Given the distribution and probable evolutionary history of the Peromyscus maniculatus species group, an interspecific comparison of microsatellite variation among these species would be logically based (at least initially) on primers isolated from the genome of a geographically central population of P. maniculatus. Additionally, as the species in the group are recently diverged, reasonably informative microsatellite data are likely to require analysis of a rapid evolving category of microsatellite loci. The initial phase of this research involved the isolation, characterization and assessment of variation for a panel of DNA microsatellites containing perfect dinucleotide repeats from a geographically central population of P. maniculatus. Theoretical predictions and empirical studies indicate that phylogenetic analyses based on microsatellite primers isolated from a focal species may be subject to ascertainment biases that can be expected to degrade the efficacy of this approach with increasing phylogenetic depth between the species from which the microsatellites were isolated and those to which these loci are being compared. Results of an analysis of allelic variation at 12 pure, dinucleotide microsatellite loci (isolated from P. maniculatus) are reported for samples of all species in the P. maniculatus species group and the sister taxon P. leucopus. Examined for the species in the P. maniculatus species group for which there is an a priori highly corroborated phylogeny, evidence of ascertainment bias was apparent only for one locus that was unique to P. maniculatus. Genealogical analyses of the data over all loci yielded inferred relationships that were entirely concordant with the a priori corroborated phylogeny for P. maniculatus, P. keeni, P. polionotus, P. melanotis and P. leucopus. Genealogical analyses of the previously unresolved relationships of P. keeni and P. sejugis consistently placed these as an independent sister-group between P. maniculatus and P. polionotus. The geographically improbable sister-group association of P. keeni and P. sejugis may be the result of an historical ancestral continuity or may reflect large-scale lineage sorting rather than true phylogenetic propinquity. These data suggest that, given the choice of an appropriate focal species, even relatively small sets of pure dinucleotide microsatellites can provide reliable population genetic and systematic implications for taxa with divergence times dating to the Pleistocene.

No description available.

Genomic data facilitate opportunities to track complex population histories of divergence and gene flow. We used 47,506 single-nucleotide polymorphisms (SNPs) to investigate cattle population history. Cattle are descendants of two independently domesticated lineages, taurine and indicine, that diverged 200,000 or more years ago. We found that New World cattle breeds, as well as many related breeds of cattle in southern Europe, exhibit ancestry from both the taurine and indicine lineages. Although European cattle are largely descended from the taurine lineage, gene flow from African cattle (partially of indicine origin) contributed substantial genomic components to both southern European cattle breeds and their New World descendants. We extended these analyses to compare timing of admixture in several breeds of taurine-indicine hybrid origin. We developed a metric, scaled block size (SBS), that uses the unrecombined block size of introgressed regions of chromosomes to differentiate between recent and ancient admixture. By comparing test individuals to standards with known recent hybrid ancestry, we were able to differentiate individuals of recent hybrid origin from other admixed individuals using the SBS metric. We genotyped SNP loci using the bovine 50K SNP panel. The selection of sites to include in SNP analyses can influence inferences from the data, especially when particular populations are used to select the array of polymorphic sites. To test the impact of this bias on the inference of population genetic parameters, we used empirical and simulated data representing the three major continental groups of cattle: European, African, and Indian. We compared the inference of population histories for simulated data sets across different ascertainment conditions using F[subscript ST] and principal components analysis (PCA). Ascertainment bias that results in an over-representation of within-group polymorphism decreases estimates of F[subscript ST] between groups. Geographically biased selection of polymorphic SNPs changes the weighting of principal component axes and can bias inferences about proportions of admixture and population histories using PCA. By combining empirical and simulated data, we were able to both test methods for inferring population histories from genomic SNP data and apply these methods to practical problems. / text

Research into human disease has classically been 'bottom-up', focussing on individual genes. However, the emergence of Systems Biology has prompted a more holistic 'top-down' approach to decoding life. Less than a decade since the complete draft of the human genome was published, we are increasingly in a position to model the interacting constituents of a cell and thus understand molecular perturbations. Given biological systems are rarely attributable to individual molecules and linear pathways, we must understand the complex dynamic interplay as cellular components interact, combine, overlap and conflict. The integrative approach afforded by Network Biology provides us with a powerful toolset to understand the vast volumes of omics data. In this thesis, I investigate both infectious disease, specifically HIV infection and heritable disease. HIV, the causative agent of AIDS, represents an extensive perturbation of the host system and results in hijacking of cellular proteins to replicate. I first introduce the HIV-interaction data and then characterise HIV's hijack, revealing the ways Network Biology can greatly enhance our understanding of host-pathogen systems and ultimately the systems itself. I find a significantly greater propensity for HIV to interact with ''key'' host proteins that are highly connected and represent critical cellular functions. Unexpectedly, however, I find there are no associations between HIV interaction and inferred essentiality and genetic disease-association. I hypothesise that these observations could be the result of ancestral selection pressure on retroviruses to minimise interactions with phenotypically crucial proteins. Investigating inherited disease, I apply a similar integrative approach to determine the relationships between inherited disease, evolution and function. I find that 'disease' genes are not a homogenous group, and that their emergence has been ongoing throughout the evolution of life; contradicting previous studies. Finally, I consider the consequence of bias in literature-curated interaction datasets. I develop a novel method to identify and correct for ascertainment bias and demonstrate that failure to do this weakens conclusions. correct for ascertainment bias and demonstrate that failure to do this weakens conclusions. The aim of this thesis has been to explore the ways Network Biology can provide an integrative biological approach to studying infectious and inherited disease. Given billions of people around the world are susceptible to disease, it is ultimately hoped that a Systems Biology approach to understanding disease will herald new pharmaceutical interventions.

Thesis advisor: Gabor T. Marth / Thesis advisor: Eric F. Tsung / My work is part of an effort in Dr. Gabor Marth's population genetics lab to extend the work of Marth's 2004 Genetics paper "The allele frequency spectrum in genome-wide human variation data reveals signals of differential demographic history in three large world populations" by applying its methods to new datasets. My contribution toward this end has been to create computer code (in Perl and Bash) to quantify ascertainment bias and determine proxy ancestral alleles in human genome-wide polymorphic data for post-doctoral fellow Dr. Eric Tsung's use in the determination of human demographic history. The final results of my efforts will be part of a poster by Dr. Tsung (with myself as a second author) displayed at the 2007 Biology of Genomes Symposium at Cold Spring Harbor Laboratory in Cold Spring Harbor, New York. Our goal is to turn that poster into a paper (on which I will be an author) for submission for publication in a major scientific research periodical and which will also be available in the future at http://bioinformatics.bc.edu/marthlab/ascertainmentancestral/. / Thesis (BS) — Boston College, 2007. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Biology. / Discipline: College Honors Program.

The aim of the present work is to describe the semantics and the discursive functions from a general cognitivist point of view of the usage of the Present Perfect in the spoken Spanish of Chile, Paraguay and Uruguay. It is argued that cross-linguistic values often ascribed to perfect, such as continuity, current relevance and recency to the speech time –ST– do not offer a consistent view of the actual usage. It is assumed that a basic meaning of the perfect operates in the studied dialects and is retrievable in all tokens, which differs significantly from the current descriptions of the perfect of “general” Spanish. The results show that the ST might very well be an inference of the basic meaning of the Perfect but it is not an intrinsic component of the Perfect’s semantics. Based mainly on Dahl & Hedin (2000), as well as on Langacker (1987), the revitalizing of the concepts type and token reference are suggested as key principles for identifying the respective domains of the Spanish Present Perfect and the Simple Past in the studied area. The Perfect, through type reference, makes an assertion of a situation as a representation of the class-type of the verbal semantics. The Simple Past, however, through token reference conceptualizes the situation as having explicit or implicit anchoring in the chronological axis of time. Three main kinds of contexts occur typically with the Perfect in the samples: detemporalized ascertainment, summary (in a broad sense of the word) and aspectual complexity. Summary scanning (Langacker, 1987), i.e. the schematic and holistic detemporalized conceptualization of the development of a given situation, is claimed to be used by informants for discursive purposes, granting a greater rhetorical weight to the Perfect. The results founded in this thesis indicate that the perfect tenses in Spanish have followed (and are following) different developmental paths that are not necessarily restricted to the same sequences and mode of grammaticalization.

Outcome dependent sampling may increase efficiency in observational studies. It is however not always obvious how to sample efficiently, and how to analyze the resulting data without introducing bias. This thesis describes a general framework for efficiency calculations in multistage sampling, with focus on what is sometimes referred to as ascertainment sampling. A method for correcting for the sampling scheme in analysis of ascertainment samples is also presented. Simulation based methods are used to overcome computational issues in both efficiency calculations and analysis of data. / At the time of doctoral defense, the following paper was unpublished and had a status as follows: Paper 1: Submitted.

Mandatory notification of disease forms the backbone of disease surveillance in New Zealand and overseas. Notification data is used by public health professionals and academics to identify cases requiring public health control, monitor disease incidence and distribution, and in epidemiological research. However, there is emerging evidence that notification rates do not accurately reflect the true extent of notifiable diseases within the community, resulting in the underascertainment of many notifiable cases. While adequate surveillance does not necessarily require that all cases of notifiable disease be captured, the systematic underascertainment of disease can have significant implications for perceived spatial and demographic trends in disease prevalence; potentially threatening the credibility of spatial epidemiological research by under or overestimating the burden of disease in different populations. There is evidence that systematic underascertainment occurs as a result of the differential actions of laboratories and general practitioners. It has also been recognised that that underascertainment can be influenced by a patient's willingness to seek medical attention and participate in laboratory tests. However, few studies have investigated whether these factors systematically influence notification either in New Zealand or overseas. Furthermore, the discipline of health geography has been slow to engage with this topic of public health importance, despite the inherently spatial nature of the processes involved, and the close ties to the geographic literature on health service utilization and healthcare provision. This thesis explores the spatial and temporal variation in notification rates in New Zealand for the period 1997-2005 and the potential relationships between notification rates and different variables. Unlike many underascertainment studies, which have used individual data and capture-recapture methods, data constraints inspired a unique ecological approach to investigating the factors which may be associated with notification in New Zealand. Variables were divided into categories based on Anderson's behavioural model for healthcare utilization and the influence of these variables on notification was determined through multiple regression analyses. The main findings of this research indicate that in New Zealand notification rates have increased during the period 1997-2005 and that there is a north-south gradient in notifications, with substantially lower rates in the North Island than in the South Island. Furthermore, it is also evident that the variables associated with notification vary according to disease, spatial aggregation and spatial scale. Notification rates are significantly associated with a range of predisposing and enabling factors which might influence patient choice to consult for many frequently underascertained diseases. More variation in enteric diseases is explained by the independent variables analysed than the variation in non-enteric diseases. However, further research into these relationships, and underascertainment in general, is required before firm conclusions can be drawn.

Mandatory notification of disease forms the backbone of disease surveillance in New Zealand and overseas. Notification data is used by public health professionals and academics to identify cases requiring public health control, monitor disease incidence and distribution, and in epidemiological research. However, there is emerging evidence that notification rates do not accurately reflect the true extent of notifiable diseases within the community, resulting in the underascertainment of many notifiable cases. While adequate surveillance does not necessarily require that all cases of notifiable disease be captured, the systematic underascertainment of disease can have significant implications for perceived spatial and demographic trends in disease prevalence; potentially threatening the credibility of spatial epidemiological research by under or overestimating the burden of disease in different populations. There is evidence that systematic underascertainment occurs as a result of the differential actions of laboratories and general practitioners. It has also been recognised that that underascertainment can be influenced by a patient's willingness to seek medical attention and participate in laboratory tests. However, few studies have investigated whether these factors systematically influence notification either in New Zealand or overseas. Furthermore, the discipline of health geography has been slow to engage with this topic of public health importance, despite the inherently spatial nature of the processes involved, and the close ties to the geographic literature on health service utilization and healthcare provision. This thesis explores the spatial and temporal variation in notification rates in New Zealand for the period 1997-2005 and the potential relationships between notification rates and different variables. Unlike many underascertainment studies, which have used individual data and capture-recapture methods, data constraints inspired a unique ecological approach to investigating the factors which may be associated with notification in New Zealand. Variables were divided into categories based on Anderson's behavioural model for healthcare utilization and the influence of these variables on notification was determined through multiple regression analyses. The main findings of this research indicate that in New Zealand notification rates have increased during the period 1997-2005 and that there is a north-south gradient in notifications, with substantially lower rates in the North Island than in the South Island. Furthermore, it is also evident that the variables associated with notification vary according to disease, spatial aggregation and spatial scale. Notification rates are significantly associated with a range of predisposing and enabling factors which might influence patient choice to consult for many frequently underascertained diseases. More variation in enteric diseases is explained by the independent variables analysed than the variation in non-enteric diseases. However, further research into these relationships, and underascertainment in general, is required before firm conclusions can be drawn.

The aims were to investigate the accuracy of ultrasound in diagnosis of structural fetal anomalies with special focus on false positive findings (I), to evaluate the additional value of second trimester fetal MRI on pregnancy management (II-III) and to estimate the ascertainment in the Swedish Birth Defects Registry and incidence of spina bifida and cleft lip/palate (IV). Retrospectively, 328 fetal autopsies were identified where pregnancies were terminated due to ultrasonographically diagnosed fetal anomalies. In 175 (53.4 %) cases ultrasound and fetal autopsy were identical, in 124 (37.8 %) ultrasound was almost correct, in 23 (7.0 %)  ultrasound diagnoses could not be verified, but fetal autopsy showed other anomalies with at least the same prognostic value and in six (1.8 %)  ultrasound diagnosis could not be verified and autopsy showed no or less severe anomalies (I). Prospectively, 29 pregnancies with CNS- (II) and 63 with non-CNS-anomalies (III) were included. In the CNS study MRI provided no additional information in 18 fetuses (62 %), additional information without changing the management in 8 (28 %) and additional information altering the pregnancy management in 3 (10%). In the non-CNS study the corresponding figures were 43 (68 %), 17 (27 %) and three (5 %), respectively. MRI in the second trimester might be a clinically valuable adjunct to ultrasound for the evaluation of CNS anomalies, especially when the ultrasound is inconclusive due to maternal obesity (II) and in non-CNS anomalies in cases of diaphragmatic hernia or oligohydramnios (III). In newborns, the ascertainments of birth defects are relatively high and assessable, but in pregnancy terminations they are lower or unknown. The incidence of newborns with spina bifida has decreased because of an increased rate of pregnancy terminations (>60%). There is room for improvement concerning the reporting of anomalies from terminated pregnancies (IV).