<p>Obesity is a medical condition whose rates have seen a rise in both the United States and worldwide in recent decades. Numerous studies have been done to understand obesity, and through the use of GWAS researchers have been able to find multiple genetic factors that can contribute to obesity in mammals. One proposed cause of obesity are genetic impacts on cilia formation in the CNS, which causes downstream effects on food intake and energy expenditure, causing obesity via overeating and decreased activity.</p> <p>In the first half of this thesis, I describe a study, in collaboration with the Berbari Lab at IUPUI, that explored the human chromosome 16:53801550-53808600 (GRCh37/hg19), an intron of the FTO alpha-ketoglutarate Dependent Dioxygenase (<i>FTO</i>) gene for transcriptional regulators that impact BMI and obesity. First, using control DNA, PCR, and gel-electrophoresis, we created an assay for 44 primer sets (forward and reverse) covering the genomic region. After optimizing the assay, we then selected 111 human DNA samples across three weight groups (underweight, normal weight, and obese) to sequence using the assay. The samples were selected from subjects enrolled in the Walsh Lab FDP study. Sequencing was completed using the Illumina MiSeq System, and sequenced results were viewed using the Integrative Genomics Viewer (IGV) program. Variants that showed in the results were analyzed across and within the weight groups, and their locations were researched for previously known BMI or enhancer activity using online genome browsers Ensembl and UCSC Genome Browser.</p> <p>The results of this study revealed two SNPs, rs8055197 and rs11642015, that provided the best correlation with the weight categories among the samples. These results were consistent with literature that previously linked these single-nucleotide polymorphisms (SNPs) to obesity, particularly in relation to genes that are regulated by <i>FTO</i> (<i>CUX1</i>, <i>POMC</i>, and <i>IRX3/5</i>). Both SNPs lie within areas that show high enhancer activity in neural crest cells, important cells for cilia formation. Although there were SNPs in high LD within both regions, these two SNPs were chosen due to their homologous variant locations within the mouse genome (rs8055197 - GRCm38/mm10 8:91376305; rs11642015 - GRCm38/mm10 8:91375651), which provides a means of testing this obesity correlation, with a proposed enhancer relationship through <i>FTO</i>, in mouse models. </p> <p>In the second half of this thesis, I explored new methods for quantitatively defining natural hair color categories, and attempted to find novel SNPs impacting hair color in a GWAS using the quantitative values as phenotypes. In previous publications, the development and validation of the HIrisPlex-S Prediction Tool for hair prediction was made using categorical hair colors, which were defined and classified by individual researchers or lab personnel. Using spectrophotometer measurements and HSV color values, we used a machine-learning tool to objectively classify sample hair photos into natural hair color classes. We then used this quantitative data as the input phenotype for a GWAS, using both linear regression and linear mixed model regression, to search for new genetic associations with these objectively defined hair color classes. Lastly, we also measured correlations between these hair color phenotypes and a SNP array consisting of all currently known pigment SNPs cited in recent literature.</p> <p>The results of this study showed that quantitative values can be used as a means of classifying human hair colors. Both models used in the GWAS highlighted previously known SNPs that contributed to quantitative hair color. By utilizing the linear mixed model approach which has the ability to generate more power due to the normalization of hidden population structure, there was one near genome-wide significant SNP found that is currently not linked with hair color, rs2037697 (<i>IQUB</i>), which showed strong associations with light brown hair (p-value = 1.83192E-07), however this would need to be confirmed with increased numbers to validate its association. </p> <p>The results of the correlation analysis showed that SNPs cited as having impacts on pigmentation (eye, skin, and hair) also show strong associations with these objectively defined quantitative hair color classes and these rankings may prove very useful as the field moves towards quantitative hair color prediction.</p>

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Orientador: Jaime Olbrich Neto / Resumo: Os cabelos são um importante componente de identidade social e sedução, favorece o mercado de cosméticos, notadamente o capilar, que busca inovações e novidades destinadas a obter um resultado desejado. Mulheres e homens dão importância para a saúde e aparência dos mesmos, empenhando cuidados que vão além dos habituais de higiene. A procura pelo cabelo ideal expõe a riscos de doenças, tanto os profissionais dos salões de beleza e como seus clientes. São doenças ocupacionais, em muitos casos, negligenciadas. Entre estes riscos encontra-se a dermatite de contato. No Brasil, a chamada escova progressiva é a mais conhecida e utilizada para alisamento. Neste processo o uso de formaldeído (FA) em concentrações não permitidas tem sido prática comum, expondo cabeleireiros e clientes a risco de doenças relacionadas ao contato com FA. O FA é permitido na concentração de até 0,2% como conservante de produtos. O presente estudo objetivou avaliar indivíduos expostos ao FA ao realizarem alisamento capilar, se estavam sensibilizados ao FA. Para identificar FA em produtos de alisamento capilar, usado pelos cabeleireiros participantes desta pesquisa, utilizou-se um kit comercialmente disponível. Foram incluídos profissionais expostos ao FA, clientes (esporadicamente expostos) e indivíduos nunca expostos. Foram realizados patch teste com a bateria brasileira para dermatite de contato, e um participante apresentou teste cutâneo positivo para formol, onze para bicromato de potássio e oito para s... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Hair is an important component of social identity and seduction, it favors the cosmetics market, notably the capillary, which seeks innovations and novelties designed to obtain a desired result. Women and men give importance to their health and appearance, engaging in care that goes beyond the usual hygiene. The search for the ideal hair exposes the risks of diseases, both the professionals of the beauty salons and their clients. Occupational diseases that are, in many cases, neglected. Contact dermatites is one of the risks. In Brazil, the so-called brazilian hair straightening is the preferred for straightening. In this process, the use of formaldehyde (FA) in unallowed concentrations has been common practice, exposing hairdressers and clients to the risk of diseases related to contact with FA. At a concentration of up to 0.2%, as a p preservative, FA is permitted. The present study aimed to evaluate individuals exposed to FA when performing hair straightening, and if they were sensitized to FA. To identify FA in hair straightening products, used by hairdressers participating in this research, a commercially available kit was used. Professionals exposed to the FA, clients (sporadically exposed) and individuals never exposed were included. Patch tests were performed with the Brazilian battery for contact dermatitis, and one participant presented a positive skin test for formaldehyde, eleven for potassium bichromate and eight for nickel sulfate. Clinical symptoms were more se... (Complete abstract click electronic access below) / Mestre

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Indiana University-Purdue University Indianapolis (IUPUI) / Age-related hearing loss is an acute health problem affecting people worldwide, often arising due to defects in the proper functioning of sensory hair cells in the inner ear. The apical surface of sensory hair cells contains actin-based protrusions known as stereocilia, which detect sound and head movements. Since hair cells are not regenerated in mammals, it is important to maintain the functioning of stereocilia for the life of an organism to maintain hearing ability. The actin filaments within a stereocilium are extensively crosslinked by various actin crosslinking proteins, which are important for stereocilia development and maintenance. Multiple studies have shown that the stereocilia actin core is exceptionally stable whereas actin is dynamic only at the tips of stereocilia. However, whether the actin crosslinking proteins, which are nearly as abundant as actin itself, are similarly stable or can freely move in and out of the core remains unknown. Loss or mutation of crosslinkers like plastin-1, fascin-2, and XIRP2 causes progressive hearing loss along with stereocilia degeneration while loss of espin prevents stereocilia from even developing properly. Do these phenotypes stem from an unstable stereocilia core? Does crosslinking confer stability to the core? To address these questions, we generated novel transgenic reporter lines to monitor the dynamics of actin in mice carrying fascin-2R109H mutation and espin null mice and also to study the dynamics of actin crosslinkers, in vivo and ex-vivo. We established that actin crosslinkers readily exchange within the highly stable F-actin structure of the stereocilia core. In addition, we determined that stereocilia degeneration in mice carrying fascin-2R109H mutation and espin null mice could possibly occur due to a less stable actin core. These studies suggest that dynamic crosslinks stabilize the core to maintain proper stereocilia functioning. Future work warrants understanding the reason behind the importance of dynamic crosslinks within a stable stereocilia core. Actin stability not only depends on actin crosslinkers, but also on actin filament composition as evident from distinct stereocilia degeneration and progressive hearing loss patterns in hair-cell specific knockout of actin isoforms. Although beta- and gamma- actin polypeptide sequences differ by only 14 four amino acids, whether the latter determine the unique function of each cytoplasmic actin isoform was previously unknown. Here we determined that these four critical amino acids determine the unique functional importance of beta-actin isoform in sensory hair cells. Taken together, our study demonstrates that actin cytoskeletal proteins are important for the morphogenesis and maintenance of stereocilia.

Indiana University-Purdue University Indianapolis (IUPUI)

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