring the Joint Demographic History of Multiple Populations from Multidimensional SNP Frequency Data

Demographic models built from genetic data play important roles in illuminating prehistorical events and serving as null models in genome scans for selection. We introduce an inference method based on the joint frequency spectrum of genetic variants within and between populations. For candidate models we numerically compute the expected spectrum using a diffusion approximation to the one-locus, two-allele Wright-Fisher process, involving up to three simultaneous populations. Our approach is a composite likelihood scheme, since linkage between neutral loci alters the variance but not the expectation of the frequency spectrum. We thus use bootstraps incorporating linkage to estimate uncertainties for parameters and significance values for hypothesis tests. Our method can also incorporate selection on single sites, predicting the joint distribution of selected alleles among populations experiencing a bevy of evolutionary forces, including expansions, contractions, migrations, and admixture. We model human expansion out of Africa and the settlement of the New World, using 5 Mb of noncoding DNA resequenced in 68 individuals from 4 populations (YRI, CHB, CEU, and MXL) by the Environmental Genome Project. We infer divergence between West African and Eurasian populations 140 thousand years ago (95% confidence interval: 40–270 kya). This is earlier than other genetic studies, in part because we incorporate migration. We estimate the European (CEU) and East Asian (CHB) divergence time to be 23 kya (95% c.i.: 17–43 kya), long after archeological evidence places modern humans in Europe. Finally, we estimate divergence between East Asians (CHB) and Mexican-Americans (MXL) of 22 kya (95% c.i.: 16.3–26.9 kya), and our analysis yields no evidence for subsequent migration. Furthermore, combining our demographic model with a previously estimated distribution of selective effects among newly arising amino acid mutations accurately predicts the frequency spectrum of nonsynonymous variants across three continental populations (YRI, CHB, CEU).</p

Learning from community forestry experience: Challenges and lessons from British Columbia

A multiple case study approach is used to investigate community forest implementation challenges in British Columbia, Canada. Stakeholder interviews, document review and visits to the case sites (Denman Island, Malcolm Island, Cortes Island and Creston) were used to collect data on events occurring between 1990 and 2005. In addition to case-specific challenges, our analysis confirmed common challenges related to a lack of support, consensus, and organizational resources as well as poor forest health and timber profiles, resistance from conventional forest management, and competition for land and tenures. Development pressure emerged as a challenge for communities without land use decisionmaking authority. The final section offers some lessons and recommendations. / Une approche d’études de cas multiples est utilisée pour étudier les défis découlant de l’implantation de forêts communautaires en Colombie-Britannique, Canada. Nous avons effectué des entrevues auprès des intervenants, une revue des documents et des visites sur le terrain (Denman Island, Malcolm Island, Cortes Island et Creston) afin de recueillir des données sur les événements survenus entre 1990 et 2005. En plus des défis spécifiques à chaque cas, notre analyse a confirmé des défis communs reliés à la faiblesse des appuis, à un consensus mitigé et un manque de ressources organisationnelles ainsi qu’un mauvais état de santé des forêts et une pauvre répartition de la qualité au niveau des tiges, à la résistance par rapport à l’aménagement forestier conventionnel et à la compétition pour l’utilisation du territoire et la forme de tenure. Les communautés n’ayant pas d’autorité en matière de prise de décision sur l’utilisation du territoire ont connu l’émergence de défis face à des pressions de développement. La dernière section présente quelques leçons et recommandations.Support for this work has been provided by the Social Sciences and Humanities Research Council and inkind support has been generously provided by Western Forest Products.http://pubs.cif-ifc.org/doi/10.5558/tfc85293-

Derivation of Enriched Oligodendrocyte Cultures and Oligodendrocyte/Neuron Myelinating Co-cultures from Post-natal Murine Tissues

Identifying the molecular mechanisms underlying OL development is not only critical to furthering our knowledge of OL biology, but also has implications for understanding the pathogenesis of demyelinating diseases such as Multiple Sclerosis (MS). Cellular development is commonly studied with primary cell culture models. Primary cell culture facilitates the evaluation of a given cell type by providing a controlled environment, free of the extraneous variables that are present in vivo. While OL cultures derived from rats have provided a vast amount of insight into OL biology, similar efforts at establishing OL cultures from mice has been met with major obstacles. Developing methods to culture murine primary OLs is imperative in order to take advantage of the available transgenic mouse lines

Identification and cost of adverse events in metastatic breast cancer in taxane and capecitabine based regimens.

PurposeWe sought to compare the economic impact of treatment-related adverse events (AEs) in patients with metastatic breast cancer (mBC) using taxane- or capecitabine-based treatment regimens as either first- or second-line (FL or SL) therapy in the US.MethodsWe used healthcare claims data from the Truven Health Analytics MarketScan® Commercial Databases to conduct a retrospective cohort study comparing the economic impact of AEs amongst taxane- and capecitabine-treated mBC patients in the US. We selected women diagnosed with mBC between 2008-2010 who received a taxane or capecitabine as first- or second-line (FL or SL) chemotherapy. Costs related to hospitalization, outpatient services, emergency department visits, chemotherapy and other medications were tabulated and combined to determine total healthcare costs. The incremental monthly costs associated with the presence of AEs compared to no AEs were estimated using generalized linear models, controlling for age and Charlson Comorbidity Index.ResultsWe identified 15,443 mBC patients meeting inclusion criteria. Adjusted total monthly costs were significantly higher in those who experienced AEs than in those without AEs in both lines of treatment (FL incremental cost: taxanes $1,142, capecitabine$1,817; SL incremental cost: taxanes $1,448, capecitabine$4,437). Total costs increased with the number of AEs and were primarily driven by increased hospitalization amongst those with AEs.ConclusionsAdverse events in taxane- or capecitabine-treated mBC patients are associated with significant increases in costs. Selecting treatment options associated with fewer AEs may reduce costs and improve outcomes in these patients

Bioinformatic Comparison of Genes in the Leucine Biosynthesis Pathway of \u3cem\u3eEscherichia coli\u3c/em\u3e to \u3cem\u3eMeiothermus ruber\u3c/em\u3e

We predict that Mrub_1905 and Mrub_1906 encode the enzyme 2-isopropylmalate synthase (Mrub_1906 DNA coordinates complement(1965044..1966603) Mrub_1905 DNA coordinates complement(1963455..1965041)), which is the first step of the leucine biosynthesis pathway (KEGG map number 00290). It catalyzes the conversion of (2S)-2-isopropylmalate to 2-isopropylmaleate. The E. coli K12 MG1655 ortholog is predicted to be b0074, which has the gene identifier leuA. We predict that Mrub_1846 encodes the enzyme 3-isopropylmalate dehydrogenase (DNA coordinates complement(1903909..1904961)), which is the third step of the leucine biosynthesis pathway (KEGG map number 00290). It catalyzes the conversion of (2R,3S)-3-isopropylmalate to (2S)-2-isopropyl-3-oxosuccinate. The E. coli K12 MG1655 ortholog is predicted to be b0073, which has the gene identifier leuB. We predict that Mrub_1850 encodes for 3-isopropylmalate dehydratase (DNA coordinates complement(1906426..1907850)), the large subunit of the heteromeric enzyme, which is the second step of the leucine biosynthesis pathway (KEGG map number 00290). It catalyzes the conversion of (2S)-2-isopropylmalate to (2R,3S)-3-isopropylmalate. The E. coli K12 MG1655 ortholog is predicted to be b0072, which has the gene identifier leuC. We predict that Mrub_1847 encodes the enzyme isopropylmalate isomerase (DNA coordinates complement(1904975..1905580)), the small subunit of the heteromeric enzyme, which is the second step of the leucine biosynthesis pathway (KEGG map number 00290). It catalyzes the conversion of (2S)-2-isopropylmalate to (2R,3S)-3-isopropylmalate. The E. coli K12 MG1655 ortholog is predicted to be b0071, which has the gene identifier leuD