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Introduced organisms experience founder effects including genetic bottlenecks that result in significant reductions in genetic variation. Genetic bottlenecks may constrain the evolution of phenotypic traits that facilitate success in novel habitats. We examined the effect of introduction into novel environments on genetic diversity of an insect pest, Adelges cooleyi , which was introduced into the eastern United States during the mid nineteenth century. We compared variation in mitochondrial and nuclear genomes in native and introduced samples to determine the effect of introduction on genetic variation experienced by this insect. We also measured an ecologically important phenotype, variation in host preference, in both native and introduced samples to compare variation in that trait with molecular genetic variation. To further investigate the relationship between genetic and phenotypic variation, we examined the degree to which mtDNA haplotypes provide information about host preference. Adelges cooleyi in eastern North America has significantly reduced genetic and phenotypic variation, but this low variation does not appear to have prevented persistence in a novel environment. Introduced insects appear to have retained host preference phenotypes similar to those of insects found where introductions likely originated.

We investigated the relative contribution of minimum residence time, growth habit, and history of invasiveness to the spread of exotic plants in Michigan and California. Our data include minimum residence time as estimated by earliest herbarium collection records, growth habit, and history of invasiveness for over 2000 records from two herbaria (MI = 943, CA = 1131). Our data support the hypothesis that minimum residence time is highly associated with landscape spread, explaining 39–44% of variation in the number of counties invaded. In contrast, growth habit and history of invasiveness explained a small fraction of variation in spread in California but not Michigan. Over the past 30 years exotic plant species frequently became established in Michigan and California (≥50 species per decade), suggesting that many more species will become invasive over time. There is an urgent need to develop effective policies for exotic plant management. In both states we found significant positive correlations between minimum residence time and species occurrence on state invasive plant lists. Further, we found historical information on the pest status of a plant species introduced into a similar environment to be relevant in determining landscape spread of exotic plants. We conclude that efforts to predict exotic species spread based on biological characteristics may have limited success, and instead endorse pest risk analysis for proposed new imports coupled with rapid detection and early response for unintended and unwanted introductions.

Adelges cooleyi (Hemiptera: Adelgidae), a host-alternating gall-making insect pest native to the Rocky Mountains and Pacific Northwest and introduced into the eastern United States during the mid-19th century, was studied to address questions about phylogeography, to determine effects of introduction on genotypic and phenotypic variation, and to compare genetic variation associated with host use in native and introduced ranges. In Chapter One, sequence data from two mitochondrial (mtDNA) genes and amplified fragment length polymorphisms (AFLPs) were used to quantify the structure of genetic variation in the insect's native range. Several well-supported, divergent mtDNA lineages were identified. The structure of genetic variation among sampled locations is consistent with patterns shaped by glaciations. Samples from the southern edge of the insect's distribution are genetically isolated from the rest of the species, and hybridization of divergent mtDNA lineages via secondary contact was inferred from AFLP data. Changes in genetic and phenotypic variation associated with introduction were quantified in Chapter Two. Introduced populations had decreased genetic variation relative to native populations. Variation in an ecologically important trait, host preference, was also significantly lower in introduced populations than in native populations. An association between mtDNA haplotypes and host preference was identified. Adelges cooleyi in the eastern US have low genetic and phenotypic variation but appear to be sufficiently adapted for persistence. My results call into question the utility of neutral genetic variation to assess the probability of persistence in new environments by introduced species. Host-plants that A. cooleyi requires to complete its lifecycle are not native to the eastern US and occur together in patches that are often widely separated. In Chapter Three, analyses of mtDNA and AFLP genetic variation were conducted to determine the distribution of genetic variation within and among host plants in the native range and identify discrepancies that may be consistent with an incomplete lifecycle in the introduced range. Distribution of genetic variation within and among host-plants in the introduced range was not significantly different than that in the native range, as indicated by fixation indices, and I found no evidence for asexual populations in the introduced range.

Background The 12-item Short-Form Health Survey version 2 (SF-12v2), a widely used, generic patient-reported measure of health status that provides summary scores of physical and mental health. No study to date has examined the measurement properties of the SF-12v2 in patients with lung cancer using Rasch analysis. The aim of this study was to extend the psychometric evaluations of the SF-12 within the lung cancer population to ensure its validity and reliability to assess the health status in this population. Methods Participants in the Victorian Lung Cancer Registry (VLCR) who completed the SF-12v2 between 2012 and 2016 were included in this study. The structural validity of the SF-12v2 was assessed using Rasch analysis. Overall fit to the Rasch measurement model was examined as well as five key measurement properties: uni-dimensionality, response thresholds, internal consistency, measurement invariance and targeting. Results A total of 342 participants completed the SF-12v2 three months following their lung cancer diagnosis. The SF-12 Physical Component Score (PCS-12) did not fit the overall Rasch measurement model (χ 2 107.0; p  < 0.001). Three items deviated significantly from the Rasch model (item fit residual beyond ± 2.5) with signs of dependency between item responses and disordered thresholds. Nevertheless, the PCS-12 was uni-dimensional with good internal consistency (person separation index [PSI] 0.83) and reasonable targeting. In contrast, the SF-12 Mental Component Score (MCS-12) had good overall model fit (χ 2 35.1; p  = 0.07), reasonable targeting and good internal consistency (PSI 0.81). Conclusions Rasch analysis suggests that there is general support for the reliability of the SF-12v2 as a measure of physical and mental health in people with lung cancer. However, the appropriateness of some items (e.g. pain) in the PCS-12 is questionable and further refinement of the scale including changing the response options may be required to improve the ability of the SF-12v2 to more appropriately assess the health status of this population.

Background The behavioural variant of frontotemporal dementia (bvFTD) is a challenging diagnosis due to overlapping symptoms with psychiatric and other neurological conditions. Accordingly, misdiagnosis is common. The present study aimed to identify clinical factors contributing to misdiagnoses of bvFTD by specialist physicians. Methods We retrospectively analysed 100 consecutive referrals by specialist physicians (primarily psychiatrists, neurologists and geriatricians) to a tertiary cognitive disorders clinic specializing in frontotemporal lobar degenerative disorders. Patients were included if the referring specialist suspected bvFTD or if bvFTD was confirmed as the final diagnosis. Diagnostic factors were assessed by comparing the initial referral information with final clinical diagnoses. Results Of the 100 patients, 34 were true‐positive and 66 were false‐positive for bvFTD. False‐positive diagnoses were often based on misinterpretation of neuroimaging, particularly nuclear imaging (FDG‐PET and HMPAO‐SPECT), where subjective interpretation errors led to incorrect bvFTD diagnoses in 32 patients. Cognitive testing also contributed to misdiagnosis, with formal neuropsychological testing incorrectly leading to a bvFTD diagnosis in 20 patients. Patients with prior psychiatric histories were more likely to be misdiagnosed. Observable behavioural features of bvFTD and physical neurological signs were significantly more prevalent in true‐positive patients. Conclusions Misinterpretation of neuroimaging and cognitive testing, in particular formal neuropsychological testing, significantly contributed to false‐positive bvFTD diagnoses. Physicians should be cautious not to over‐interpret neuroimaging and neuropsychology studies and be wary of patients with prior psychiatric histories. In contrast, greater weight should be placed on objective clinical observations of behavioural signs of bvFTD and the emergence of physical neurological signs.

Benzoxazinoids are important defense compounds in grasses. Here, we investigated the biosynthesis and biological roles of the 8-O-methylated benzoxazinoids, DIM2BOA-Glc and HDM2BOA-Glc. Using quantitative trait locus mapping and heterologous expression, we identified a 2-oxoglutarate-dependent dioxygenase (BX13) that catalyzes the conversion of DIMBOA-Glc into a new benzoxazinoid intermediate (TRIMBOA-Glc) by an uncommon reaction involving a hydroxylation and a likely ortho-rearrangement of a methoxy group. TRIMBOA-Glc is then converted to DIM2BOA-Glc by a previously described O-methyltransferase BX7. Furthermore, we identified an O-methyltransferase (BX14) that converts DIM2BOA-Glc to HDM2BOA-Glc. The role of these enzymes in vivo was demonstrated by characterizing recombinant inbred lines, including Oh43, which has a point mutation in the start codon of Bx13 and lacks both DIM2BOA-Glc and HDM2BOA-Glc, and Il14H, which has an inactive Bx14 allele and lacks HDM2BOA-Glc in leaves. Experiments with near-isogenic maize lines derived from crosses between B73 and Oh43 revealed that the absence of DIM2BOA-Glc and HDM2BOA-Glc does not alter the constitutive accumulation or deglucosylation of other benzoxazinoids. The growth of various chewing herbivores was not significantly affected by the absence of BX13-dependent metabolites, while aphid performance increased, suggesting that DIM2BOA-Glc and/or HDM2BOA-Glc provide specific protection against phloem feeding insects.

The maize W22 inbred has served as a platform for maize genetics since the mid twentieth century. To streamline maize genome analyses, we have sequenced and de novo assembled a W22 reference genome using short-read sequencing technologies. We show that significant structural heterogeneity exists in comparison to the B73 reference genome at multiple scales, from transposon composition and copy number variation to single-nucleotide polymorphisms. The generation of this reference genome enables accurate placement of thousands of Mutator ( Mu ) and Dissociation ( Ds ) transposable element insertions for reverse and forward genetics studies. Annotation of the genome has been achieved using RNA-seq analysis, differential nuclease sensitivity profiling and bisulfite sequencing to map open reading frames, open chromatin sites and DNA methylation profiles, respectively. Collectively, the resources developed here integrate W22 as a community reference genome for functional genomics and provide a foundation for the maize pan-genome. Sequencing and de novo assembly of the maize W22 reference genome enable accurate placement of Mutator ( Mu ) and Dissociation ( Ds ) transposable element insertions, providing a foundation for maize functional genomics and transposon biology.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified > 300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alíeles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e − 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e − 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e − 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.