Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2016-06-08T20:29:50Z No. of bitstreams: 2 Tese - Alex Silva da Cruz - 2015.pdf: 4189617 bytes, checksum: f21e8815a51e44f144dd811005f32bdd (MD5) license_rdf: 19874 bytes, checksum: 38cb62ef53e6f513db2fb7e337df6485 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-06-09T11:41:47Z (GMT) No. of bitstreams: 2 Tese - Alex Silva da Cruz - 2015.pdf: 4189617 bytes, checksum: f21e8815a51e44f144dd811005f32bdd (MD5) license_rdf: 19874 bytes, checksum: 38cb62ef53e6f513db2fb7e337df6485 (MD5) / Made available in DSpace on 2016-06-09T11:41:47Z (GMT). No. of bitstreams: 2 Tese - Alex Silva da Cruz - 2015.pdf: 4189617 bytes, checksum: f21e8815a51e44f144dd811005f32bdd (MD5) license_rdf: 19874 bytes, checksum: 38cb62ef53e6f513db2fb7e337df6485 (MD5) Previous issue date: 2015-10-19 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / Genomic selection in a dairy cattle breeding is a new strategy in national livestock. Genome wide association study (GWAS) is known as a strategy that involve the use of molecular markers panels distributed throughout the genome which are selected for the identification of chromosomal regions that are important for the interest traits. The aim of this study was apply the GWAS strategy for 305-day milk yield in Girolando cows. We did the genotype from 404 Girolando and after quality control analysis remained 337 individuals and 45.622 markers. The GWAS analysis resulted in 52 SNPs associated to 305-day milk yield. Of these, 23 SNPs were linked to Known genes and only 3 SNPs were linked to NUB1, SLC24A2 and DGAT1 genes that already were associated with cattle lactation. The other SNPs have no relationships described in the cattle lactation literature. In addition, the milk production QTL analysis resulted in 52 SNPs and 14 genes linked or close to 1Mb of the SNP marker. The ARS-BFGL-NGS-414 SNP on BTA19 at 47.9Mbp is located near to GH1 gene. This gene is commonly accepted as causal gene for Quantitative Character Locus of milk production mainly affecting the yield in liters and solid milk components. Thus, our data suggest that NUB1 and SLC24A2 genes could be considered as candidate genes to understand the milk production in Girolando breed. Like this DGAT1 and GH1 genes are valuable predictive markers to be added to genomic selection of dairy cattle in breeding program. / A seleção genômica, aplicada em bovino em associação à produção de leite é uma inovação estratégica na pecuária nacional, e que poderá se tornar uma ferramenta prática importante para a atividade. Estudos de Associação Ampla do Genoma (GWAs) caracteriza-se como uma estratégia que envolve o uso de painéis de marcadores moleculares distribuídos por todo o genoma, selecionados para a identificação de regiões dos cromossomos associadas com um fenótipo de interesse. O objetivo deste estudo foi aplicar a estratégia de GWAS para a característica de lactação total ajustada em 305 dias de vacas Girolando. Inicialmente, foram genotipados 404 vacas Girolando que após procedimento de controle de qualidade resultou em um total de 337 indivíduos e 45.622 marcador. O GWAS resultou em 52 SNPs associados a lactação ajustada em 305 dias. Destes, 23 SNPs apresentaram-se ligados a genes conhecidos e somente 3 SNPs estão ligados aos genes NUB1, SLC24A2 e DGAT1, descritos relacionados a lactação em bovinos. Os demais SNPs não apresentam relações descrita na literatura a lactação em bovinos. Para o QTL de produção de leite (MY), dos 52 SNPs, foram identificados 14 genes ligados ou próximos a 1Mb de distância do SNP marcador. Em particular, o SNP ARS-BFGL-NGS-414 associado ao QTL de lactação bovina, constituído de aproximadamente 47,9 Mbp localizado no BTA19 está localizado muito próximo do gene GH1 (Hormônio do Crescimento 1), comumente aceito como gene causal para o Lócus de Caráter Quantitativo (QTL) de produção de leite, afetando principalmente o rendimento em litros e componentes sólidos do leite. Dessa forma, nossos dados sugerem que os genes NUB1, e SLC24A2 poderiam ser considerados como genes candidatos para ajudar a explicar a produção de leite em animais da raça Girolando, assim como os genes DGAT1 e GH1, são considerados como valiosos marcadores preditivos a serem adicionados à seleção genômica do gado leiteiro em programas de melhoramento.

Submitted by Gabriela Lopes (gmachadolopesufpel@gmail.com) on 2018-05-24T17:18:08Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Thesis Liane_Final version.pdf: 4719459 bytes, checksum: 27c7e78c16dd0cfaf24b4611c1aff8ff (MD5) / Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2018-05-30T12:53:36Z (GMT) No. of bitstreams: 2 Thesis Liane_Final version.pdf: 4719459 bytes, checksum: 27c7e78c16dd0cfaf24b4611c1aff8ff (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-05-30T12:53:36Z (GMT). No. of bitstreams: 2 Thesis Liane_Final version.pdf: 4719459 bytes, checksum: 27c7e78c16dd0cfaf24b4611c1aff8ff (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-03-14 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / O pessegueiro (Prunus persica) é uma das espécies decíduas geneticamente melhor caracterizadas e a terceira frutífera mais importante de clima temperado em todo o mundo. A cultura é vulnerável à bacteriose causada pelo patógeno Xanthomonas arboricola pv. pruni (Xap) e o melhoramento genético visando resistência têm sido a melhor forma de controle da doença. Com o objetivo de contribuir para desenvolvimento de cultivares com maior resistência e implementar análises de associação genômica ampla (GWAS), foi explorado o uso de genotipagem por sequenciamento (GBS) para descoberta e genotipagem simultânea de SNPs em larga escala e realizada caracterização fenotípica para resposta à Xap, em um painel de 220 genótipos de pessegueiro, representativos do germoplasma disponível para melhoramento no Brasil. Um total de 93.353 marcadores SNPs foram descobertos e após filtragem de alta qualidade 18.373 SNPs foram utilizados. Destes, 34% estavam localizados em regiões genômicas, sendo 70% destes em regiões codificantes. Foi detectada forte estrutura genética de população e a distribuição dos genótipos dentro de subpopulações baseou-se principalmente em características relacionadas à fruta: polpa fundente e polpa não-fundente. Padrões de desequilíbrio de ligação (LD) sugeriram uma queda média de LD em relação à distância e a extensão do LD altamente dependente da subpopulação e das regiões do genoma. Avaliações de campo e através do bioensaio de folhas destacadas mostraram resultados confiáveis e complementares para identificar fontes resistentes à Xap. Os genótipos 'Norman', 'Cristal Taquari', 'La Feliciana' e 'Precocinho' foram considerados fontes altamente resistentes e podem ser alternativas efetivas para melhorar a resistência à Xap em pessegueiro. Em geral, o germoplasma avaliado mostrou grande variabilidade para resposta à Xap, permitindo a identificação de genótipos contrastantes para a característica de interesse. Os genótipos com resistência podem ser preferencialmente utilizados em áreas de produção com maior ocorrência da doença, ou utilizados como genitores no programa de melhoramento visando aumentar o nível de resistência. Análises de GWAS validaram e definiram com mais precisão as regiões genômicas identificadas com resistência ao patógeno em estudos anteriores, bem como possibilitaram a identificação de novos genes candidatos que necessitam ser melhor ix estudados. Vários SNPs informativos foram funcionalmente anotados em genes envolvidos em mecanismos de defesa à infecção por patógenos, com destaque para duas regiões genômicas, localizadas no cromossomo 1 (2,59 Mpb) e 2 (2,85 Mpb), respectivamente, ambas identificadas com vários genes R. Os resultados encontrados abrem novos caminhos para o melhoramento genético visando resistência a Xap, com grande potencial para subsequente aplicação de seleção assistida por marcadores. / Peach (Prunus persica) is one of the best genetically characterized deciduous trees and the third most important temperate fruit crop worldwide. This crop is vulnerable to bacterial spot caused by Xanthomonas arboricola pv. pruni (Xap) and breeding for resistance has been the main choice to control the disease. With the aim to contribute with breeding for more resistant cultivars, and perform genome-wide association analysis (GWAS), we explored the use of genotyping by sequencing (GBS) for large-scale SNP discovery and simultaneous genotyping and performed high quality phenotyping for Xap response, among a panel with 220 peach genotypes, representative of the Brazilian breeding germplasm. A total of 93,353 SNP markers were discovered, and after filtering 18,373 high quality SNPs were used in analyses. Thirty-four percent of selected SNPs were located in genic regions and 70% of these in the coding sequence. Strong population genetic structure was detected, with the distribution of genotypes within subpopulations based mainly on fruit-related traits: melting and non-melting flesh. Linkage disequilibrium (LD) patterns suggested a medium LD level, with the extent of LD highly dependent on the subpopulations and genome regions. Field evaluation and detached leaf assessments were reliable and complementary methods to identify Xap resistant sources. The genotypes ‘Norman’, ‘Cristal Taquari’, ‘La Feliciana’ and ‘Precocinho’ were considered highly resistant sources and may be effective alternatives to improve Xap resistance in peach. Overall, the germplasm evaluated showed great variability for response to Xap, allowing the identification of contrasting genotypes for the trait of interest. Genotypes with resistance could be preferred for peach production areas more subjected to disease occurrence, or used as parents by the breeding program to improve resistance. GWAS analysis validated and defined more accurately the known genomic regions underlying Xap resistance, as well as identified novel candidate genes that provide useful targets for further investigation. Several informative SNPs were functionally annotated in genes involved in defense mechanisms against pathogen infection, highlighting two genomic regions, located on chromosome 1 (2.59 Mbp) and 2 (2.85 Mbp), respectively, both housing several R genes. Our results provide new insights into breeding for Xap resistance in peach, with great potential for subsequent application of marker-assisted selection.

No description available.

Orientador: Josineudson Augusto II de Vasconcelos Silva / Resumo: A raça Gir (Bos indicus) é importante recurso genético para produção de carne e leite no Brasil e em países tropicais. Estudos genômicos entre populações são de interesse para identificar regiões genômicas importantes e aplicar na seleção de caraterísticas de produção. As corridas de homozigose (ROH) são regiões homozigotas contíguas do genoma, utilizadas na identificação de genes associados a características de interesse econômico, bem como na obtenção dos coeficientes de endogamia. A interação genótipo ambiente (IGA), também representa papel importante no estudo de populações de bovinos e na seleção dos melhores reprodutores para os diferentes ambientes. Com isto, os objetivos do presente estudo foram analisar o comprimento e a distribuição das ilhas ROH do genoma, com identificação dos gene presentes, além de avaliar a acurácia da imputação utilizando diferentes painéis comerciais e a interação genótipo ambiente da produção de leite em bovinos da raça Gir do Brasil e Colômbia. Na avaliação das ilhas ROH foram utilizados dados genotípicos de 173 animais selecionados para produção de carne e 291 animais selecionados para produção leiteira e obtidos os resultados via programa Plink. Análise da acurácia utilizando diferentes painéis de SNPs (GGP Bovine 30K, GGP indicus 35K e HD 777K) de 464 animais do Brasil e da Colômbia foram avaliados e os resultados comparados via correlação simples (CS) e taxa de concordância (CR). Na análise da IGA foi utilizado modelo de norma de reação... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The Gir breed (Bos indicus) is an important genetic resource for meat and milk production in Brazil and in tropical countries. Genomic studies between populations are of interest to identify important genomic regions and apply in the selection of production traits. Runs of Homozygosity (ROH) are contiguous homozygous regions of the genome, used to identify genes associated with characteristics of economic interest, as well as to obtain inbreeding coefficients. The environment genotype (IGA) interaction also plays an important role in the study of bovine populations and in the selection of the best breeders for different environments. Thus, the objectives of the present study were to analyze the length and distribution of the ROH islands of the genome, with identification of the present genes, in addition to assessing the accuracy of imputation using different commercial panels and the environment genotype interaction of milk production in cattle of the Gir breed from Brazil and Colombia. In the evaluation of the ROH islands, genotypic data from 173 animals selected for beef production and 291 animals selected for milk production were used and the results were obtained through the Plink program. Accuracy analysis using different SNP panels (GGP Bovine 30K, GGP indicus 35K and HD 777K) from 464 animals from Brazil and Colombia were evaluated and the results were compared using simple correlation (CS) and concordance rate (CR). The IGA analysis used a bi-traits reaction standard... (Complete abstract click electronic access below) / Doutor

In this project, two different machine learning models were tested in an attempt at imputing missing genotype data from patients on two different panels. As the integrity of the patients had to be protected, initial training was done on data simulated from the 1000 Genomes Project. The first model consisted of two convolutional variational autoencoders and the latent representations of the networks were shuffled to force the networks to find the same patterns in the two datasets. This model was unfortunately unsuccessful at imputing the missing data. The second model was based on a UNet structure and was more successful at the task of imputation. This model had one encoder for each dataset, making each encoder specialized at finding patterns in its own data. Further improvements are required in order for the model to be fully capable at imputing the missing data.

<div><div><div><p>Impacting individual’s social and physical well-being, psychiatric disorders have been a substantial burden on public health. As such disorders are frequently observed aggregating in families, we can expect a large involvement of heritable components underlying their etiologies. Therefore, studying the genetic architecture and basis is one of the most important aims toward developing effective treatments for psychiatric disorders. The overall objective of this dissertation is to contribute to understanding the genetics of psychiatric disorders. Analyzing summary statistics from genomewide association studies (GWAS) of psychiatric disorders, we mainly present results of two projects. In the first one, we evaluated commonalities and distinctions in genetic risk of four highly comorbid childhood onset neuropsychiatric disorders: attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and Tourette’s syndrome (TS). Through systematic analysis of genetic architecture and correlation, we confirmed exitance of genetic components shared across ADHD, ASD and TS, as well as OCD and TS. Subsequently, we identified those components at variant, gene, and tissue specificity levels through meta-analyses. Our results pointed toward possible involvement of hypothalamus-pituitary-adrenal (HPA) axis, a human stress response system, in the etiology of these childhood onset disorders. The second project includes the proposition of a novel framework for general GWAS summary statistics-based analyses. Instead of regular odds ratio and standard errors archived in the summary statistics, we proposed a recounstruction approach to rewrite the results in terms of single nucleotide polymorphisms (SNP) allelic and genotypic frequencies. We also put forward three applications built-upon the proposed framework, and evaluated the performance on both synthetic data and real GWAS results of psychiatric disorders for each of them. Through these three applications, we demonstrated that this framework can broaden the scope of GWAS summary statistics-based analyses and unify various of analyses pipelines. We hope our work can serve as a stepping-stone for future researchers aiming at understanding and utilizing GWAS results of complex psychiatric disorders.</p></div></div></div>

Escherichia coli is an incredibly diverse group of bacteria that consist of both commensal and pathogenic strains that cause disease in a wide variety of tissues in many different animals. The current dogma, based on years of extensive molecular and genetic studies, is that individual strains have adapted to specific environments through acquisition of specific genes or come from lineages that are particularly suited to a unique tissue or host. However, mastitis-associated E. coli (MAEC) have thus far resisted such descriptions. The fitness and virulence factors of MAEC are poorly understood and molecular tools are rarely applied. This dissertation reports new approaches to assess virulence of MAEC strains, enabling comparative genomic studies across multiple strains as well as genome-wide analysis of specific successful MAEC isolates. I outline the identification of the first virulence factor of MAEC, a ferric dicitrate receptor that is essential for colonization of a lactating mammary gland in a murine model. Genes previously studied in the contexts of other extraintestinal E. coli infections were also implicated in mastitis. These include a type III capsule found in the MAEC strain M12, which is crucial for dissemination from the mammary gland to the spleen. A mutant unable to produce capsule had diminished lethality in Galleria mellonella and decreased kidney colonization in a mouse urinary tract infection. I also report a link between zinc uptake, bile salts, and capsule production. I have utilized a transposon mutant library paired with deep sequencing of transposon junctions to elucidate the fitness factors needed to grow in milk and colonization of both murine and insect models. This analysis implicates a broad set of genes and metabolic pathways pertinent to these conditions. In addition to Tn-seq, I sequenced 94 MAEC genomes and identified genes associated with disease severity, growth in milk, and colonization of mammary glands in cow and mouse models. Employing bioinformatic tools to interrogate the pan-genome, I identified genes that are involved in biofilm formation and adhesion that were specifically associated with either mild or severe disease. In summary, I have employed several powerful genetic, genomic, computational, and molecular approaches to the characterization of mastitis associated E. coli. This work provides the groundwork for future experiments to better understand the host-pathogen interface and a model for mastitis-associated E. coli.

In der Epidemiologie spielen Körpermaße eine wichtige Rolle als Indikatoren für häufig vorkommende Zivilisationskrankheiten wie zum Beispiel Herz-Kreislauf-Erkrankungen oder Diabetes. Die Vermessung von Hand ist dabei als Goldstandard etabliert. Betrachtet werden häufig Körpergröße, Körpergewicht, Oberarmlänge, Oberarmumfang, Taillenumfang, Hüftumfang, Oberschenkellänge, Oberschenkelumfang und Wadenumfang. Für viele dieser Maße beziehungsweise davon abgeleiteter Größen existieren bereits genomweite Assoziationsstudien, wie zum Beispiel innerhalb des GIANT-Konsortiums zu Körpergröße, Body Mass Index und Taille, Hüfte und Taille-Hüfte-Verhältnis. Ziel dieser Arbeit war es, die 3D-Anthropometrie über den Körper-Scanner als neue Messmethode zu etablieren. Dazu stand das ANTHROSCAN VITUS XXL SYSTEM, bestehend aus dem Körper-Scanner VITUS XXL und der Software ANTHROSCAN BASIS von dem Unternehmen Human Solutions zur Verfügung. Die Körper-Scanner-Software bestimmt gemäß DIN EN ISO 20685 standardmäßig über 150 Maße mit der Möglichkeit der Hinzunahme weiterer Körpermaße. Das Hauptaugenmerk lag auf der Untersuchung der Messgenauigkeit der neuen Körper-Scanner-Methode. Dies beinhaltete zunächst die Analyse der Übereinstimmung von Mehrfachmessungen durch den Körper-Scanner. Dazu wurden sowohl Intra-Beobachter-Reliabilitäten als auch Inter-Beobachter-Reliabilitäten bestimmt. Zur Quantifizierung der Konkordanz wurde der Overall Concordance Correlation Coefficient verwendet. Diese Ergebnisse wurden mit denen aus der klassischen Anthropometrie verglichen. Für beide Messmethoden konnten dabei – bis auf wenige Ausnahmen für die 3D-Anthropometrie – sehr gute Ergebnisse ermittelt werden. Im Anschluss daran erfolgt die Untersuchung der Validität, das heißt der Vergleich der manuellen mit der automatisierten Messung. Die Konkordanz wurde ebenfalls über den Overall Concordance Correlation Coefficient bestimmt. Die resultierenden Übereinstimmungen liegen alle im guten bis sehr guten Bereich. Darauf aufbauend wurde untersucht, wie gut sich aus den bestehenden Körper-Scanner-Maßen Derivate bilden lassen. Dies wurde am Beispiel der Körperoberfläche als zweidimensionales Objekt analysiert. Dabei erfolgten zunächst auch wieder Reliabilitätsuntersuchungen bezüglich Intra-Beobachter-Reliabilität und Inter-Beobachter-Reliabilität. Die berechneten Werte gemäß Overall Concordance Correlation Coefficient lagen beide im sehr guten Bereich. Zur Bestimmung der Körperoberfläche werden im Alltag empirische Formeln zur Schätzung der Körperoberfläche über Körpergröße und Körpergewicht herangezogen. Dementsprechend wurde, unter der Annahme der validen Bestimmung der Körperoberfläche über den Körper-Scanner, diese tatsächliche Oberfläche mit der geschätzten Oberfläche aus den empirischen Formeln verglichen. Die Ergebnisse waren überraschend gut. Insgesamt hervorzuheben sind die Formeln nach Fujimoto & Watanabe, Shuter & Aslani und Sendroy & Cecchini. Dennoch war es über Reparametrisierung mit den vorliegenden Daten möglich, eine Verbesserung der Oberflächenschätzung durch empirische Formeln mit Körpergröße und Körpergewicht zu erreichen. Entsprechende Formeln wurden entsprechend zur weiteren Anwendung vorgeschlagen. Da die Bestimmung von Körpermaßen durch die händische Vermessung bisher nur auf einige wenige Maße beschränkt war, existieren folglich auch nur für diese Phänotypen Resultate aus genetischen Assoziationsanalysen. Dies betrifft vor allem die Körpergröße, den Body Mass Index und das Taille-Hüfte-Verhältnis. Durch Ermittlung von mehr als dem Zehnfachen der bisher üblichen Maße, können nun auch genomweite Assoziationsstudien bezüglich dieser Körpermaße durchgeführt werden. Dies erfolgte hier für die über 150 Körpermaße der knapp 7.500 vermessenen und genotypisierten LIFE-Adult-Probanden. Zunächst wurden die Daten hinsichtlich ihrer Korrelationsstruktur analysiert. Jeder Proband lässt sich über die etwa 150 Maße charakterisieren, welche jedoch Korrelationen untereinander aufweisen. Dementsprechend war es erforderlich, diese Korrelationsstruktur zu untersuchen und gegebenenfalls eine Dimensionsreduktion beziehungsweise eine Einteilung in Gruppen von Körpermaßen vorzunehmen. Es zeigte sich, dass sich die knapp 150 Körpermaße in weniger als zehn Gruppen zusammenfassen lassen. Auf der Suche nach einem Referenzmaß für jede Gruppe fiel auf, dass bisher im Rahmen der klassischen Anthropometrie nicht betrachtete Maße eine beachtenswerte Rolle spielen. Dazu zählen Abstand Taillenband zur Taille, Höhe Taille, Schulterbreite aber auch Armumfang, Armdurchmesser, Beinumfang und beispielsweise Schrittlänge. Im Rahmen der genomweiten Assoziationsanalyse wurden in dieser Arbeit einige ausgewählte Resultate derjenigen Körpermaße der 3D-Anthropometrie präsentiert, für welche es ein passendes Äquivalent in der klassischen Anthropometrie gibt. Dabei konnten genomweit signifikante Assoziationen für Körpergröße, Oberarmlänge und Oberarmumfang festgestellt werden.:1. Einführung 1.1 Bedeutung der Anthropometrie 1.2 Klassische Messung und 3D-Körper-Scanner 1.3 Fragestellung der Arbeit 2. Validität, Reliabilität und Akzeptanz der automatisierten und klassischen Messung bei Erwachsenen und Kindern 3. Möglichkeit der Ableitung weiterer Größen aus dem 3D-Körper-Scan am Beispiel der Körperoberfläche 4. Genomweite Assoziationsanalyse bezüglich 3D-Körper-Scanner-Maßen 4.1 Warum noch eine GWAS zu Körpermaßen? 4.2 Welche Daten stehen zur Verfügung? 4.3 Vorbereitungen der GWAS 4.3.1 Fallzahl, Datenvollständigkeit und Ausreißer 4.3.2 Korrelation zwischen den Merkmalen 4.3.3 Hauptkomponentenanalyse 4.3.4 Partielle Kleinste-Quadrate-Methode (Diskriminanzanalyse) 4.3.5 Cluster-Verfahren 1: k-Means-Clustering 4.3.6 Clusterverfahren 2: Hierarchische Cluster-Analyse 4.3.7 Vergleich 4.4 Was genau passiert bei einer GWAS? 4.4.1 Qualitätskontrolle 4.4.2 Imputation 4.4.3 Statistische Tests 4.5 Ergebnisse der GWAS 5. Zusammenfassung Literaturverzeichnis Abbildungsverzeichnis Darstellung des eigenen Beitrags Selbstständigkeitserklärung Lebenslauf Publikationen Danksagung

Understanding the regenerative capacity and the role of human AT2s in the distal lung is imperative for defining alveolar response to injury and disease. Additionally, due to human AT2 expression of COPD genome wide association study (GWAS) genes, they are an especially relevant cell type to study the disease. Here we apply CRISPR-interference (CRISPRi) to reduce the expression of COPD GWAS gene, ADGRG6, to interrogate its function in induced pluripotent stem cell-derived type 2 alveolar epithelial cells (iAT2s). We find that decreased expression of ADGRG6 in iAT2s caused disruption to iAT2 cell polarity, organization of the actin cytoskeleton, and establishment of tight junctions. In addition, ADGRG6 knockdown (kd) causes a hyperproliferative phenotype. Finally, we find that ADGRG6-kd may contribute to dysregulation of tight junction formation in the presence of cigarette smoke.

Genome-wide association studies(GWAS) are used to find associations betweengenetic markers and diseases. One part of GWAS is to study interactions be-tween markers which can play an important role in the risk for the disease. Thesearch for interactions can be computationally intensive. The aim of this thesiswas to improve the performance of software used for gene-environment interac-tion by using parallel programming techniques on graphical processors. A studyof the new programs performance, speedup and efficiency was made using mul-tiple simulated datasets. The program shows significantly better performancecompared with the older program.