Comparative analyses of seven algorithms for copy number variant identification from single nucleotide polymorphism arrays.

Determination of copy number variants (CNVs) inferred in genome wide single nucleotide polymorphism arrays has shown increasing utility in genetic variant disease associations. Several CNV detection methods are available, but differences in CNV call thresholds and characteristics exist. We evaluated the relative performance of seven methods: circular binary segmentation, CNVFinder, cnvPartition, gain and loss of DNA, Nexus algorithms, PennCNV and QuantiSNP. Tested data included real and simulated Illumina HumHap 550 data from the Singapore cohort study of the risk factors for Myopia (SCORM) and simulated data from Affymetrix 6.0 and platform-independent distributions. The normalized singleton ratio (NSR) is proposed as a metric for parameter optimization before enacting full analysis. We used 10 SCORM samples for optimizing parameter settings for each method and then evaluated method performance at optimal parameters using 100 SCORM samples. The statistical power, false positive rates, and receiver operating characteristic (ROC) curve residuals were evaluated by simulation studies. Optimal parameters, as determined by NSR and ROC curve residuals, were consistent across datasets. QuantiSNP outperformed other methods based on ROC curve residuals over most datasets. Nexus Rank and SNPRank have low specificity and high power. Nexus Rank calls oversized CNVs. PennCNV detects one of the fewest numbers of CNVs.

Ink Under the Fingernails: Making Print in Nineteenth-Century Mexico City

This dissertation examines Mexico City’s material politics of print—the central actors engaged in making print, their activities and relationships, and the legal, business, and social dimensions of production—across the nineteenth century. Inside urban printshops, a socially diverse group of men ranging from manual laborers to educated editors collaborated to make the printed items that fueled political debates and partisan struggles in the new republic. By investigating how print was produced, regulated, and consumed, this dissertation argues that printers shaped some of the most pressing conflicts that marked Mexico’s first formative century: over freedom of expression, the role of religion in government, and the emergence of liberalism. Printers shaped debates not only because they issued texts that fueled elite politics but precisely because they operated at the nexus where new liberal guarantees like freedom of the press and intellectual property intersected with politics and patronage, the regulatory efforts of the emerging state, and the harsh realities of a post-colonial economy.

Historians of Mexico have typically approached print as a vehicle for texts written by elites, which they argue contributed to the development of a national public sphere or print culture in spite of low literacy levels. By shifting the focus to print’s production, my work instead reveals that a range of urban residents—from prominent printshop owners to government ministers to street vendors—produced, engaged, and deployed printed items in contests unfolding in the urban environment. As print increasingly functioned as a political weapon in the decades after independence, print production itself became an arena in struggles over the emerging contours of politics and state formation, even as printing technologies remained relatively unchanged over time.

This work examines previously unexplored archival documents, including official correspondence, legal cases, business transactions, and printshop labor records, to shed new light on Mexico City printers’ interactions with the emerging national government, and reveal the degree to which heated ideological debates emerged intertwined with the most basic concerns over the tangible practices of print. By delving into the rich social and cultural world of printing—described by intellectuals and workers alike in memoirs, fiction, caricatures and periodicals— it also considers how printers’ particular status straddling elite and working worlds led them to challenge boundaries drawn by elites that separated manual and intellectual labors. Finally, this study engages the full range of printed documents made in Mexico City printshops not just as texts but also as objects with particular visual and material qualities whose uses and meanings were shaped not only by emergent republicanism but also by powerful colonial legacies that generated ambivalent attitudes towards print’s transformative power.

Police is Dead: On the Birth of Economism

Police is Dead is an historiographic analysis whose objective is to change the terms by which contemporary humanist scholarship assesses the phenomenon currently termed neoliberalism. It proceeds by building an archeology of legal thought in the United States that spans the nineteenth and twentieth centuries. My approach assumes that the decline of certain paradigms of political consciousness set historical conditions that enable the emergence of what is to follow. The particular historical form of political consciousness I seek to reintroduce to the present is what I call “police:” a counter-liberal way of understanding social relations that I claim has particular visibility within a legal archive, but that has been largely ignored by humanist theory on account of two tendencies: first, an over-valuation of liberalism as Western history’s master signifier; and second, inconsistent and selective attention to law as a cultural artifact. The first part of my dissertation reconstructs an anatomy of police through close studies of court opinions, legal treatises, and legal scholarship. I focus in particular on juridical descriptions of intimate relationality—which police configured as a public phenomenon—and slave society apologetics, which projected the notion of community as an affective and embodied structure. The second part of this dissertation demonstrates that the dissolution of police was critical to emergence of a paradigm I call economism: an originally progressive economic framework for understanding social relations that I argue developed at the nexus of law and economics at the turn of the twentieth century. Economism is a way of understanding sociality that collapses ontological distinctions between formally distinct political subjects—i.e., the state, the individual, the collective—by reducing them to the perspective of economic force. Insofar as it was taken up and reoriented by neoliberal theory, this paradigm has become a hegemonic form of political consciousness. This project concludes by encouraging a disarticulation of economism—insofar as it is a form of knowledge—from neoliberalism as its contemporary doctrinal manifestation. I suggest that this is one way progressive scholarship can think about moving forward in the development of economic knowledge, rather than desiring to move backwards to a time before the rise of neoliberalism. Disciplinarily, I aim to show that understanding the legal historiography informing our present moment is crucial to this task.

Posttranscriptional Regulation of Embryonic Neurogenesis by the Exon Junction Complex

The six-layered neuron structure in the cerebral cortex is the foundation for human mental abilities. In the developing cerebral cortex, neural stem cells undergo proliferation and differentiate into intermediate progenitors and neurons, a process known as embryonic neurogenesis. Disrupted embryonic neurogenesis is the root cause of a wide range of neurodevelopmental disorders, including microcephaly and intellectual disabilities. Multiple layers of regulatory networks have been identified and extensively studied over the past decades to understand this complex but extremely crucial process of brain development. In recent years, post-transcriptional RNA regulation through RNA binding proteins has emerged as a critical regulatory nexus in embryonic neurogenesis. The exon junction complex (EJC) is a highly conserved RNA binding complex composed of four core proteins, Magoh, Rbm8a, Eif4a3, and Casc3. The EJC plays a major role in regulating RNA splicing, nuclear export, subcellular localization, translation, and nonsense mediated RNA decay. Human genetic studies have associated individual EJC components with various developmental disorders. We showed previously that haploinsufficiency of Magoh causes microcephaly and disrupted neural stem cell differentiation in mouse. However, it is unclear if other EJC core components are also required for embryonic neurogenesis. More importantly, the molecular mechanism through which the EJC regulates embryonic neurogenesis remains largely unknown. Here, we demonstrated with genetically modified mouse models that both Rbm8a and Eif4a3 are required for proper embryonic neurogenesis and the formation of a normal brain. Using transcriptome and proteomic analysis, we showed that the EJC posttranscriptionally regulates genes involved in the p53 pathway, splicing and translation regulation, as well as ribosomal biogenesis. This is the first in vivo evidence suggesting that the etiology of EJC associated neurodevelopmental diseases can be ribosomopathies. We also showed that, different from other EJC core components, depletion of Casc3 only led to mild neurogenesis defects in the mouse model. However, our data suggested that Casc3 is required for embryo viability, development progression, and is potentially a regulator of cardiac development. Together, data presented in this thesis suggests that the EJC is crucial for embryonic neurogenesis and that the EJC and its peripheral factors may regulate development in a tissue-specific manner.