The cost of feed remains an important factor affecting the profitability of beef production, and the difficulty of recording feed intake is a major limitation in an industry-wide selection program. Novel genomics approaches offer opportunities to select for efficient cattle. Therefore, the main objective of this work was to identify genetic markers responsible for genetic variation in feed efficiency traits as well as to understand the molecular basis of feed efficiency traits. The candidate gene approach revealed new single nucleotide polymorphisms (SNPs) in the Cholecystokinin B receptor (CCKBR) and pancreatic anionic trypsinogen (TRYP8) genes that showed strong evidence of association with feed efficiency traits. An in silico approach was proposed as a cost-effective method for SNP discovery. SNPs within genes Pyruvate carboxylase, ATPaseH+, UBQEI, UCP2, and PTI showed evidence of association with carcass traits without negatively affecting feed efficiency traits. The polymorphisms within genes CCKBR and TRYP8 were associated with pancreas mass and pancreatic exocrine secretion. A fine-mapping study on 1,879 SNPs revealed 807 SNPs with significant associations corresponding to 1,012 genes. These 807 SNPs represented a genomic heritability of 0.32 and 89% of the genetic variance of residual feed intake (RFI). Genomic breeding values estimated from the SNP set (807) were highly correlated (0.96) to the breeding values estimated from a mixed animal model. The 10 most influential SNPs were located in chromosomes 16, 17, 9, 11, 12, 20, 15, and 19. Enrichment analysis for the identified genes (1,012) suggested 110 biological processes and 141 pathways contributed to variation in RFI. The 339 newly identified SNPs corresponding to 180 genes identified by fine-mapping were tested for association with feed efficiency, growth, and carcass traits. Strong evidence of associations for RFI was located on chromosomes 8, 15, 16, 18, 19, 21, and 28. Combing validated SNPs from fine-mapping and the candidate gene approach may help develop a DNA test panel for commercial use and increase our understanding of the biological basis of feed efficiency in beef cattle. / The Ministry of Higher Education of Egypt

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The aim of this thesis is to apply recently developed technologies for genomic variation analyses, and to ensure quality of the generated information for use in preclinical cancer research. Faster access to a patients’ full genomic sequence for a lower cost makes it possible for end users such as clinicians and physicians to gain a more complete understanding of the disease status of a patient and adjust treatment accordingly. Correct biological interpretation is important in this context, and can only be provided through fast and simple access to relevant high quality data. Therefore, we here propose and validate new bioinformatic strategies for biomarker selection for prediction of response to cancer therapy. We initially explored the use of bioinformatic tools to select interesting targets for toxicity in carboplatin and paclitaxel on a smaller scale. From our findings we then further extended the analysis to the entire exome to look for biomarkers as targets for adverse effects from carboplatin and gemcitabine. To investigate any bias introduced by the methods used for targeting the exome, we analyzed the mutation profiles in cancer patients by comparing whole genome amplified DNA to unamplified DNA. In addition, we applied RNA-seq to the same patients to further validate the variations obtained by sequencing of DNA. The understanding of the human cancer genome is growing rapidly, thanks to methodological development of analysis tools. The next step is to implement these tools as a part of a chain from diagnosis of patients to genomic research to personalized treatment. / <p>QC 20121105</p>

Post-zygotic genetic variation has previously been shown in healthy individuals and linked to various disorders. The definition of post-zygotic or somatic variation is the existence of genetically distinct populations of cells in a subject derived from a single zygote. Structural changes in the human genome are a major type of inter-individual genetic variation and copy number variation (CNV), involving changes in the copy number of genes, are one of the best studied category of structural genetic changes. In paper I we reported a pair of healthy female monozygotic (MZ) twins discordant for aneuploidy of chromosomes X and Y, contributing to the delineation of the frequency of somatic variation in MZ twins. It also illustrates the plasticity of the genome for tolerating large aberrations in healthy subjects. In paper II we showed age-related accumulation of copy number variation in the nuclear genomes in vivo for both megabase- and kilobase-range variants. Using age-stratified MZ twins and single-born subjects, we detected megabase-range aberrations in 3.4% of people ≥60 years old but not in individuals younger than 55 years. Moreover, the longitudinal analysis of subjects with aberrations suggests that the aberrant cell clones are not immortalized and disappear from circulation. We also showed that sorted blood cells display different genomic profiles.  The detected recurrent rearrangements are candidates for common age-related defects in blood cells. This work might help to describe the cause of an age-related decline in the number of cell clones in the blood, which is one of the hallmarks of immunosenescence. In paper III we described a variable number tandem repeat (VNTR) ~4 kb upstream of the IFNAR1 gene, which was somatically variable.  We detected 14 alleles displaying inter- and intra-individual variation. Further analyses indicated strong clustering of transcription factor binding sites within this region, suggesting an enhancer. This putative VNTR-based enhancer might influence the transcriptional regulation of neighboring cytokine receptor genes and the pathways they are involved in. These three studies stress the importance of research on post-zygotic variation in genetics. Furthermore, they emphasize that biobanks should consider sampling of multiple tissues to better address this issue in the genetic studies.

The purpose of this study was to design and test five SNP markers in an inbred chicken cross between Red Junglefowl and domestic White Leghorn of the 8th generation. The markers lie in a region affecting the tonic immobility behaviour which differs significantly between the two species. The markers could be identified by usage of PCR and pyrosequencing. The data obtained were further used in a small scale quantitative trait locus (QTL) analysis. QTL analysis is a statistical method to link phenotypic traits to genotypic data. Four out of five markers could be genotypes and thereby, made it possible to proceed with the QTL analysis. The results showed that there is no QTL associated with the markers identified. The two flanking markers were closest to a significant difference between genotypes and it is therefore a possibility that a QTL lies close further down or up the searched region. From the line map it is indicated that there is little recombination in the marker region.

Breast cancer is a heterogeneous, polygenic disease and is influenced by genetic, environmental and life-style factors. Many single nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified in genome-wide association studies (GWASs) by several research groups for different populations. However, the variants identified so far contribute to a small proportion of disease risk. The objectives of the work described in this thesis were (i) to seek relevance/replicability of reported risk alleles from SNP scans to our study population; and (ii) to perform an independent GWAS for identification of additional/novel polymorphisms in the Albertan population. We approached these two end points by using cases and controls recruited in Alberta (total sample size, n=3064) in a two-stage association study (discovery study followed by replication study). We reproduced 14 of the 28 variants reported by others and also identified seven novel variants associated with breast cancer risk in our study population.

A whole genome scan was conducted to identify and fine map QTL regions for ultrasound and carcass merit traits in beef cattle. A total of 465 steers and bulls, genotyped for 4592 SNPs, were analysed for 16 ultrasound and carcass merit traits using interval mapping, single marker regression and Bayesian shrinkage approaches. Thirty QTL and 22 SNPs associated with traits were identified by interval mapping and single marker regression respectively. In Bayesian shrinkage estimation, 218 QTL were identified, wherein 11 of the 30 QTL identified by interval mapping were confirmed. The proportions of QTL variance on the trait variations estimated by Bayesian shrinkage analysis were relatively small. They ranged from 0.1 to 4.8% compared to 6.1 to 11.7% in interval mapping because the QTL in Bayesian approach were adjusted to remove effects of other QTL in the genome. These results are useful for detection of underlying causative QTN variants. / Animal Science