Genetic Interactions and Gene-by-Environment Interactions in Evolution

The phenotypic effect of a mutation depends on both genetic interactions (G×G) and gene-by-environment interactions (G×E). G×G and G×E can distort the additive relationship between genotypes and phenotypes and complicate biological and biomedical studies. Understanding the patterns and mechanisms of these interactions is important for predicting evolutionary trajectories, designing plant and animal breeding strategies, detecting “missing heritability”, and guiding “personalized medicine”. In this thesis, I study how G×G and G×E affect mutational effects, including developing new methods and new models. Recent advancements in high-throughput DNA sequencing and high-throughput phenotyping provide powerful tools to study the relationships among genotypes, phenotypes, and the environment at unprecedented scales. Therefore, I take advantage of several published large datasets in my study, each containing hundreds to thousands of different genotypes of model organisms and their corresponding phenotypes in tens of environments. In Chapter 2, I report some general patterns of G×E and demonstrate the importance of considering potential environmental variations in mapping quantitative trait loci. In Chapter 3, I report how the environment affects diminishing returns epistasis and propose a modular life model to explain the patterns of diminishing returns. In Chapter 4, I propose and demonstrate that genetic dominance is a special case of diminishing returns epistasis. In Chapter 5, I report how and why the relationship between growth rate (r) and carrying capacity (K) in density-dependent population growth varies across environments. In Chapter 6, I demonstrate the existence of an intermediate optimal mating distance for hybrid performance in three model organisms. Overall, I find that large genomic and phenomic data are useful resources to address classical genetic questions, such as the origin of dominance (Chapter 4), the relationship between r and K (Chapter 5), and presence of an optimal mating distance (Chapter 6). The environment is a key player in the phenotypic effects of mutations, but it is also a high-dimension complex system that is hard to quantify. In this thesis, I define environment quality (Q) as the average fitness of many different genotypes measured in the environment. I demonstrate that Q is useful in studying how the environment affects additive (Chapter 3), interactive (Chapters 3 and 4), and pleiotropic mutational effects (Chapter 5). Many classical theories and models were developed based on observations made in a single environment, and they are often insufficient to explain across-environment observations. Studying across-environment effects provides valuable information for testing old models and for designing new models when old models fail. I conclude that studying G×G and G×E shed light on underlying biological mechanisms.PHDEcology and Evolutionary BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144160/1/xinzhuw_1.pd

Sex Differences in Antidepressant Effect of Sertraline in Transgenic Mouse Models

The main purpose of this study is to explore sex differences in the antidepressant effect of sertraline in genetic knockout or overexpression estrogen-synthesizing enzyme aromatase (Ar) gene mouse models in the forced swim test (FST). Our results demonstrated a significant reduction of depression-like behavior in the mice with overexpression of brain aromatase (Thy1-Ar) compared to sex- and age-matched Ar+/− mice or wild type control mice. Using HPLC analysis, we also found an association between the brain estrogen-related antidepressive behavior and the regulation of serotonin (5-HT) system. Interestingly, a single dose administration of sertraline (10 mg/kg, i.p.) induced reduction of immobility time was found in all genotypes, except male Ar+/− mice. While the underlying mechanisms of sex-specific response on antidepressive effect of sertraline remain to be investigated, our data showed that female mice appear to be more sensitive to sertraline-induced changes of 5-HT system than male mice in the prefrontal cortex (PFC) and the hippocampus (HPC). Further investigation of sex-specific effect of brain estrogen on antidepressant is needed

Isolation, Structure Determination, and Anti-HIV Evaluation of Tigliane-Type Diterpenes and Biflavonoid from Stellera chamaejasme

Five novel tigliane-type diterpenes, stelleracins A–E (3–7), a novel flavanone dimer, chamaeflavone A (8), and six known compounds were isolated from roots of Stellera chamaejasme. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds 3–5 showed potent anti-HIV activity (EC90 0.00056–0.0068 μM) and relatively low or no cytotoxicity (IC50 4.4–17.2 μM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.</p

CCR5-∆32 is deleterious in the homozygous state in humans.

We use the genotyping and death register information of 409,693 individuals of British ancestry to investigate fitness effects of the CCR5-∆32 mutation. We estimate a 21% increase in the all-cause mortality rate in individuals who are homozygous for the ∆32 allele. A deleterious effect of the ∆32/∆32 mutation is also independently supported by a significant deviation from the Hardy-Weinberg equilibrium (HWE) due to a deficiency of ∆32/∆32 individuals at the time of recruitment

Environment-dependent pleiotropic effects of mutations on the maximum growth rate r and carrying capacity K of population growth.

Maximum growth rate per individual (r) and carrying capacity (K) are key life-history traits that together characterize the density-dependent population growth and therefore are crucial parameters of many ecological and evolutionary theories such as r/K selection. Although r and K are generally thought to correlate inversely, both r/K tradeoffs and trade-ups have been observed. Nonetheless, neither the conditions under which each of these relationships occur nor the causes of these relationships are fully understood. Here, we address these questions using yeast as a model system. We estimated r and K using the growth curves of over 7,000 yeast recombinants in nine environments and found that the r-K correlation among genotypes changes from 0.53 to -0.52 with the rise of environment quality, measured by the mean r of all genotypes in the environment. We respectively mapped quantitative trait loci (QTLs) for r and K in each environment. Many QTLs simultaneously influence r and K, but the directions of their effects are environment dependent such that QTLs tend to show concordant effects on the two traits in poor environments but antagonistic effects in rich environments. We propose that these contrasting trends are generated by the relative impacts of two factors-the tradeoff between the speed and efficiency of ATP production and the energetic cost of cell maintenance relative to reproduction-and demonstrate an agreement between model predictions and empirical observations. These results reveal and explain the complex environment dependency of the r-K relationship, which bears on many ecological and evolutionary phenomena and has biomedical implications