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A candidate gene approach was used to identify single nucleotide polymorphisms (SNPs) and their associations with body fat deposition and carcass merit traits in beef cattle. In total, 37 SNPs from 9 candidate genes have been genotyped on 463 hybrid, 206 Angus and 187 Charolais steers for association analyses with 10 different fat deposition and carcass merit traits. In single SNP analyses, 28 SNPs of 9 genes have been found significantly (P<0.05) associated with different traits in the cattle populations. Gene-specific linkage disequilibrium assessment of SNPs revealed the existence of haplotype blocks within 4 genes. Haplotype analyses have identified 31 haplotypes of 6 genes having significant associations (P<0.05) with different fat deposition and carcass merit traits in the cattle populations. These findings will provide insight into the genetic mechanism regulating body fat deposition in beef cattle and will assist the beef industry to improve beef quality through marker assisted selection. / Animal Science

Abstract Low back pain (LBP) is the leading cause of years lived with disabilities worldwide. Intervertebral disc (IVD) degeneration is a strong contributing factor to LBP. Recent studies have shown that genetic determinants contribute markedly to IVD degeneration but knowledge about the actual genes involved as well as their roles is still limited. The aim of this thesis work was to study genetic factors that may predispose to IVD degeneration. Using both family and case-control association study designs, variants in five genes showed association with IVD degeneration on magnetic resonance imaging (MRI) in a population-based sample and among patients with sciatica due to lumbar disc herniation (LDH). We performed a candidate gene association study of the known variants implicated in IVD degeneration in a Finnish cohort of 538 young individuals with a moderate degree of lumbar IVD degeneration on MRI. We were able to confirm the associations of variants in the IL6, SKT, and CILP genes, which provides further evidence for true associations. Based on our earlier linkage study in Finnish sciatica families, we performed a candidate gene analysis and identified IL17F as a potential candidate gene. To the best of our knowledge this is the first study to observe an association between this gene and discogenic sciatica. Both IL-6 and IL-17 are pro-inflammatory cytokines with elevated expression levels in herniated tissues, which suggest a role in IVD degeneration. Study of the role of genes coding for inflammatory mediators is of interest as it may contribute to the understanding of the overall inflammatory response of the disc. In addition, we reported on the involvement of SKT in the etiology of lumbar disc herniation (LDH) both in Japanese and Finnish case-control samples. Experimental studies in mice have shown that Skt homozygous mutants exhibit disc abnormalities resulting in a kinky tale phenotype. We hypothesized that the human homolog SKT could have long-term importance in the onset of IVD degeneration by making the discs more vulnerable. Finally, through linkage studies and in the subsequent association analyses, the role of CHST3 as a novel risk factor for IVD degeneration was identified. CHST3 encodes an enzyme that catalyzes the sulfation of chondroitin, and mutations in this gene are associated with spondylepiphyseal dysplasia and humerospinal dysostosis. In our study, we identified this gene using genome –wide linkage based on data from a Southern Chinese family and speculated that mild CHST3 reduction caused by the reported susceptibility SNP could result in disc degeneration in adults in conjunction with other risk factors. This thesis provides new information about the genetic background of IVD degeneration and new insights into the etiology of the disease. The specific roles of these genes in the IVD function and pathogenesis of sciatica are not clear however, and need to be elucidated. / Tiivistelmä Alaselkäkipu on yksi yleisimmistä sairauksista ja johtava syy työkyvyttömyyteen. Välilevyrappeuma myötävaikuttaa merkittävästi alaselän kipuun. Vaikka aiemmat tutkimukset ovat osoittaneet, että perintötekijöillä on vahva osuus välilevyrappeumaan, altistavat geenit ja niiden rooli tunnetaan huonosti. Tämän tutkimuksen tavoitteena oli arvioida tiettyjen perintötekijöiden osuutta välilevyrappeumassa ja tunnistaa taudille altistava geeni perheaineistossa aiemmin havaitulta kromosomialueelta. Aineistoina tutkimuksessa olivat perheaineistot sekä laajat potilas-kontrolliaineistot suomalaisesta ja aasialaisista väestöistä. Tutkimuksessa osoitimme, että perimän vaihtelut viidessä tutkitussa geenissä altistivat erilaisille välilevyrappeuman taudin muodoille. Tutkimus, jossa analysoimme aiemmin tunnistettuja alttiusgeenejä, vahvisti IL6, SKT ja CILP geenien vaihteluiden osuuden taudin alttiustekijöinä. Tutkimusaineistona oli pohjoissuomalainen syntymäkohortti, jossa välilevyrappeuma oli määritetty magneettikuvauksella (MRI). Suomalaisessa perheaineistossa tehdyn kokogenomin laajuisen kartoituksen pohjalta analysoimme IL17F geenin mahdollisena uutena alttiusgeeninä oireiselle välilevytaudille. Kahdesta geenin variantista koostuva haplotyyppi assosioitui tautiin merkitsevästi. Lisäksi osoitimme, että SKT-geenin tietty muutos altistaa välilevyn pullistumille sekä japanilaisessa että suomalaisessa potilasaineistossa. Hiirikokeissa on havainnoitu, että SKT-geenin homotsygootti mutaatio johtaa välilevy-poikkeamaan, joka edelleen aiheuttaa hiiren poikkeavan häntäilmiasun-. Hypoteesimme oli, että ihmisen SKT -geeni voi myötävaikuttaa välilevypullistuman kehittymiseen altistamalla välilevyt rappeumalle. Edelleen, laajassa usean populaation aineiston käsittävässä tutkimuksessa osoitimme CHST3-geenin muutoksen altistavan välilevyrappeumalle. Peittyvästi periytyvät muutokset tässä geenissä aiheuttavat perinnöllisiä harvinaisia luusairauksia. Tämä väitöstutkimus tarjoaa uutta tietoa välilevyrappeuman geneettisestä taustasta ja auttaa taudin syiden tutkintaa. Geenien rooli välilevyn toiminnassa ja muutosten vaikutus taudin kulkuun vaativat kuitenkin vielä lisätutkimuksia.

Made available in DSpace on 2015-03-26T13:42:31Z (GMT). No. of bitstreams: 1 texto completo.pdf: 1165643 bytes, checksum: afd121bfd728867f85eb3916457d8ba4 (MD5) Previous issue date: 2013-07-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A qualidade do sêmen de reprodutores suínos pode ser avaliada de acordo com vários critérios, sendo a motilidade espermática o mais utilizado e importante. A motilidade, essencial para a fertilização, refere-se ao movimento retilíneo dos espermatozóides. Apesar da importância da avaliação de características de qualidade do sêmen de reprodutores, tradicionalmente estes animais têm sido selecionados com ênfase em características de carcaça e crescimento, com pouca atenção dispensada à sua capacidade reprodutiva. Devido ao fato de características seminais poderem ser avaliadas nos reprodutores somente após a puberdade, técnicas moleculares e genotipagem dos animais utilizando chips de alta densidade de marcadores SNPs poderiam ser utilizados como ferramentas para avaliar e melhorar a seleção para fertilidade e qualidade de sêmen em reprodutores suínos em uma idade jovem. O estudo de associação genômica ampla (GWAS) requer o conhecimento de uma associação entre um marcador genético e alguma variação no fenótipo e assume que associação significativa pode ser detectada porque os SNPs estão em desequilíbrio de ligação (LD) com as mutações causais para as características de interesse, a nível de população. Assim, este estudo foi conduzido com o objetivo de identificar, através do GWAS, marcadores SNPs e genes candidatos relacionados com motilidade espermática em duas diferentes linhas de suínos. Os dados fenotípicos são provenientes de avaliações repetidas de motilidade de espermatozóides logo após a coleta do sêmen através do método denominado CASA (Computer Assisted Sperm Analysis). Animais de duas linhas (linha 1, n=760 animais da raça Landrace e linha 2, n=645 animais da raça Large White) foram fenotipados para a construção do arquivo de dados, que possui 32884 observações para a linha 1 e 32576 para a linha 2. Um total de 1507 animais da linha 1 e 1383 animais da linha 2 foram genotipados com o uso do chip de 60K da Illumina®. Os valores genéticos dos animais foram estimados utilizando o programa ASREML e os valores genéticos desregressados foram calculados para serem utilizados no GWAS. Após o controle de qualidade, 42551 SNPs e 602 animais genotipados (linha 1) e 40890 SNPs e 525 animais genotipados (linha 2) foram utilizados no GWAS. SNPs que possuíram q-valores baseados na taxa de falsos descobertos (FDR) menores ou iguais a 0.05 foram considerados significativos. Para a linha 1 não foram encontrados SNPs significativos relacionados com motilidade. Já para a linha 2, seis SNPs localizados no cromossomo 1 (SSC1) foram significativamente relacionados com a característica estudada. Essa diferença pode ser explicada pela baixa correlação (r = 0.0926) entre os valores de LD entre marcadores calculados para as duas linhas na região que abrange os seis SNPs significativos. O alto valor médio de r2 (r2 = 0.7275), calculado para medir o LD entre os seis SNPs significativos para a linha 2, revela que todos esses SNPs podem estar ligados a um mesmo QTL. O gene metionil-tRNA formiltransferase mitocondrial (MTFMT) é um possível gene candidato controlando a característica. Esse estudo fornece marcadores SNPs e um gene candidato associados com motilidade espermática em suínos. No entanto, por ser o primeiro trabalho a encontrar tais marcadores relacionados com motilidade espermática em suínos em uma nova região do SSC1, é necessária replicação e validação do estudo em outra população para confirmação dos resultados encontrados a fim de incluir tais informações na seleção de melhores animais. / The boar semen quality can be evaluated according to several parameters. Sperm motility is the most widely used and important test. Sperm motility, essential for fertility, is measured as the proportion of sperm cells with a straightforward movement. Despite its importance, traditionally boar selection has been done based on growth rate and carcass traits and little attention has been given on their semen quantity and quality. Because reproductive traits and sperm quality traits can only be measured on boars after puberty, molecular techniques and animal genotyping using chips with high density of SNP markers could be used to evaluate and improve selection on boar fertility at a young age. The Genome Wide Association Study (GWAS) requires knowledge of an association of a genetic marker with some variation in phenotype and it assumes that significant association can be detected because the SNPs are in linkage disequilibrium (LD) with the causative mutations for the traits of interest at the population level. Therefore, this study was conducted with the objective of performing a GWAS in order to find markers and candidate genes in the pig genome associated with sperm motility in two different pig lines. The phenotypic data consisted of repeated records of fresh sperm motility evaluated with CASA (Computer Assisted Sperm Analysis), obtained from two pure dam lines: a Landrace based line (line 1), n=760 animals and a Large White based line (line 2), n=645. The phenotypic database had in total 32,884 observations for line 1 and 32,576 observations for line 2, with 43.27 ± 36.81 observations per animal for line 1 and 50.51 ± 39.15 observations per animal for line 2. The PorcineSNP60 Beadchip of Illumina (San Diego, CA, USA, Ramos et al., 2009) was used to identify the association between sperm motility and the SNP markers. After quality control, a total of 42,551 SNPs and 602 genotyped animals (line 1) and 40,890 SNPs and 525 animals (line 2) were used in the association analyses. A False Discovery Rate based q-value of 0.05 was used as threshold for significant association. Six SNPs on pig chromosome 1 (SSC1) were significantly associated with the trait in line 2, whereas no SNPs were considered significantly associated with the trait in line 1. This difference can be explained by the low correlation (r = 0.0926) between the LD measurements (r2) between markers located in the region covering the six significant SNPs for line 2, calculated for both lines. The high average value of r2 (r2 = 0.7275), calculated to measure the LD between the six significant SNPs for line 2 reveals that all these SNPs may be linked to one QTL. The mitochondrial methionyl-tRNA formyltransferase (MTFMT) is a possible candidate gene affecting sperm motility on SSC1. This study provides some SNPs markers and a candidate gene associated with the trait of interest in a novel region on SSC1. However, replication, validation in another population and confirmation of published QTL or candidate genes related to boar sperm motility in the same region that we found in this study is necessary before using such information in selection.

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