This thesis investigated behaviour and behavioural phenotypes in the Mucopolysaccharide (MPS) disorders. The MPS disorders are a group of rare lysosomal storage disorders which are characterised by a period of normal development followed by gradual cognitive and/or physical decline.Paper 1 describes a systematic review of the extant literature on cognitive, motor, social, linguistic and behavioural presentation in all of the MPS disorders. 25 papers were reviewed and the methodology they employed was assessed. Sleep disturbance was found to be part of the behavioural phenotype of MPS III. In MPS I and II fearfulness and sleep problems occurred in most cases. In MPS II participants with the mild form were found to have relatively normal development and few or no behavioural problems, while those with the severe form had behavioural problems, delayed speech, delayed development and limited motor function. High rates of challenging behaviour, most commonly associated with aggression, hyperactivity, orality, unusual affect and temper tantrums were consistently observed in children with MPS III.Paper 2 describes an empirical study investigating the behavioural phenotype of MPS III, Sanfilippo syndrome. Parents of 20 children with MPS III, 5 adults with MPS III and 25 children with Intellectual Disability (ID) completed questionnaires relating to their son/daughter’s behaviour and adaptive skills. The frequency of challenging behaviours displayed by children aged 2-9 years with MPS III and ID were high but not significantly different. Behaviours associated with hyperactivity, orality, body movements and inattention were seen significantly more frequently in 2-9 year olds with MPS III than ID. The frequency of challenging behaviours displayed by children with MPS III and their adaptive skills was found to decrease with age. Children age 10-15 years with MPS III displayed significantly fewer problem behaviours than children of the same age with ID. It is recommended that parents with a child with MPS III aged 2-9 years are offered clinical services to support them with managing challenging behaviour while those with a child of 10 years or over are offered support with managing health concerns and end of life care.The third Paper, provides an evaluation of the strengths and limitations of the literature review and the empirical study. The findings and clinical implications from both studies are discussed. The process of conducting research into rare, life limiting, genetic syndromes is reflected upon and recommendations for replication and further research are made.

Campylobacter species are the primary cause of bacterial food-borne diarrhoea worldwide. Comparative genomic analyses of Campylobacter strains reveal genome plasticity providing insight into the evolution of virulence traits. The goal of this study was to identify genes important for infectivity and for naturally occurring variability in phenotypic traits in C. jejuni and C. coli strains. Transcriptome and phenotype analyses were conducted to determine if genetic and phenotypic characteristics could be attributed to the source of the strains. Isolates from water sources had higher biofilm formation than animal strains. Clinical strains had decreased sensitivity to hydrogen peroxide as well as increased adherence and invasion when compared to animal strains. A number of genetic differences were observed; however, without further analysis it is difficult to determine which of these impact virulence in Campylobacter. Ultimately, this project will lead to the identification of markers associated with strains of Campylobacter causing illness.

Genetic studies of lung disease in Cystic Fibrosis are faced with the challenge of identifying a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. This thesis uses data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies (CGS), Johns Hopkins University Twins and Siblings Study (TSS), and University of North Carolina/Case Western Reserve University Gene Modifier Study (GMS)), to calculate two novel phenotypes using age-specific CF percentile values of FEV1 (Forced Expiratory Volume in 1 second), with adjustment for CF age-specific mortality. The normalized residual, mortality adjusted (NoRMA) was designed for population based samples, while KNoRMA, using Kulich percentiles, is robust to sample ascertainment; both account for the effects of age-related disease progression and mortality attrition. NoRMA was computed for 2122 patients representing the Canadian CF population. KNoRMA was computed for these 2122 patients and also 1137 extreme phenotype patients in the GMS study and 1323 patients from multiple CF sib families in the TSS study. Phenotype was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype was highly correlated with the previously recommended mixed model phenotype1; 2, but computationally much easier and suited to studies with limited follow up time. As an example of its use, KNoRMA was used to test the association between locus variants in a previously published candidate gene, Transforming Growth Factor β1(TGFβ1), and lung function in CF, in an attempt to provide insight into discrepant results in the literature. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible interpolation distortions.

Two studies were conducted on gene mapping analysis. For the first study, genetic simulation experiments were conducted to address the effects of marker density, method of mapping analysis, and gaps in a marker map on the efficiency of QTL detection and the accuracy of QTL parameter estimation. The simulated genome consisted of seven chromosomes with seven or eight segregating QTL affecting the simulated quantitative trait. A set of six randomly segregating QTL outside the test region was consistently used to represent 40% of phenotypic variation. An individual QTL or a linkage block of two QTL on a target chromosome contributed 10% of phenotypic variation. The marker map was either dense (with markers every 4 cM) or sparse (with markers every 20 cM). The gap in the marker map was either 32 cM or 56 cM. Interval mapping and composite interval mapping were used to map QTL on the target chromosome. A dense map provided more power of QTL detection, better accuracy of QTL parameter estimation, and higher false-positive error rates for the target chromosome than a sparse map. Composite interval mapping provided more power of QTL detection, better accuracy of QTL parameter estimation, and lower false-positive error rates than interval mapping. Presence of a large gap in a marker map affected QTL detection and QTL parameter estimation for a QTL inside or near the gap. The use of a dense map with composite interval mapping was the most efficient combination tested in this study. For the second study, a mixed factorial regression model for interval mapping was developed for conducting QTL-by-environment interaction analysis and for providing inferences about QTL that are applicable beyond the environments used in the experiments. Genetic simulation was used to test the model for the power of detecting QTL-by-environment interaction and identifying the types of such interaction as crossover or non-crossover, and for the accuracy of estimating QTL parameters. The model prov

A significant proportion of potential lambs are lost (commonly 15-20%) between ovulation and day 30 of gestation. Moreover, little is known about factors associated with multiple birth capacity of the uterus which would be necessary to convert gains in ovulation rate to the birth of live lambs. This project has investigated the relationship between maternal uterine and hormonal environment as well as the heritability of embryonic survival (ES) in prolific ewes. Litter size (LS) from known ovulation rate (OR) records (n=6393) collected over 16 years were analysed for heritability. ASReml analysis reported ES to be a trait of low repeatability (r� = 0.103) and heritability (h� = 0.04) which is consistent with earlier studies of this trait. However, pedigrees of outlier animals indicated a segregation pattern consistent with a single autosomal gene with a major affect on enhanced ES. From this flock, closely related high ovulation rate ewes with significantly different litter sizes (High ES; OR2.6/LS2.4 versus Low ES; OR2.9/LS1.6) were selected for further study. The anatomy and gene expression of the uterus collected at day 14 of the oestrous cycle (n=5 High and n=5 Low ES ewes) and day 16 of gestation (n=14 high and n=10 Low ES ewes) as well as systemic concentrations of hormones indicative of uterine (activin-A, follistatin) and ovarian (inhibin-α, progesterone) function during the oestrous cycle and early gestation were compared. Progesterone concentrations were found to rise earlier in high ES ewes with a difference in number of ewes with detectable levels of progesterone apparent by day 4 of gestation. The peak concentration and slope of progesterone increase as well as plasma profiles of oestradiol and inhibin-α were not different between groups. A number of pathways worthy of closer investigation were implicated by microarray analysis with Ingenuity Pathway Analysis, Pubmatrix, and candidate gene approaches. In particular, the altered expression of many immune cell factors suggests that high ES ewes have maternal gene expression of the inflammatory pathways favourable to embryo implantation. The plasma concentration of activin, but not follistatin, was found to be significantly higher in low ES ewes, a difference that remained apparent when the concentration of follistatin was corrected for individual samples. Furthermore, the concentration of activin, but not follistatin, was significantly elevated on day 16 of gestation in the uterine fluid of low ES ewes. Further investigation of the pattern of gene expression during the oestrous cycle and early gestation (day10-16 oestrus and days10-20 gestation) revealed that a significant increase in follistatin mRNA in the luminal epithelia and interacting trophoblast cells of the embryo occurs on day 18 and 20 of gestation. It is likely the appropriate balance between activin and follistatin during the time of implantation enhances embryonic survival in this line of ewes. This may be secondary to or concomitant with the observed earlier rise in progesterone concentration. The implication that embryo survival may be positively influenced by a single autosomal gene has important implications for New Zealand's agricultural industry.

A significant proportion of potential lambs are lost (commonly 15-20%) between ovulation and day 30 of gestation. Moreover, little is known about factors associated with multiple birth capacity of the uterus which would be necessary to convert gains in ovulation rate to the birth of live lambs. This project has investigated the relationship between maternal uterine and hormonal environment as well as the heritability of embryonic survival (ES) in prolific ewes. Litter size (LS) from known ovulation rate (OR) records (n=6393) collected over 16 years were analysed for heritability. ASReml analysis reported ES to be a trait of low repeatability (r� = 0.103) and heritability (h� = 0.04) which is consistent with earlier studies of this trait. However, pedigrees of outlier animals indicated a segregation pattern consistent with a single autosomal gene with a major affect on enhanced ES. From this flock, closely related high ovulation rate ewes with significantly different litter sizes (High ES; OR2.6/LS2.4 versus Low ES; OR2.9/LS1.6) were selected for further study. The anatomy and gene expression of the uterus collected at day 14 of the oestrous cycle (n=5 High and n=5 Low ES ewes) and day 16 of gestation (n=14 high and n=10 Low ES ewes) as well as systemic concentrations of hormones indicative of uterine (activin-A, follistatin) and ovarian (inhibin-α, progesterone) function during the oestrous cycle and early gestation were compared. Progesterone concentrations were found to rise earlier in high ES ewes with a difference in number of ewes with detectable levels of progesterone apparent by day 4 of gestation. The peak concentration and slope of progesterone increase as well as plasma profiles of oestradiol and inhibin-α were not different between groups. A number of pathways worthy of closer investigation were implicated by microarray analysis with Ingenuity Pathway Analysis, Pubmatrix, and candidate gene approaches. In particular, the altered expression of many immune cell factors suggests that high ES ewes have maternal gene expression of the inflammatory pathways favourable to embryo implantation. The plasma concentration of activin, but not follistatin, was found to be significantly higher in low ES ewes, a difference that remained apparent when the concentration of follistatin was corrected for individual samples. Furthermore, the concentration of activin, but not follistatin, was significantly elevated on day 16 of gestation in the uterine fluid of low ES ewes. Further investigation of the pattern of gene expression during the oestrous cycle and early gestation (day10-16 oestrus and days10-20 gestation) revealed that a significant increase in follistatin mRNA in the luminal epithelia and interacting trophoblast cells of the embryo occurs on day 18 and 20 of gestation. It is likely the appropriate balance between activin and follistatin during the time of implantation enhances embryonic survival in this line of ewes. This may be secondary to or concomitant with the observed earlier rise in progesterone concentration. The implication that embryo survival may be positively influenced by a single autosomal gene has important implications for New Zealand's agricultural industry.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 65-81).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.