David Houle - US grants

Abstract

Evolution in response to human activities is of great economic importance, for example in agriculture. It would be extremely useful to be able to predict when and how such changes will evolve. We know that mutation and genetic variation is necessary for evolution. This project will search for simple general features of mutation and genetic variation to use as the basis for predictions about evolution, and test these predictions against the differences observed among species. The wings of fruit flies (Drosophila) will be used as a model system. Surprisingly, integration of mutation, variation and evolution in one study has never been attempted with a multicellular organism.

If the predictions of this project are borne out, the methods developed would be applicable to evolution in domesticated plants and animals. If one can predict combinations of features that are unlikely to evolve, costly breeding programs that are doomed to fail could be avoided. Alternatively, features that are unlikely to evolve with natural variation would be attractive targets for genetic manipulations. If the predictions are not borne out, this will point to the need for a more detailed understanding of the functional basis of biological traits before predictions are useful.

This project uses Drosophila melanogaster (fruit flies) to investigate how genes interact with one another. Flies will be selectively bred to change specific aspects of the shape of their wings then studied to reveal how the genes responsible for wing shape interact. First, selection to change some wing aspects while constraining others will be conducted. Comparing the constrained and non-constrained populations will allow estimation of genetic pleiotropy (when single genes influence several traits). Second, experiments will transplant genes between fly populations with different wing shapes. Comparing the effects of these transplants will allow us to estimate the genetic epistasis (how the effects of a particular gene depend on other genes present). Finally, the project tests and investigates a new mathematical model of epistasis and it's implications for evolutionary biology.

While pleiotropy and epistasis are known to be common, their properties are poorly understood. These experiments will be among the first to carefully investigate the nature and magnitude of these genetic factors. Understanding these factors has the potential to greatly impact all fields studying genetic interactions, including medicine and livestock breeding. The data will be gathered largely by undergraduate students from the ethnically and economically diverse population of Florida State University.

Genetic change is a dominant theme in the evolutiona and diversification of organisms, yet surprisingly little is known about which traits and organisms are most likely to undergo major shifts in gene frequency in response to natural selection and environmental change. Empirical study of change in heritable traits depends on having an operational measure of potential change that reflects the ability of a trait to respond to a given external selection pressure under the constraint of stabilizing or opposing selection on correlated characters. The investigators suggest that the additive genetic variance conditioned on correlated traits and scaled by the square of the trait mean, "conditional IA," is a better measure of short-term change than the traditional measure, "heritability." They will use these new measures to test hypotheses about the role of genetic constraints in determining large-scale patterns of variation in the blossoms of Dalechampia, a neotropical vine. They will use a combination of artificial-selection and field experiments to document potential for evolution and patterns of natural selection.

This project will advance our understanding of how organisms evolve in response to natural selection, with possible applications to understanding response of plants to climate change, crop breeding, and the origins of pesticide and drug resistance. The project will train two postdoctoral researchers, one master's student, and several undergraduate students. It will also promote international collaboration between the USA, Norway, the United Kingdom, and several Latin American countries.

This project will use the Drosophila melanogaster model system to address two fundamental questions in the study of sexual selection. First, what is the effect of sexual selection on a population's ability to adapt? Second, what male traits are under sexual selection and how are these traits formed? The presence or absence of female choice and male-male competition will be manipulated experimentally in a laboratory evolution experiment. Fitness and traits will be measured in the experimentally evolved populations and in the ancestral laboratory population to assess which trait values confer higher fitness and how sexual selection can change these trait optima.

The results of this research will help to clarify whether sexual selection has a positive or negative effect on adaptation in natural populations. Undergraduates will participate in the project and will conduct related independent research projects and will learn techniques of experimental design and data analysis. This project begins a collaboration between biologists and chemists.

DESCRIPTION (provided by applicant): This project will implement a novel approach to understanding the relationship between genetic variation and its effects on the phenotype that is to the genotype-phenotype (GP) map. Genotypes exist and are inherited in a discrete space convenient for many sorts of analyses, but the causation of the important phenomena such as disease status and natural selection takes place in a continuous phenotype space whose relationship to the genotype space is only dimly grasped. Direct study of genomes alone, with minimal reference to phenotypes is insufficient to understand why some individuals are sick and some are healthy. This project takes an integrative approach to the study of the GP map, combining both genetic and phenotypic studies that potentially reinforce each other. Wing shape in Drosophila melanogaster is an excellent model system for this because the phenotype can readily be characterized in many dimensions, there is substantial natural genetic variation, and because of the genetic control possible in Drosophila. Aim 1 of the project is to characterize the effects of variation in gene expression at a large number and variety of genes by controlled manipulations of gene expression. Aim 2 will develop a model of wing development that incorporates these results and produces a complete wing phenotype, something that has only rarely been attempted. Aim 3 is to identify naturally occurring genetic variation in wing phenotype using association mapping of multivariate effects on wings. By simultaneously considering all phenotypes in the analysis, the problems of mapping multiple traits one at a time will be avoided. In Aim 4 emerging generalizations about the causes of variation in wing form from Aims 1-3 will be tested by predicting how a population should respond to artificial selection, then testing these predictions in a series of experiments. If a coherent picture of how genetic variation produces phenotypic variation emerges from these experiments, the combination of genetic manipulations, detailed modeling, and characterization of natural variation and its effects can readily be applied to mammalian systems and ultimately to humans. If no such picture emerges, the precise ways in which predictions fail will focus attention on those aspects of the GP map that we do not yet understand. PUBLIC HEALTH RELEVANCE: This work will test whether detailed phenotypic data can be combined with existing genomic data to provide improved predictions of important events, such as disease status or outcome. Current research emphasizes using genotypic data alone for prediction. Recent results show that the nature of genetic causation is very complex, and highly influenced by the environment, strongly limiting the efficacy of a genes-alone approach to health. These problems may be lessened if genomic data is combined with a comprehensive characterization of the phenotype and detailed knowledge of how genetic variation affects those phenotypes.

The success of genome-sequencing projects highlights how little we know about how the whole organism is put together. Deciphering the relationship between the genome and the organism requires study of the effects of subtle genetic changes on the whole organism. This project will develop and apply one such approach by manipulating the expression of hundreds of genes and observing the effects on body shape, then using modeling to test understanding of how these effects occur. The project will focus on the genetic basis of shape of the wing of fruit flies, one of the few multi-cellular organisms where the necessary genetic manipulations are easy to accomplish and detailed data can be obtained in large quantities.
This project has broad significance for biology, because health and disease in humans, improvement of domesticated plants and animals, and the ability of organisms to adapt, all derive from the relationship between the genome and the organism. This project will provide more detailed data on the genetic basis of variation in the whole organism than has previously been available. The research will provide a procedural model and analytical software which can be used by others to extend such studies to other organisms and that ultimately is applicable to humans and the species we interact with. Many undergraduates and a post-doctoral research will receive training through participation in this project.

Scientists can rapidly obtain the DNA sequence of an individual, and find sites in the DNA that affect one trait. It is believed that many sites will affect more than one trait, a phenomenon called pleiotropy. The proportion of sites that are pleiotropic is not known, in part because how to find such sites is unclear. This project investigates the patterns of pleiotropy in a model organism to see whether those effects are typically restricted to one simple part of the body, or are likely to have effects on many different parts. If the team finds that a DNA change generally affects many traits, then this will suggest that those studying human genomes will have to look at diverse traits to understand how DNA changes affect specific aspects of heath. This project makes a fundamental contribution to our understanding of how genotypes map onto phenotypes. Additionally, the PIs will provide research opportunities for undergraduates in computational biology and will develop statistical software for the research community.

To characterize pleiotropy, the scientific team will use the fruit fly because of its rapid generation time and low cost. They will develop methods to automate the measurement of multiple body parts, and then characterize these parts in a set of 200 fully sequenced fly stocks. They will develop statistical techniques to quantitatively characterize pleiotropy using these data. The data and statistical techniques will then be used to find the DNA sites that affect the shape of the body, and to determine whether those effects typically are restricted to one part of the body, or affect many parts. The statistical techniques to characterize pleiotropy developed in this project will apply directly to other species, including humans. This project also includes active collaboration with Norwegian scientists, including international training for US graduate students and postdoctoral researchers, which was partially funded by the NSF Office of International Science and Engineering.

Individuals are enormously genetically diverse, even when those individuals live close together in the same environments. This high diversity has important implications for sustainable agriculture and for the conservation of biodiversity because genetic diversity allows crops and wild plants and animals to persist in the face of disease and other environmental challenges. Understanding genetic diversity is also important in medicine because individuals have different susceptibility to disease and they can respond differently to the same treatment; this is the foundation of the recent emphasis on "personalized medicine". However, high genetic diversity is surprising because we expect that local populations that share a common gene pool and experience similar environments should be relatively genetically homogenous. This project addresses the debate about why individuals within populations (including humans) are so genetically diverse. Specifically, the research team will test a prominent hypothesis: that high diversity is maintained because rare gene variants confer an advantage to individuals who bear them (i.e., they are favored by natural selection). The project will also identify the genes that are the direct targets of this kind of selection. Because experiments required to answer these questions would be impossible in humans or agricultural species, the project will use a vertebrate animal that has well-known natural history, ecology, and behavior, and for which the genome sequence has recently become available (the Trinidad guppy). These small fish have high genetic diversity for body color, and this research will examine competing ideas about why: (1) fish with rare patterns survive better, or (2) fish with rare patterns reproduce more successfully. This project will also produce educational material and activities for school children. This material will enhance students' understanding of genetics, ecology, and evolutionary biology by using an animal with which many students are already familiar since guppies are popular in home aquariums.

Accounting for the persistence of high genetic diversity in ecologically-important traits is a fundamental problem in population genetics, and one that has fundamental implications for agriculture, medicine, and conservation biology. Debate about what processes maintain variation has led to the development of important population-genetic principles and hypotheses, but the larger question remains unanswered. This project will test the hypothesis that selection that varies in space or time ("balancing selection") maintains genetic diversity in natural populations and will link these selective processes directly to the genetic variants they target. Researchers will combine genomic and ecological approaches in a species exhibiting one of the best-known cases of adaptive polymorphism, the colour patterns in the Trinidadian guppy (Poecilia reticulata). Field and laboratory studies of predator density, reproductive behavior, and color-pattern variation will determine which ecological processes promote genetic variation. Whole-genome sequencing of guppies from 13 natural populations will identify regions of the genome enriched for intermediate-frequency alleles; using data from many populations will allow us to differentiate between loci under balancing selection and those that are polymorphic because of non-selective processes such as random genetic drift and migration. This multipronged approach will enable linking evolutionary processes that maintain variation directly to the genetic variants (polymorphisms) they target.