Parents modulate the phenotypes of their offspring, beyond the effects of the genes they pass on. These parental effects can have impacts on the fitnesses of those offspring, as well as the fitness of the parents themselves. Parental investment in offspring is expected to be under antagonistic selection through its beneficial effects to offspring, and its detrimental effects on the parent's own fitness. Evolutionary conflict over parental care is therefore expected to occur, and may cause evolutionary stasis. Furthermore, selection is also expected to act on offspring traits, in order to maximise offspring fitness within a given parental environment, generating predictions of parent-offspring coadaptation. I tested the predictions of conflict and coadaptation in parent-offspring interactions, using a population of blue tits (Cyanistes caeruleus), a species in which adults provide biparental care to their offspring. I found evolutionary conflict over offspring body mass, which may explain stasis in this trait. I also used a cross-fostering design to test for coadaptation between parents and offspring, and siblings. I did not find evidence for parent-offspring coadaptation, nor did I find that siblings were important through either direct interactions, or in mediating parent-offspring interactions, suggesting that there is little family coadaptation in this species. In addition, I investigated whether a maternal effect on hatching time was a passive consequence of environmental changes, or was an anticipatory maternal effect actively placed in eggs to manipulate hatching time. The results from this analysis suggest the latter to be the case, and mothers appear to actively manipulate offspring hatching time to reduce the extent of hatching asynchrony, which may reduce fitness costs to the offspring. By measuring the effects of interactions between individuals on phenotypes and fitness measures, I was able to show how parental effects on offspring can affect evolutionary dynamics. Such evidence of evolutionary conflicts has not previously been found, due to methodological issues with the ways in which selection has been measured. Thus, I highlight how gaps in knowledge about the evolutionary consequences of parental effects can be addressed using appropriate statistical tools and measures of fitness.

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Background dependence is a ubiquitous attribute of eukaryotic gene systems that modulates the phenotypic effects of a mutant allele due to segregating genetic variation among different wildtype strains. Despite the wealth of literature demonstrating the presence of genetic background effects, very little is known about how they functionally or mechanistically contribute to the relationship between genetic variation and phenotypic expression. It has been postulated that background dependent effects may be highly specific to the activity of individual alleles or genes. A recent examination of mutant alleles in two interacting genes in the Drosophila wing network demonstrated the magnitude of phenotypic effect of a mutant allele may predict it’s sensitivity to the genetic background. To further understand this, I examined the background dependence of many alleles for genes across the regulatory network of Drosophila wing development in many inbred strains. Our goal was to understand whether effects of the genetic background are an attribute of individual alleles, alleles of the same gene, or genes with similar phenotypes or developmental roles. Our analysis suggests that background dependence is highly positively correlated among alleles of the same gene, especially between alleles with similar magnitudes of phenotypic effect. Similarly, the background dependence of genes within the same regulatory network were also positively correlated. Alleles from different genes, but of the same magnitude of phenotypic effect, generally demonstrated the highest degree of intergenic correlation. However, the background dependence of mutant alleles were generally not well correlated with the wildtype allele. Interestingly, we also found no recovery of any lethal alleles, despite thousands of individuals screened and evident suppression of mutant effects in some strains. We also analyzed the magnitude of intra-line variance in among a subset of our genes. This demonstrated a strong positive relationship between the magnitude of intra-line variation and the severity of phenotypic effects, regardless of the identity of the mutant allele. However, we show no correlation between intra-line variability in the wildtype and the magnitude of perturbation for a given mutant allele. To confirm the quantitative estimates of mean wing size accurately reflected subtle perturbations to wing tissue, we conducted a semi-quantitative analysis and compared it to our quantitative estimates. We demonstrate a high degree of correlation between the quantitative and semi-quantitative approaches, indicating semi-quantitative analysis is a useful way to capture subtle phenotypic effects. In addition, we repeated the quantitative analysis with a subset of the genes and inbred strains from the original data. Importantly, results of the repeated study largely recapitulate our original results. / Thesis / Master of Biological Science (MBioSci)

<p dir="ltr">Genome-wide association studies (GWAS) have uncovered numerous variants linked to a wide range of complex traits. However, understanding the mechanisms underlying these associations remains a challenge. To determine genetically regulated mechanisms, additional layers of gene regulation, such as transcriptome and proteome, need to be assayed. Transcriptome-wide association studies (TWAS) and Proteome-wide association studies (PWAS) offer a gene-centered approach to illuminate these mechanisms by examining how variants influence transcript expression and protein expression, thereby inferring their impact on complex traits. In the introductory chapter of this dissertation, I discuss the methodology of TWAS and PWAS, exploring the assumptions they make in estimating SNP-gene effect sizes, their applications, and their limitations. In Chapter 2, I undertake an integrative analysis of TWAS and PWAS using the largest cohort of individuals affected with Tourette’s Syndrome within the Psychiatric Genomics Consortium (PGC) – Tourette’s Syndrome working group. I identified genomic regions containing multiple TWAS and PWAS signals and integrated these results using the computational colocalization method to gain insights into genetically regulated genes implicated in the disorder. In Chapter 3, I conduct an extensive TWAS of the Myasthenia Gravis phenotype, uncovering novel genes associated with the disorder. Utilizing two distinct methodologies, I performed individual tissue-based and cross-tissue-based imputation to assess the genetic influence on transcript expression. A secondary TWAS analysis was conducted after removing SNPs from the major histocompatibility complex (MHC) region to identify significant genes outside this region. Finally, in Chapter 4, I present the conclusions drawn from both studies, offering a comprehensive understanding of the genetic architecture underlying these traits. I also discuss future directions aimed at advancing the mechanistic understanding of complex non-Mendelian disorders.</p>

Os Xenarthra representam um clado de mamíferos eutérios. Pouco se sabe sobre a evolução morfológica craniana do grupo. Esta tese iniciou os estudos relativos a esta questão com base na genética quantitativa, na morfometria e na sistemática, e teve por objetivos específicos: 1) avaliar empiricamente se as matrizes de variância e covariância fenotípica (matriz-P) dos diversos gêneros de Xenarthra estudados podem ser utilizadas como substitutas das respectivas matrizes de variância e covariância genética aditiva (matriz-G), uma vez que não existem matrizes-G estimadas para os Xenarthra, e também se elas podem ser utilizadas em estudos macroevolutivos; 2) testar se a diversificação morfológica craniana no grupo ocorreu somente através de deriva genética; e 3) compreender como a relação entre os caracteres morfológicos (módulos) e a magnitude geral de integração podem influir na evolução morfológica craniana. Além destes objetivos focados na evolução do grupo, também foi escopo desta tese inferir o hábito alimentar de taxa fósseis do final do Pleistoceno/início do Holoceno para melhorar o conhecimento sobre a ecologia de alguns grupos fósseis. O banco de dados utilizado foi composto por medidas lineares de aproximadamente 1150 espécimes adultos, representando 12 dos 14 gêneros atuais e sete dos diversos gêneros extintos de Xenarthra. Com base nesses dados, matrizes-P de variância e covariância e de correlação foram estimadas para cada gênero. Essas matrizes foram posteriormente comparadas par a par para avaliar a semelhança na estrutura das diferentes matrizes. Também a partir dessas matrizes, foram obtidas as variâncias entre e intra populações para testar se a diversificação morfológica ocorreu de acordo com a expectativa teórica de diversificação sob a ação exclusiva de deriva genética. As mesmas matrizes-P foram comparadas a diferentes matrizes teóricas de hipóteses de modularidade craniana. As matrizes teóricas expressaram a relação entre os caracteres com base no desenvolvimento e/ou desempenho de função compartilhado pelas partes do crânio. Para cada matriz-P de correlação calculou-se a magnitude geral de integração. Além disto, a dieta dos grupos extintos foi inferida através de análises de funções discriminantes a partir da relação entre forma e função dos animais atuais. Os resultados obtidos indicam que as matrizes-P dos diversos gêneros são similares entre si, o que sugere que matrizes-P podem ser utilizadas tanto como substitutas das matrizes-G quanto no contexto macroevolutivo. Os resultados obtidos refutaram a hipótese nula da diversificação morfológica craniana ocorrendo somente por deriva genética, ao menos nos níveis mais inclusivos da filogenia dos Xenarthra. Consequentemente, a seleção natural provavelmente atuou neste processo de diversificação. Os resultados também sugeriram que o crânio desse grupo está organizado em módulos, sendo os módulos mais conspícuos os relacionados à face. Além disso, foi detectada grande variação na magnitude geral de integração entre gêneros. A variação no padrão modular, mas principalmente na magnitude geral de integração, faz com que os gêneros apresentem diferenças nas possíveis capacidades de responder de forma alinhada às pressões seletivas. Por último, as análises morfofuncionais indicaram elevada diversidade de hábitos alimentares entre os Xenarthra extintos / Xenarthra are an eutherian mammal clade and little is known about their cranial morphological evolution. This thesis has initiated studies related to this topic and, based on quantitative genetics, morphometrics and systematics, aimed to: 1) empirically assess if the phenotypic variance and covariance matrices (P-matrix) of several genera can be used as surrogates for their respective additive genetic variance and covariance matrices (G-matrix), since G-matrices for Xenarthra are not available, and also if P-matrices can be used in macroevolutionary studies; 2) test whether the skull morphological diversification within the group occurred only through genetic drift; and 3) understand how the relationship between the traits (modules) and overall magnitude of integration may influence cranial morphological evolution. Besides these objectives focused on the evolution of the group, it was also within the scope of this thesis to infer the feeding habits of late Pleistocene/early Holocene fossil taxa to better understand the ecology of some fossil groups. The database used consist of linear measurements of approximately 1150 adult specimens, representing 12 of the 14 extant genera and seven of the several extinct genera of Xenarthra. The data gathered were used to estimate variance/covariance and correlation P-matrices for every genus. These matrices were compared between pairs of genera to evaluate the matrices\' structural similarities. Based on these matrices, within and between population variances were obtained and it was tested whether morphological diversification was in accordance to the theoretical expectation of diversification under genetic drift alone. The same matrices were compared to theoretical matrices expressing modularity hypotheses. These theoretical matrices represent the relationship among traits in reference to the shared development and/or function of different skull\'s anatomical regions (modules). For every correlation P-matrix the overall magnitude of integration was calculated. Moreover, the extinct groups\' diet was inferred through discriminant function analysis relying on the relationship between form and function of extant animals. Results indicate that P-matrices from several genera were structurally similar. This suggests that P-matrices can be used as surrogates of their G-matrices and in the macroevolutionary context. Results refuted the null hypothesis of cranial morphological diversification occurring only due to genetic drift, at least in more inclusive levels of Xenarthran phylogeny. Consequently, natural selection probably acted on this diversification process. The results also suggested that the Xenarthran skull is organized in modules, and the most conspicuous modules are in the face region. A large variation in the overall magnitude of integration among genera was detected. The variation in the modular pattern, but especially in the overall magnitude of integration, allows genera to differ in their potential capacity to respond aligned with selective pressures. Finally, morphofunctional analyses indicate a high diversity of feeding habits among extinct Xenarthra

Os padrões de covariância genética entre caracteres, expressos pela matriz de covariância aditiva G, desempenham um papel importante na evolução de morfologias complexas, visto que esta matriz influencia a direção e magnitude da resposta à seleção em uma população. Assumindo-se a estabilidade da matriz G ao longo do tempo, pode-se testar explicitamente hipóteses acerca da influência de processos evolutivos sobre a diversificação. Espera-se que esta matriz influencie os padrões expressos por sua equivalente fenotípica P, devido a contingências funcionais e ontogenéticas na relação entre genótipo e fenótipo, que levam à estruturação de modularidade nesta relação, de modo a otimizar a evolvabilidade. No presente trabalho, investiguei a estrutura da covariância genética no crânio e mandíbula de uma população do roedor sigmodontíneo Calomys expulsus, com o objetivo de estimar a similaridade entre covariâncias fenotípicas e genéticas; também avaliei a influência de padrões de modularidade sobre ambos os níveis de organização da variação morfológica. As matrizes P e G que obtive para o crânio e para a mandíbula se mostraram bastante similares no que diz respeito à sua estrutura de covariação e se relacionam parcialmente às hipótese de modularidade estabelecidas. Os resultados que obtive aqui são bastante similares àqueles obtidos para os mamíferos como um todo, portanto suportando a hipótese de estabilidade no padrão de covariâncias genéticas e fenotípicas na evolução do grupo. / Patterns of genetic covariance between characters (represented by the additive covariance matrix G) play an important role in the evolution of morphological complexes, since they influence the direction and norm of the response to selection in a population. Therefore, the assumption that G-matrices are stable through evolutionary timescales allows evolutionary biologists to infer the influence of evolutionary processes that operate over biological diversification. These matrices are also expected to influence the patterns expressed in their phenotypic counterparts (P-matrix), because of the imposition of multiple developmental and functional contingencies over the genotype/phenotype map, that leads to its modular organization in order to increase evolvability. Here, I have investigated patterns of genetic covariance structure in the skull and mandible of a population of the vesper mouse Calomys expulsus in order to estimate the level of similarity between additive and phenotypic covariances; I have also evaluated the influence of expected patterns of modularity over both levels of morphological variation. For either skull and mandible, I have obtained P- and G-matrices that are strongly similar in their structure; these matrices also support the modularity hypotheses for developmental and functional constrains, akin to the overall results obtained for mammals, thus supporting the hypothesis of stability in genetic and phenotypic covariance structure in mammalian evolution.

Mainstream evolutionary biology lacks a mature theory of phenotype. Following from the Modern Synthesis, researchers tend to assume an unrealistically simple mapping of genotype to phenotype, or else trust that the complexities of developmental architecture can be adequately captured by measuring trait variances and covariances. In contrast, the growing field of evolutionary developmental biology (evo-devo) explicitly examines the relationship between developmental architecture and evolutionary change, but lacks a rigorous quantitative and predictive framework. In my dissertation, I strive to integrate quantitative genetics and evo-devo, using both theoretical and empirical studies of plasticity. My first paper explores the effect of realistic development on the evolution of phenotypic plasticity when there is migration between two discrete environments. The model I use reveals that nonadditive developmental interactions can constrain the evolution of phenotypic plasticity in the presence of stabilizing selection. In my second paper, I examine the manner in which the genetically controlled responsiveness of traits to each other is shaped by selection and can in turn shape the phenotypic response to selection. Here, results indicate that developmental entanglement through plasticity can facilitate rapid multivariate adaptation in response to a novel selective pressure. In my final paper, I examine patterns of gene expression underlying ancestral plasticity and adaptive loss of melanin in Daphnia melanica. My results indicate that the developmental mechanism underlying ancestral plasticity has been co-opted to facilitate rapid adaptation to an introduced predator.