Mendelian Randomization (MR) methods use genetic variants as instrumental variables (IV) to infer causal relationships between an exposure and an outcome, which overcomes the inability to infer such a relationship in observational studies due to unobserved confounders. There are several MR methods, including the inverse variance weighted (IVW) method, which has been extended to deal with correlated IVs; the median method, which provides consistent causal estimates in the presence of pleiotropy when less than half of the genetic variants are invalid IVs but assumes independent IVs. In this dissertation, we propose two new methods to improve precision for MR analysis. In the first chapter, we extend the median method to correlated IVs: the quasi-boots median method, that accounts for IV correlation in the standard error estimation using a quasi-bootstrap method. Simulation studies show that this method outperforms existing median methods under the correlated IVs setting with and without the presence of pleiotropic effects. In the second chapter, to overcome the lack of an effective solution to account for sample overlap in current IVW methods, we propose a new overall causal effect estimator by exploring the distribution of the estimator for individual IVs under the independent IVs setting, which we name the IVW-GH method. In the final chapter, we extend the IVW-GH method to correlated IVs. In simulation studies, the IVW-GH method outperforms the existing IVW methods under the one-sample setting for independent IVs and shows reasonable results for other settings. We apply these proposed methods to genome-wide association results from the Framingham Heart Study Offspring Study and the Million Veteran Program to identify potential causal relationships between a number of proteins and lipids. All the proposed methods are able to identify some proteins known to be related to lipids. In addition, the quasi-boots median method is robust to pleiotropic effects in the real data application. Consequently, the newly proposed quasi-boots median method and IVW-GH method may provide additional insights for identifying causal relationships. / 2025-01-23T00:00:00Z

In D. melanogaster, resistance to DDT is conferred by the upregulation of a cytochrome P450 enzyme, CYP6G1. Resistant flies have tandemly duplicated Cyp6g1 alleles that possess the LTR (Long Terminal Repeat) of an Accord retrotransposon inserted in the cis-regulatory region, 291bp upstream of the transcription start site. This DDT resistance allele (DDT-R) has been shown to have pleiotropic fitness benefits for female flies in at least one genetic background and with evidence of sexually antagonistic selection at this locus. In this thesis, I first review the role of transposable elements in conferring insecticide resistance and the evidence to date regarding the pleiotropic effects of DDT-R in D. melanogaster. By conducting life history and behavioural tests on flies of two genetic backgrounds I examine the sex-specific effects of expressing DDT-R in the absence of DDT. Finally I develop a single locus population genetics model based on these sex-specific effects and test the model using replicate laboratory populations. The first main finding is that DDT-R incurred a male mating cost that depended on the genetic background in which DDT-R was found and that this cost coincided with strong epistasis between genetic background and DDT-R that influenced male size (Chapter 3). Following on from this result, it was confirmed that the effect of DDT-R on male size does contribute to lowered mating success but does not fully explain this fitness cost (Chapter4). Additionally, resistant males were found to have a lowered rate of courtship behaviour driven by aborted chasing of females and lower male-male aggression than susceptible males (Chapter 4). Fitness assays in wild caught strain females revealed that DDT-R confers a fecundity increase but unlike previous work, no offspring viability increases were detected (Chapter 5). Thus as with male costs, specific pleiotropic female fitness benefits to resistance depend on genetic background. Modelling of DDT-R using a simple single-locus approach (Chapter 6) provides, for the first time, a unifying explanation for past and present DDT-R frequencies in nature and in old laboratory populations. The model is consistent with an old origin for the original DDT-R mutation held at low equilibrium frequency through balancing selection of a sexually antagonistic nature. It is also consistent with continued near fixation of DDT-R long after discontinued use and matches empirical observations in laboratory populations of the Canton-S background.

<p>Examining the genetic basis across repeated origins of the same phenotypic adaptation allows us to address several questions pertaining to the genetic basis of adaptation. First, whether the genes and types of mutations that are involved in adaptation are predictable. Second, whether the underlying genetic changes can constrain future evolutionary trajectories. Here, I have focused on the genetics of blue to red flower color shifts, an adaptive shift that has repeatedly occurred across angiosperms. First, I review the literature and determine the relative contribution of functional vs. regulatory mutations to the evolution of red flowers can be predicted both on the mutational target size of each type of mutation and the degree of their associated deleterious pleiotropy. Chapter 2 characterizes the genetic basis of red flowers in Penstemon barbatus using a combination of gene expression and protein function assays. I demonstrated that multiple inactivating mutations to one anthocyanin pathway enzyme, F3'5'h, have occurred, but no mutations to any other component of the anthocyanin pathway have contributed to the evolution of red flowers. This suggests that F3'5'h may be a particularly favorable target for selection and also that evolutionary reversal to blue flowers would be highly unlikely. Chapter 3 investigates the genetic basis of an additional 12 origins of red flowers within Penstemon. Again, using a combination of gene expression and enzyme function assays, I found the genetic basis of these additional origins red flowers in Penstemon is highly predictable, involving redundant inactivating mutations to F3'5'h, and tissue-specific regulatory mutations to a second gene F3'h. Thus, the genetics of red flowers in Penstemon often involves inactivation of a non-pleiotropic gene, F3'5'h, but tissue-specific regulatory mutations to the pleiotropic gene F3'h. Furthermore, the presence of redundant inactivating mutations in many red-flowered Penstemon species indicates that the evolutionary reversal to blue flowers would be unlikely.</p> / Dissertation

Objectives: This article presents estimates of narrow-sense heritability and bivariate genetic correlation for 14 tooth crown morphological variants scored on permanent premolars, first molars, and second molars. The objective is to inform data collection and analytical practices in dental biodistance and to provide insights on the development of molar crowns as integrated structures. Materials and Methods: African American dental casts from the Menegaz-Bock collection were recorded for the Arizona State University Dental Anthropology System. Estimates of narrow-sense heritability and genetic correlation were generated using SOLAR v.8.1.1, which included assessment of age, sex, and birth year as covariates. Both continuous scale and dichotomized estimates are provided. Results: Heritability estimates were nonsignificant for the majority of variables; however, for variables yielding significant estimates, values were moderate to high in magnitude and comparable to previous studies. Comparing left and right-side heritability estimates suggests directional asymmetry in the expression of environmental variance, something not seen in anterior tooth traits. Genetic correlations were moderate among antimeres and metameres and low for different traits scored on the same tooth crown. Although several negative correlations were noted, few reached statistical significance. Results affirm some of the current data cleaning and analytical practices in dental biodistance, but others are called into question. These include the pooling of males and females and combining left and right-side data into a single dataset. Conclusions: In comparison to anterior tooth crown traits, postcanine heritabilities were more often non-significant; however, those traits with significant heritability also tended to produce higher estimates. Genetic correlations were unremarkable, in part, because they were underpowered. However, M1 results may provide insight into the complex relationship between genes, environment, and development in determining ultimate crown form.

Objectives: This article presents estimates of narrow-sense heritability and bivariate genetic correlation for a series of morphological crown variants of the anterior dentition. These results provide insight into the value of dental phenotypes as evolutionary proxies, as well as the development of tooth crowns as integrated or modular structures. Materials and Methods: African American dental casts from the Menegaz-Bock collection were scored for a standard set of dental morphological variables using the Arizona State Dental Anthropology System. Estimates of narrow-sense heritability and genetic correlations were generated using SOLAR v. 8.1.1, controlling for the covariates of age, sex, and birth year. Analyses were run using ordinal/continuous scale variables that were then dichotomized at various breakpoints, consistent with standard practices in dental anthropology. Results: Heritability estimates were low to moderate for most traits, and lower in magnitude than those reported for odontometric data from the same study sample. Only winging, canine shoveling, and canine double shoveling returned narrow-sense heritabilities that did not differ significantly from zero. Genetic correlations were high among antimeres and metameres and low for different traits scored on the same tooth crown. These results affirm standard data cleaning practices in dental biodistance. Double shoveling was atypical in returning strong negative correlations with other traits, shoveling in particular. Conclusions: Additive genetic variation contributes to dental morphological variation, although the estimates are uniformly lower than those observed for odontometrics. Patterns of genetic correlation affirm most standard practices in dental biodistance. Patterns of negative pleiotropy involving lingual and labial crown features suggest a genetic architecture and developmental complex that differentially constrain morphological variation of distinct surfaces of the same tooth crown. These patterns warrant greater consideration and cross-population validation.

Objectives: This article provides estimates of narrow-sense heritability and genetic pleiotropy for mesiodistal tooth dimensions for a sample of 20th century African American individuals. Results inform biological distance analysis and offer insights into patterns of integration in the human dentition. Materials and Methods: Maximum mesiodistal crown dimensions were measured using Hillson-FitzGerald calipers on 469 stone dental casts from the Menegaz-Bock Collection. Narrow-sense heritability estimates and genetic and phenotypic correlations were estimated using SOLAR 8.1.1 with covariate screening for age, sex, age*sex interaction, and birth year. Results: Heritability estimates were moderate (∼0.10 – 0.90; h2 mean = 0.51) for most measured variables with sex as the only significant covariate. Patterns of genetic correlation indicate strong integration across tooth classes, except molars. Comparison of these results to previously published work suggests lower overall heritability relative to other human populations and much stronger genetic integration across tooth classes than obtained from nonhuman primate genetic pleiotropy estimates. Conclusions: These results suggest that the high heritabilities previously published may reflect overestimates inherent in previous study designs; as such the standard estimate of 0.55 used in biodistance analyses may not be appropriate. For the Gullah, isolation and endogamy coupled with elevated levels of physiological and economic stress may suppress narrow-sense heritability estimates. Pleiotropy analyses suggest a more highly integrated dentition in humans than in other mammals.

The genome-wide association study (GWAS) approach has identified novel loci for a variety of complex diseases. However, for most of these disorder much of the heritability is not explained by this approach, which focuses on identifying common variants that are associated with disease risk. The unexplained heritability may be due to genetic or phenotypic heterogeneity or the influence of rare variants. The motivation behind this thesis was to uncover the unexplained heritability by applying joint analyses of sets of variants (gene-based association test) and multiple disease-related phenotypes (called multivariate gene-based association test). First, we evaluated multivariate gene-based methods for detecting association of common genetic variants with correlated phenotypes. An extensive simulation study showed that the method combining the MultiPhen and GATES software performed best for most tested scenarios especially when correlations among phenotypes are relatively low. We developed a new multivariate gene-based test using rare variants called VEMPHAS. A simulation study using VEMPHAS showed that this method correctly controls for type I error in all tested scenarios. We applied VEMPHAS to analysis of various phenotypes related to Alzheimer disease (AD) and found suggestive association (P < 4.15x10-6) with the gene TRIM22, which has been identified in a previous sequencing study of AD onset in PSEN1/2 mutation carriers. We also developed software with a graphical user interface which is designed for integrating information from different types of data sources including genetic data (from GWAS or sequencing), expression data (from RNA-Seq), and protein structures (from protein data banks). This software has several features including 1) testing associations between genetic variants and gene expressions; 2) locating amino acids, encoded by the variants, in a protein structure; and 3) retrieving genetic locations (chromosome and base pair positions) of amino acids of interest in the protein structure. The last feature can be applied for prioritizing coding variants for gene-based association testing. The methods and strategies developed for this dissertation project can effectively uncover a portion of the remaining heritability of complex diseases that is unexplained by traditional GWAS approaches.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21158号 / 農博第2284号 / 新制||農||1060(附属図書館) / 学位論文||H30||N5132(農学部図書室) / 京都大学大学院農学研究科地域環境科学専攻 / (主査)教授 田中 千尋, 教授 本田 与一, 教授 宮川 恒 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

Genetic predisposition to obesity presents a paradox: how do genetic variants with such a detrimental impact on human health persist through evolutionary time? Numerous hypotheses, for instance the thrifty genotype hypothesis, attempt to explain this phenomenon, yet fail to provide a satisfying answer to the modern obesity epidemic. In this critical review, I appraise existing theories explaining the evolutionary origins of obesity and explore novel biological and sociocultural agents of evolutionary change that may help explain the distribution of obesity and leanness predisposing variants in modern human populations. Gene pleiotropy and adaptations to diverse environmental niches may explain the rise and subsequent selection of obesity risk alleles. The regulation of gene expression by epigenetic mechanisms may serve as a stochastic factor affecting the manifestation of obesity phenotypes. Finally, exposure to malnutrition and disease epidemics in the wake of colonialism, culturally mediated notions of attractiveness and desirability, and diverse mating systems – including forced copulation, consanguinity and polygamy – may play a role in shaping the human genome. In short, I posit that in order to explain ethnic variation in obesity susceptibility, we must examine the origin of physiological adaptations and understand the sociocultural experiences of individuals and populations. As an imperative first step towards the identification of important drivers of obesity gene evolution, this review will inform empirical research focused on testing evolutionary theories by way of population genetics and mathematical modelling. Ultimately, these data will promote a better understanding of the aetiology of obesity and are expected to guide the development of targeted management, treatment, and prevention strategies. / Thesis / Master of Science (MSc)

Este estudo teve por objetivo mapear QTLs para características de desempenho e de carcaça em Gallus gallus . Foram estudadas 350 aves F2 oriundas de um cruzamento, na primeira geração, de machos de corte da linhagem TT com fêmeas de postura da linhagem CC. O peso vivo com 1, 35 e 42 dias de idade; o ganho de peso, o consumo de ração e a conversão alimentar de 35 a 41 dias de idade; os pesos dos pulmões, fígado, coração, moela, peito, coxas (peso de coxas e sobre-coxas), carcaça (sem vísceras, pés e cabeça), carcaça residual (peso da carcaça sem peito, asas e coxas), asas, cabeça, pés e gordura abdominal; o comprimento do intestino e o percentual de hematócrito, foram os fenótipos analisados. Foram utilizados 79 marcadores microssatélites, os quais cobriram 1510,7 cM dos cromossomos 1, 2, 3, 4, 5, 8, 11 e 13. Primeiramente, foram realizadas análises isoladas de cada fenótipo original e de variáveis canônicas obtidas por análise de componentes principais dos fenótipos. O teste razão de verossimilhanças (LRT) entre um modelo incompleto (apenas com efeitos fixos de sexo, incubação e o efeito aleatório de valor genético infinitesimal) e um completo (todos os efeitos anteriores mais os efeitos de QTL) foi o procedimento utilizado nas análises, exceto para testar modelos com interações epistáticas, onde a metodologia de quadrados mínimos foi utilizada. Modelos com interação QTL x sexo também foram testados. Posteriormente, foram feitas análises de múltiplos fenótipos simultaneamente, onde foi possível testar a hipótese de QTL pleiotrópico x QTLs ligados, além dos testes descritos acima, com exceção de efeitos epistáticos. As análises descritivas e de componentes principais foram obtidas no SAS, enquanto o mapeamento de QTL foi realizado no programa QxPak, exceto para análise de efeitos epistáticos, em que um código em Fortran 90 foi empregado. O modelo univariado, sem interações, permitiu mapear oito QTLs altamente significativos (cinco no GGA1 para PV35, PV42, gordura abdominal, comprimento do intestino e peso da cabeça; dois QTLs no GGA2 para PV35 e PV42; e um QTL no GGA3 para gordura abdominal) seis significativos (dois no GGA1 para conversão alimentar e ganho de peso; dois no GGA3 para peso das asas e das coxas; um no GGA4 para peso da cabeça; e um no GGA8 para peso da moela), além de 13 ligações sugestivas para diversas características. Dez QTLs apresentaram interação com sexo, sendo cinco específicos para machos. O modelo com busca simultânea de dois QTLs mapeou seis QTLs anteriormente perdidos (cinco para PV35 e PV42; e um para peso da cabeça). Interações epistáticas foram observadas para PV35 e PV42 entre um QTL em 69 cM do GGA1 com QTLs em 333 cM do GGA1, 272 cM do GGA3 e 77 cM do GGA5. Dois QTLs e seis ligações sugestivas foram mapeados na análise de variáveis canônicas, os quais não haviam sido mapeados com as variáveis originais. Com o procedimento de múltiplas características foi possível mapear nove QTLs pleiotrópicos e o aumento de poder do teste foi evidenciado, principalmente, no GGA2. / This study aim to map QTL for performance and carcass traits in (Gallus gallus) . There were used 350 F2 chickens developed by crossing a broiler male line (TT) with a layer line (CC). The body weight with 1, 35 and 42 days of age, weight gain, feed intake and feed conversion from 35 to 41 days, weights of lung, liver, heart, gizzard, breast, drums and thighs, carcass (without giblets, feet and head), residual carcass (weight of carcass without breast, drums, thighs, and wings), wings, head, feet, and abdominal fat, intestine length and hematócrito value were the phenotypes analyzed. Seventy nine microssatellite markers were used, which covered 1510.7 cM of chromosomes 1, 2, 3, 4, 5, 8, 11, and 13. Firstly, QTL analysis was carried out for each original trait and for canonical variables, obtained from principal components analysis of the phenotypes. The likelihood ratio test (LRT) between a reduced model (only fixed effects of sex, hatch and random effect of infinitesimal genetic value) and a full model (all anterior effects and QTL effects) was applied to map QTL, but mean square approach was used for mapping QTL with epistatic effect. Besides, models with QTL by sex interaction were also tested. Finally, multi-trait analysis was used to test the hypothesis of pleiotropic x linkage QTLs, besides of the tests previously described, except models with epistatic effects. For descriptive and principal components analysis the SAS software was used. QTL mapping was carried out with QxPak software and a fortran 90 source code to test models with epistatic effect. The univariate model, without interactions, allowed to map eight highly significant QTLs (five in the GGA1, for PV35, PV42, abdominal fat, intestine length, and head weight; two QTLs in the GGA2, for PV35 and PV42; and one QTL in the GGA3 for abdominal fat), six significant QTLs (two in the GGA1 for feed conversion and weight gain; two in the GGA3 for wings and drums and thighs weights; one in the GGA4 for head weight; and one in the GGA8 for gizzard weight), besides 13 suggestive linkages for several traits. Ten QTLs interacted with sex, being five of them male specific QTLs. The model with simultaneous search for two QTLs was important to map six QTLs previously lost (five for body weight at 35 and 42 days; and one for head weight). Epistatic Interactions were observed for body weight among a QTL in 69 cM of GGA1 with QTLs in 333 cM of GGA1, 272 cM of GGA3 and 77 cM of GGA5. Two QTLs and six suggestive linkages were mapped with the analysis on canonical variables, which have not been mapped with the original variables. With the multi-trait approach nine pleiotropic QTLs were mapped and an increase in the test power was observed mainly in the GGA2 chromosome.