This work analyzes the genetic basis of three neurodegenerative diseases using several thousands of individuals of European descent to determine a range of phenotypic heritability outside of what has been identified by prior methods. By measuring additive genetic variance genome-wide, measures of its contribution to the phenotypic variance of these diseases were substantially increased, in some instances by a factor of 10 or more. Additionally, regional-mapping methods identified segments of the genome exhibiting significantly high heritability estimates associated with one of the neurodegenerative diseases, Amyotrophic lateral sclerosis. This resulted in the detection of novel candidate regions and provided conclusive evidence for the polygenic architecture of this disease. Lastly, novel risk variants associated with Parkinson's disease were identified on the X chromosome, a previously ignored genomic region. Overall, the employment of new analytic methods produced robust and novel results, adding substantial information to the neurodegenerative disease literature and connecting the anthropological perspective with growing informatics-based methods. / Anthropology

The broad goals of this dissertation were to explore possible causes of erectile dysfunction (ED), and examine outcomes associated with the condition. To address these objectives, data from the Vietnam Era Twin Study of Aging (VETSA), a longitudinal study of cognitive aging, were utilized. Previous research demonstrated moderate heritability of ED in middle-aged men, but questions remain about the replicability of these findings given that only one study exists on the topic and it utilized an unvalidated ED measure. Additionally, it is unknown to what extent genetic factors account for stability and change of ED symptomatology over time. In the first study, we conducted a longitudinal assessment of ED using the Sexual Health Inventory for Men (SHIM) administered to 668 male twins. Results revealed that the heritability (proportion of variance explained by genetic factors) of ED at both time points is moderate (0.3 –0.6). Over the past two decades ED has been recognized as primarily a disorder of vascular dysfunction. Inflammation is an important correlate of vascular dysfunction. Chapter 2 examined the association of ED with four inflammatory serum protein indices [albumin, globulin, albumin/globulin ratio (AGR), and the albumin*globulin interaction (AGI)] in 388 men free from cardiovascular disease (CVD). Results indicated that the AGR, albumin, and globulin protein levels are significantly associated with ED, even after accounting for other risk factors. Intriguingly, AGR and globulin levels were found to be more strongly associated with ED than conventional vascular risk factors, such as hypertension, high cholesterol, obesity, and smoking. As such, globulin and AGR may be useful biomarkers when diagnosing and managing ED. The simplicity and affordability of these assays make these markers particularly valuable. Given the negative impact that vascular disease has on cognition, Chapter 3 explored whether men with ED are at greater risk for experiencing cognitive decline compared to healthy peers. In total, 485 men free from CVD were administered cognitive tests across 13 domains. Tests were readministered 5 years later. Results revealed that men with ED were more likely to show significant decline on tasks of set-shifting, tool/mechanical knowledge, vocabulary, and verbal fluency.

The objectives of this dissertation were to evaluate genetic and environmental relationships between lamb and ewe traits including body weight, fleece weight and quality, prolificacy, body condition, ewe stayability and lamb survival. Average heritability estimates for lamb birth weight (BWT), weaning weight (WW), maternal weaning weight, yearling body weight, fleece weight, spinning count and staple length were 0.19, 0.09, 0.08, 0.35, 0.38, 0.25, and 0.31 respectively. Heritability estimates for adult traits averaged 0.43 for body weight (AW), 0.13 for body condition (AC), and 0.12 for number of lambs born per ewe lambing (NLB). Correlations between direct additive AW and direct additive and maternal lamb weights ranged from 0.21 to 0.96 (P < 0.05) and 0.29 to 0.53 (P < 0.05), respectively, with residual correlations ranging from 0.05 to 0.95. Correlations of lamb traits with adult body condition and NLB were generally not different from zero; genetic and residual correlations ranged from -0.52 to 0.69 and -.39 to 0.31, respectively. Ewe stayability was analyzed as overall stayability (STAYn|2) which indicated the presence or absence of a ewe at n yrs of age, given that she was present at 2 yrs of age, and marginal stayability (STAYn|1-n) recording the presences of a ewe at n yrs of age, given that she was in the flock the previous year. Additive variance in ewe stayability was only found in stayability at 5 and 6 yr of age (P < 0.05). Heritability estimates for STAY5|4 and STAY6|2 from multiple trait analyses with other traits averaged 0.08 and 0.10, respectively. Phenotypic correlations between STAY and all other traits were near zero, ranging from -0.04 to 0.03. The estimated correlations between additive effects on STAY5|4 and STAY6|2 and additive maternal effects on WW were positive (both 0.46; P < 0.05). Genetic correlations between STAY5|4 and WW, adult weight, and NLB were 0.06, 0.13 and -0.06 (P > 0.10), respectively. However, genetic correlations between STAY6|2 and WW, adult weight, and NLB were negative (-0.17, -0.32 (P < 0.05) and -0.03, respectively). Significant genetic variation was thus present in stayability, with nonzero genetic correlations present between STAY, maternal milk, WW, and adult weight. Survival analysis was performed using a proportional hazards model to measure the probability of lamb death before weaning. Lamb survival was recorded as the day of age at death. Records were censored if a live lamb was artificially removed from their litter before death. Fixed effects on survival included ewe age, litter size, sex, and linear and quadratic BWT. Average age of death was 13.7 d. Censoring of records before weaning occurred in 12.9% of the total lambs born. Risk ratios indicated lambs from yearlings and ewes older than 5 yr had the greater risk of death, as did triplet and quadruplet lambs. Linear and quadratic BWT effects on lamb survival were found (P < 0.05) and accounted for most of the litter size effects in large litters. The influence of informative censoring was considered by assuming that lambs censored by 3 d of age had died at the time of censoring. Heritability of lamb survival at 3 d of age (estimated using an animal model in MTDFREML) was near zero, ranging from 0.00 to 0.01. The lack of additive variance suggests that improvement in lamb survival should be made through changes in management practices. / Ph. D.

Environmental variation is ubiquitous in natural systems. The genetic and physiological mechanisms governing population-level responses to this variation will impact the process of speciation and the capacity for populations to persist in a changing climate. Until recently, population-level responses to environmental selection remained largely unexplored in marine systems due to the historical assumption that the inherently dispersive nature of most marine taxa would preclude their ability to specialize to local environments. This dissertation represents the first investigation of population-level responses to environmental variation in a Caribbean reef-building coral. This research integrates ecological, physiological, genetic and genomic methods to (1) determine patterns of local adaptation in the Florida Keys, (2) identify stressors driving adaptive responses, (3) distinguish the physiological and genetic mechanisms underlying coral adaptation and (4) assess the potential for future adaptation in the common reef-building coral Porites astreoides. Results demonstrate that corals adapt and/or acclimatize to their local habitat and that this specialization incurs fitness costs. Temperature differences between reefs likely play a selective role in differentiating inshore and offshore coral populations. Genetic and gene expression differences indicate that coral hosts play a substantial role in driving these population-level differences. Inshore corals exhibit greater gene expression plasticity, which may be involved in stabilizing physiological responses to temperature fluctuations experienced at inshore reefs. In addition, naïve juvenile coral recruits from inshore reefs exhibit a growth rate advantage over offshore recruits under elevated temperature treatment, suggesting that thermotolerance differences observed in adult populations could continue to evolve in response to climate change. Taken together these results provide novel insight into the drivers of reef decline in the Florida Keys and the role of the host in coral adaptation capacity. / text

AIM: This study aims to determine what portion of specific autoantibody phenotypes are genetically determined by using a twin model. METHODS: This study specifically examines Anti-Ro(SSA), Anti-La (SSB), Anti-Sn/RNP, Anti-Sm, Anti-Jo-1, Anti-Scl-70, Anti-Tg & Anti-TPO, Anti-dsDNA, Anti-PS, and Anti-cardiolipin antibodies for their heritability. This study examined 104 same-sex adult twins (66 monozygous, 38 dizygous) for the above mentioned autoantibody values. The serum autoantibody values in each subject were quantified using automated ELISA. Descriptive statistics including, distributions, quantiles, and moments were calculated by zygosity for continuous antibody values, subject ages, gender, race and smoking status. Categorical antibody levels were used to determine twin pair concordance rates. Continuous and rank ordered autoantibody values were used to determine the presence and portion of a genetic component. To evaluate how strongly the antibody values in each twin group resembled each other, the intraclass correlation was calculated for each antibody by zygosity. The genetic variances, environmental variances, and heritability were estimated using path models with maximum likelihood estimation techniques. The phenotypic variance was modeled as a linear function of underlying additive genetic (A), dominant genetic (D), common environmental (C), and random environmental (E) effects. RESULTS: Several antibodies demonstrated a genetic component in our study population. Anti-cardiolipin had a genetic component with an estimated 69% heritability. Anti-dsDNA yielded a genetic component with a heritability estimate of 55-62%. Anti-Jo-1 presented a genetic component with the heritability estimate to be 41-51%. Anti-SCL-70 demonstrated a genetic component with a heritability estimate of 42-59%. Anti-PL had a genetic component with a heritability estimate of 52-54%. Several antibodies did not have a measurable genetic component. These included anti-Sm, anti-Ro(SSA), anti-La(SSB), anti-sn/RNP, anti-Tg, and anti-TPO. Some possibilities for the lack of a measureable genetic component may be due to the limited number of discordant twin pairs and/or the small number of subjects with higher levels of antibodies. CONCLUSION: The results of this study suggest several clinically relevant markers of auto-immunity may be partially genetically determined. These include: anti-cardiolipin, anti-dsDNA, anti-Jo-1, anti-SCL-70, and anti-phospholid.

Master of Science / Department of Statistics / Wei-Wen Hsu / Polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) are endocrine disrupting chemicals which can imbalance the hormonal system in the human body and lead to deleterious diseases such as diabetes, irregular menstrual cycles, endometriosis, and breast cancer. These chemicals as environmental exposures still exist in the environment and food chains and can be accumulated in human fatty tissues for many years. These chemicals can also be passed from mothers to their children through placental transfer or breastfeeding; therefore, their offspring may be at increased risk of adverse health outcomes from these inherited chemicals. However, it is still unclear how the parental association with offspring health outcomes and the inter-generational phenotypic inheritance could be affected by these chemical compounds. In this study, we mainly focus on how PCBs and DDE can affect the inheritance of Body Mass Index (BMI) across generations, as BMI is the primary health outcome (or phenotype) linked to diabetes. We propose a biometrical inheritance model to investigate the effects of PCBs and DDE on the heritability of BMI over two generations. Technically, a linear mixed effects model is developed based on the decomposition of phenotypic variance and assuming the variance of the environmental effect depends on parental exposures. The proposed model is evaluated extensively by simulations and then is applied to Michigan Fisheater Cohort data for answering the research question of interest.

Barley is the second largest grain crop produced in Australia and has two primary end uses. The first use is the premium market for malt and beer production. The second use is animal consumption. The quality of barley for the range of end uses is influenced by the cultivar itself as well as the growing environment. A detailed understanding of these factors at the genetic and biochemical levels was required to enable breeding program to select for quality improvement. A number of grain and end product quality traits were assessed for genetic and environmental affects as well as their interaction.Grain size has an important impact on quality and large plump grain is desirable for malt and feed quality. The results from the research conducted in this study clearly show that grain size was affected by cultivar and environmental conditions. Using screenings (< 2.2 mm) and retention (> 2.5mm) data provided information on how cultivars performed under a range of environmental conditions, which included irrigated (water unlimited) to terminal moisture stress (no in crop rain). The results showed a strong genetic component in the variation in grain size and it would be possible to select for increased grain size but also stable grain size when considering cultivars grown under adverse environmental conditions.The husk content in barley impacts on malt and feed quality. The results in this studied showed there were significant genetic effects as well as environments effects on the level of husk. In addition, it was identified that the genetic regions controlled husk expression were associated with two other quality traits, namely, resistance to kernel discolouration and resistance to pre-harvest sprouting (dormancy). These regions on chromosome 4H and 6H are also associated with previously identified dormancy genes.Hardness is a trait not usually considered when assessing barley quality but the results from this study showed there are differences in the level of barley hardness, as measured by three methods, as well as differences in the hardness gene sequence. The three hardness methods used showed that barley hardness could be measured independently of the method used, but also that there were significant genetic and environmental effects on hardness. However, the results from sequencing for allelic variation in the hardness genes showed that while there was polymorphism, and hance the transcribed protein had little effect on variation in quality. The cultivars used were malting and feed cultivars and a set of iv breeding lines targeted at malt quality. It may be possible to identify diverse haplotypes from the use of wild relatives or landraces.This study also investigated the variation in barley for cattle feed quality. Feed quality was determined using an in-sacco dry matter digestibility (ISDMD) assay in fistulated cows as well as three other laboratory assays, namely acid detergent fibre, starch and particle size. These four traits are then used to calculate Net Energy (NE) and Average Daily Gain (ADG). The results show that there were genetic and environmental effects on feed quality. The key trait was the ISDMD assay and there were significant differences between the cultivars tested. The data suggested feed quality was a measurable and definable attribute that could be used in breeding selection.The final aspect of this study compared the feed data obtained with routine malt quality traits, of friability and hot water extract. There were strong genetic and environmental effects. The malting cultivars generally had the highest level of ADG and NE. The results also showed that there were negative correlations between extract and husk, ISDMD and ADG. Positive correlations were shown between friability and hardness, extract and test weight, and there was only a slight correlation between average daily gain and extract.An important aspect of this study was the calculation of the genetic component for each trait. This was carried using spatial analysis of mixed models. It was necessary to use this approach so a true estimation of the genetic component could be calculated which would then allow for the calculation of heritability. In plant breeding, the cultivar is not a fixed effect but rather a random variable, hence it was not possible to use normal analysis of variation (ANOVA) models. Rather models were written with cultivars, like environment and field position, as random effects which will allow the effect of each random variable to be accounted for in the analysis. Best Linear Unbiased Predictions (BLUPs) are calculated and presented for all traits.For all the traits measured in this study, heritability values were calculated to ascertain the level of success in improving these traits through breeding. The range in heritability for grain size was 40 to 90%, husk 30 to 60%, hardness, 40 to 90%, feed quality traits 20 to 80% and malt quality traits 40 to 90%. Generally most traits exhibited a moderate to high level of heritability which indicated genetic improvement was possible through the use of appropriate genetic material.

Lately the rate of genetic gain in most agronomic crop species has been reduced due to several factors that limit breeding efficiency and genetic gain. New genetic tools and more powerful statistical analyses provide an alternative approach to enhance genetic improvements through the identification of molecular markers linked to genomic regions or QTLs controlling quantitative traits. The main objective of this research was to identify genomic regions associated with enhanced agronomic performance in lines per se and hybrid combination in Sorghum bicolor (L.) Moench. A population composed of 187 F5:6 recombinant inbred lines (RIL) was derived from the cross of restorer lines RTx430 and RTx7000. Also, a testcross hybrid population (TCH) was developed by using each RIL as a pollinator onto ATx2752. A linkage map was constructed using 174 marker loci generated from AFLP and SSR primer combinations. These markers were assigned to 12 different linkage groups. The linkage map covers 1573 cM with marker loci spaced at an averaged 9.04 cM. In this study, 89 QTL that control variation in seven different morphological traits were identified in the recombinant inbred line population, while in the testcross hybrid population, 79 QTL were identified. These traits included grain yield, plant height, days to mid-anthesis, panicle number, panicle length, panicle exsertion and panicle weight. These putative QTL explained from 4 to 42% of the phenotypic variation observed for each trait. Many of the QTL were not consistent across populations and across environments. Nevertheless, a few key QTL were identified and the source of the positive additive genetics isolated. RTx7000 was consistently associated with better agronomic performance in RIL, while in testcrosses, RTx430 was. Some genomic regions from RTx7000 may be utilized to improve RTx430 as a line per se. However, it is very unlikely that such regions will have a positive effect on the combining ability of RTx430 since testcross results did not reveal any transgressive segregants from the RIL population.

Raffinose family oligosaccharides (RFO) are major soluble carbohydrates of lentil (Lens culinaris Medik) seeds. When consumed by humans, RFO pass indigested through upper digestive tract as ¦Á-galactosidase enzyme required for RFO breakdown is not produced in humans. Consumption of lentils with high concentrations of RFO result in stomach discomfort, bloating and diarrhea due to bacterial fermentation of RFO in large intestine. This has lead to a relatively low use of lentils for human consumption. RFO are therefore considered anti-nutritional factors and development of lentil cultivars with reduced RFO concentrations is desired to improve lentil quality and consumption. To explore the possibility to develop lentil cultivars for low-RFO concentration, heritability of RFO trait and influence of environmental conditions on RFO must be known. In addition, RFO biosynthesis and accumulation in lentil seeds must be understood. However, very limited information is available on the above mentioned aspects of RFO in general and in lentil in particular. Therefore, the objectives of this study were: (1) to evaluate natural variation in RFO concentration and composition in commonly grown lentil cultivars and to determine the correlation between RFO concentration and other important seed constituents, (2) to investigate heritability and effect of environment on concentration and composition of lentil seed soluble carbohydrates, (3) to assess natural variation and diversity in RFO concentration in the genus Lens, (4) and to evaluate the association between galactinol synthase activity and accumulation of RFO in lentil seeds. Analysis of 22 lentil genotypes revealed significant (P ¡Ü 0.05) variation in total starch, amyolse, protein, total RFO and seed weight and seed colour. Stachyose was the major RFO in all lentil genotypes followed by raffinose and verbascose. A significant (P ¡Ü 0.05) inverse correlation was found between RFO and amylose concentration (r = -0.34); whereas RFO concentration and thousand seed weight correlated positively (r = 0.35). The analyses of variance of eleven cultivars grown at ten different environments showed that cultivar, environment and their interaction had significant effects on sugar concentration in lentil seeds. The high broad sense heritability of RFO (h2= 0.85) indicated that RFO concentration in lentil seeds is highly heritable and thus amenable to genetic improvement. An extensive evaluation of domesticated and wild species and subspecies of the genus Lens revealed significant (P ¡Ü 0.05) variation and diversity in RFO concentration and composition of individual oligosaccharides. Higher Shannon-Weaver diversity indices (SDI) for total RFO, raffinose and verbascose traits were observed in wild lentils compared to domesticated genotypes. Lens ervoides genotypes and some wild genotypes contained almost half the RFO concentration of cultivated lentils and therefore, wild genotypes may be useful for developing low-RFO lines. Higher verbascose and lower stachyose concentration was found in Lens ervoides genotypes, whereas higher raffinose and lower verbascose concentration is found in Lens nigricans genotypes. Study of galactinol synthase activity in developing seeds with varying RFO concentration showed no clear association between galactinol synthase activity and RFO concentration. The sucrose and galactinol concentration of developing seeds were also not associated with total RFO concentration of lentil seeds. This finding suggests a non-regulatory role of galactinol synthase in RFO biosynthetic pathway in lentil seeds. Together, all these findings are not only significant to devise strategies to develop lentil cultivars with reduced RFO concentration but also for understanding RFO biosynthesis in lentil seeds.

The development of cottons with improved fiber quality has been a major objective in breeding programs around the world. Breeders have focused their attention on improving fiber strength and length, and have generally not used fiber elongation in the selection process. Although literature has reported a negative correlation between fiber elongation and tenacity, this correlation is weak and should not prevent breeders from simultaneously improving fiber tenacity and fiber elongation. Furthermore, the work of rupture property, important in the spinning process, could be best enhanced by improving both fiber tenacity and fiber elongation. Fifteen populations were developed in 2007 by crossing good quality breeding lines with high elongation measurements to ‘FM 958’; a High Plains standard cultivar with good fiber quality but reduced elongation. Samples in every generation were ginned on a laboratory saw gin, and the lint was tested on HVI (High Volume Instrument). The F2 and F3 generations showed a wide range of variation for elongation (6.9% - 12.8% for the F2 and 4% - 9.20% for the F3) allowing divergent selection for low and high fiber elongation. A correlation (r) of -0.32 between strength and elongation was observed in the F2 individual plant selections. In the F3, the correlation (r) between strength and elongation was -0.36, and in the F4 the correlation (r) was -0.08. Nine lines were selected from the original 15 populations for spinning tests. The correlation between fiber elongation and strength for these lines was positive (r=0.424), indicating that with targeted selection, fiber elongation and strength can be simultaneously improved. Fiber elongation was positively correlated with yarn tensile properties tenacity (r=0.11), work-to-break (r=0.68) and breaking elongation (r=0.87); and was negatively correlated with yarn evenness properties, number of thin places (r=-0.16), number of thick places (r=-0.9), nep count (r=-0.24), hairiness (r=-0.38) and total number of imperfections (r=-0.38). All selections for high elongation were superior for all tensile properties compared to the low selections and the check in the analysis over locations and in each location. Furthermore, selections for high elongation were significantly different from the selections for low elongation and the check. In addition to developing lines for fiber spinning tests with improved, or differentiated, fiber elongation, this project was amended to evaluate and determine the heritability of fiber elongation. Three different methodologies were used to obtain estimates of heritability; variance components, parent off-spring regression, and realized heritability using F3, F4, and F5 generation. No inbreeding was assumed because there was no family structure in the generations within this study. Estimates of heritability by the variance component methods in the F3, F4 and F5 were 69.5%, 56.75% and 47.9% respectively; indicating that 40-50% of the variation was due to non-genetic effects. Parent off-spring regression estimates of heritability were 66.1% for the F3-4 and 62.8% for the F4-5; indicating a high resemblance from parents to off-spring. Estimates of realized heritability were obtained to determine the progress realized from selection for the low and high selection for fiber elongation. Estimates were intermediate (0.44–0.55), indicating moderately good progress from selection. The results from this project demonstrate that it is possible to improve fiber elongation and to break the negative correlation between elongation and strength. Furthermore, it has been demonstrated that improving fiber elongation results in the increase of length uniformity index and decreased short fiber content. Additionally, directed divergent selection was a successful methodology for the improvement of fiber elongation, and was useful to demonstrate that higher fiber elongation has a positive effect on yarn tensile properties, yarn evenness and processing. The development of new cultivars with improved fiber elongation will improve the quality and reputation of U. S.-grown cotton. The ultimate result will be better yarn quality and improved weaving efficiency, and particularly address current weaknesses in U. S. –grown cotton cultivars, especially from the High Plains of Texas, of more short fiber content, lower uniformity ratios, and weaker yarn strength.