2006 — 2008 |
Rebeiz, Mark J |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Multistep Evolution of Drosphilia Pigment Characters @ University of Wisconsin Madison
[unreadable] DESCRIPTION (provided by applicant): The evolution of form is one of the most awe-inspiring aspects of multicellular life. From the vast array of colors in nature to the changes that brought about the human race from primates, we are confronted with its aftereffects on a daily basis. A particularly important question is how the multiple components of a genetic program are modified to create a new trait. The patterned pigmentation of Drosophila wings presents an exceptional opportunity to dissect the evolution of multigene networks in the origin of complex traits. The aim of this proposal is to identify genes involved in the melanin synthesis pathway which contribute to the evolution of new pigment patterns, and understand how they were co-opted. Once identified, the molecular underpinnings of how each gene has attained a new activity will be explored. A panel of potential genes will be analyzed for expression associated with patterned areas. Using transgenesis of Drosophila melanogaster, the basis of each positive candidate's new activity will be defined. Finally, the sufficiency of identified components will be tested by ectopic expression in a species whose wings are unpatterned. [unreadable] [unreadable] [unreadable]
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0.913 |
2012 — 2014 |
Rebeiz, Mark |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Collaborative Research: the Structure, Function, and Evolution of a Regulatory Network Controlling Sexually Dimorphic Fruit Fly Development @ University of Pittsburgh
Gene networks are fundamental to animal development, and though the complexity of these networks has been mapped in model organisms, the critical connection between network evolution and organismal diversity remains unclear. This project provides a unique perspective to these complex biological networks by investigating how new fruit fly pigmentation patterns were achieved through the modification of connections between pivotal members of a pigmentation gene network. Using candidate gene and genome-scale approaches it will be determined how a key regulatory protein is connected to and thereby controls the utilization of a battery of target genes necessary to make a pigmentation pattern. Furthermore, comparing network connections within and between related species that exhibit different pigmentation patterns will reveal how these connections evolved and how network interactions affect natural variation in the production of this key regulatory protein.
An enhanced understanding of this model gene network will aid both the evolutionary and developmental biology communities in the construction and testing of hypotheses as to how other gene networks operate and have changed to control diverse traits in diverse lineages. Moreover, these outcomes bear upon the human condition as genetic differences in the DNA sequences connecting regulatory proteins to their target genes is a major yet poorly understood cause of variation between individuals. This project will achieve numerous broader impacts, including: training opportunities for undergraduate and graduate students, the development of both lab exercises for high school biology curricula and research experiences for high school students, and interactions at University symposia and on visitations to area High Schools with non-scientific students and teachers to communicate the contributions of evolutionary developmental biology to modern scientific thought and the value of scientific research to society.
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1 |
2014 — 2018 |
Rebeiz, Mark J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Tracing the Recent Origins of a Gene Network Regulating a Novel Morphological Str @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): The goal of this research is to uncover the stepwise process by which new morphological structures and the networks that control their development evolve. Each and every morphological structure evolved at some point in the past, and our understanding of the origins of the developmental networks that spatially orchestrate development is still a mystery. It is becoming increasingly appreciated that our understanding of these networks at the molecular level will lie at the heart of connecting genetic variation to differences in phenotype, including the predisposition to disease. By characterizing a recently evolved morphological novelty of Drosophila melanogaster, this project will provide a unique perspective on how networks arise and are altered to generate differences in three dimensional forms.
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0.958 |
2015 — 2018 |
Andolfatto, Peter [⬀] Rebeiz, Mark J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dissecting the Molecular Basis and Assembly of a Complex Morphological Trait
? DESCRIPTION (provided by applicant): The goal of this research is to dissect the causative genes and mutations underlying a complex trait, and trace the stepwise process by which the identified causative alleles arose and spread through an isolated population to generate a fixed morphological phenotype. The species Drosophila santomea exhibits a recently evolved, drastic shift in its pigment patterns that represents an optimal model system in which to dissect complex polygenic traits. Our previous work identified the gene underlying one of four major QTL contributing to this trait. Analysis of multiple individuals in the population revealed that causative alleles of this gene arose several times in parallel in the D. santomea population (i.e. a soft sweep). Here, we propose to employ molecular genetic techniques (introgression mapping and transgenic complementation) to identify causative genes and mutations responsible for two additional QTL. Using a combination of molecular and genomic techniques (in situ hybridization, RNA-seq), we will then assess how these loci interact with each other, as well as how they impact the genome-wide profile of expression. Finally, we will survey population variation at these additional causative loci to assess whether a similar soft sweep occurred, and determine whether these genes exhibit signs of positive selection. This study will provide a rare vista of a complex morphological trait that integrates molecular studies of gene function with processes occurring at the population level.
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0.908 |
2016 — 2020 |
Williams, Thomas Rebeiz, Mark |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Collaborative Research: Resolving the Gene Regulatory Network Alterations Responsible For the Repeated Evolution of a Hox-Regulated Trait
A unifying feature of an organism's appearance (or "phenotype") is its construction during the events of development. Each phenotypic trait requires the cooperation of a collection of genes whose participation is controlled by DNA sequences known as cis-regulatory elements (CREs). CREs work like switches to turn genes ON or OFF in certain cell types at specific life stages. The switch-like function of CREs are encoded in the DNA sequence by short stretches of ordered bases to which proteins known as transcription factors specifically bind. Combinations of transcription factors form a "logic" of instructions that determines precisely which cells, and at what time the CRE can switch a gene ON. Currently, it remains poorly understood how switch-like functions are encoded in CREs and how traits evolve through changes in their encoded logic. In particular, the Hox transcription factors represent a poorly understood class that provides CREs with positional information along the major body axis. The Williams and Rebeiz labs are collaborating to study the network of genes and CREs responsible for making a male-specific body pigmentation of the fruit fly species Drosophila melanogaster. The results will inform how such pigmentation originated and was altered in multiple lineages of fruit fly species. The outcomes will show how the construction of a new characteristic is controlled by Hox genes, CREs and how evolution can operate at the level of binding sites for transcription factors. This work will provide a picture of trait evolution that will be applicable to a wide variety of animal systems. Through this research, computational tools will be refined and online learning resources will be created to aid scientists. This research project will support the future of science personnel through the participation of high school students, undergraduate students, and graduate students in mentored research. Participation will emphasize students from under-represented groups in science.
The developmental events that pattern the animal body plan are regarded as a crucible for the evolution of novel traits. This project's overarching goal is to understand how body plan patterning information originated in a gene regulatory network (GRN), and was subsequently modified to diversify a morphological trait. GRNs are structured to pattern development through the binding of transcription factors to cis-regulatory elements (CREs) to control gene expression. The combination of factors that bind CREs form a regulatory logic that specifies timing, pattern and levels of expression. Currently, very little is known about how GRN structure evolves to generate different phenotypes. Specifically, which genes in the hierarchy were modified, and ultimately how regulatory logic evolves. The Williams and Rebeiz labs are examining the evolution of a GRN and its underlying regulatory logic for a rapidly evolving trait present in an experimentally tractable animal system. The proposed studies will focus on male-specific patterns of abdominal pigmentation that convergently evolved in two fruit fly lineages, which were then modified and lost. The first aim will characterize how the arbiters of the body plan (e.g. Hox proteins, cofactors, and activity modulators) directly interact with CREs of the GRN to control expression patterns of pigmentation enzymes in D. melanogaster. The second aim will determine how this Hox-regulated GRN was altered in cases where pigmentation was expanded, contracted, or lost in non-model fruit fly species. The third aim will trace how this GRN independently evolved a convergent pigmentation phenotype in a non-model fly. To pursue these aims, the research team will employ techniques that include reporter transgenes in multiple fruit fly species and gel shift assays between transcription factors and CRE sequences to pinpoint phenotype altering mutations and connect these to the alterations in transcription factor binding and function that they inspired.
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0.969 |
2019 — 2021 |
Pool, John E [⬀] Rebeiz, Mark J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Unraveling the Molecular and Population Genetic Complexity of Adaptive Trait Evolution @ University of Wisconsin-Madison
Project Summary This research aims for a deeper and more nuanced understanding of the genetics of adaptation than has been possible to date. While many trait-associated variants have now been detected by genome-wide association studies, very few of these SNPs have been directly connected to adaptive phenotypes, and the genetic interactions that govern whether their effects are visible to selection. Such knowledge is crucial to composing realistic and testable models for how widespread standing genetic variation within populations is funneled through the sieve of natural selection. The evolution of melanism in high altitude Drosophila melanogaster populations offers several critical advantages for this endeavor. First, the species offers key functional genetic and population genomic resources, along with a well-annotated genome. Second, prior molecular and evolutionary studies have provided strong background knowledge on the trait, including a compelling set of candidate genes. Third, the study of recent adaptive evolution between populations of the same species maximizes the utility of genetic mapping, population genetics, and functional comparisons of alleles. These features will allow the dissection of this model adaptive trait in unparalleled detail, yielding insights regarding: 1. the functional nature of causative variants, 2. genetic variability of the adaptive response, 3. the prevalence and molecular logic of epistasis among adaptive variants, 4. roles of cryptic variation in adaptive change, 5. the importance of standing genetic variation in trait evolution. Results of this research will advance basic understanding of the adaptive evolutionary process. It will also inform on the importance of genetic background in assessing the phenotypic impact of genetic variants, a key step in understanding the genetic architecture of complex traits including human disease. Investigation of these critical topics will be bolstered by a profoundly integrative research plan that leverages the investigators' complementary backgrounds to fuse novel molecular experiments, genomic analysis, and statistical inference. This research will identify genetic variants underlying melanic adaptation in Ethiopian D. melanogaster, fusing genomic mapping and variation analysis with transgenic tests to pinpoint causative changes (Aim 1). It will also advance beyond that goal to reveal the complex interactions that modulate the phenotypic impact of causative variants (Aim 2), examining tissue- and population-specific gene regulation, and non-additive interactions among melanic variants. These investigations will provide a critical case study that will clarify the complexity of adaptive trait evolution at molecular and genetic levels.
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0.913 |
2021 |
Rebeiz, Mark J |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
The Gene Regulatory Basis of the Genotype-Phenotype Map @ University of Pittsburgh At Pittsburgh
PROJECT SUMMARY This research program seeks to reveal how morphological traits are genetically encoded during development and modified during evolution. Gene regulatory networks are key to generating the physical features of an organism, as they govern the spatial and temporal expression of each gene during its development. It is now well accepted that phenotypic differences between species and within populations, including the human population, are often caused by changes to regulatory networks which alter expression levels or timing. Despite much progress in this field, our understanding of network function and evolution is lacking in several major areas: (1) how do new traits emerge from changes to networks? (2) how do networks influence the behavior of cells in developing tissues? (3) how do mutations that affect gene regulation permeate networks and populations to cause traits? This research will leverage the highly tractable Drosophila melanogaster model to answer these questions. The first theme of this program will address a gene regulatory network controlling a rapidly evolving three- dimensional anatomical structure in Drosophila. The network which patterns this structure will be dissected to determine how individual components became integrated into the network. In parallel, the proposed studies will trace the connections between these networks and the cellular processes that drive morphogenesis. Finally, genetic changes which alter the three-dimensional shape of these structures will be identified. Performing these studies will provide an unprecedented view of how gene regulatory networks are assembled and modified to generate physical differences in tissue structure and produce elaborate morphologies. The second theme comprises studies on Drosophila pigmentation traits that differ among populations and between species. Most traits involve multiple loci, and much of this polygenic variation will be derived from standing variants that persist in populations without phenotypic consequences. The accumulation of multiple genetic changes will be traced and connected to a putatively adaptive pigmentation trait in Drosophila melanogaster. The pigmentation trait under study is controlled by Hox transcription factors, which are highly conserved body-patterning genes shared between flies and humans. This project will examine Hox gene function and evolution in populations and between species to determine how the gene regulatory network for this trait arose and diversified. This work will provide a deep molecular understanding of how phenotypes are generated, informing the nature of these processes in less tractable systems, including humans.
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0.958 |
2022 — 2026 |
Williams, Thomas Rebeiz, Mark |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Tracing the Origin and Diversification of a Morphological Trait Through Transcriptional Regulators and Their Target Genes
Two goals of scientific inquiry are to understand how traits develop and evolve. These goals have proven difficult to reach for animal species with vast genomes and ones that undergo complex developmental processes. This project will use the pattern of male melanic abdomen pigmentation that develops for the fruit fly species D. melanogaster as a model for a trait’s development, and related species with differing pigmentation as models to understand how male pigmentation originated and diversified. In order to determine which gene’s use or genes’ uses have changed in route to this pigmentation diversity, the network of genes responsible for melanogaster pigmentation will be studied in species with the ancestral (D. willistoni) and modified (D. auraria) pattern of male pigmentation. For genes with differing uses, approaches will be utilized to find and characterize the parts of genes responsible for their variation. The importance of these modified gene parts will be tested by engineering melanogaster sequences into the genomes of these two less well-studied species. Collectively, this project will push the limits of genetic investigation in model and emerging-model species, resulting in one of the most insightful genetic characterizations of an evolving animal trait. This project will result in numerous broader impacts, such as the refinement of bioinformatic and online resources for genetics research, training of diverse personnel in genetics and related disciplines, and hastening scientific progress by the creation, organization, and hosting of a virtual meeting for scientists with a shared interest on the genetics of development and evolution. <br/><br/>Animal morphology develops through the operation of Gene Regulatory Networks (GRNs) that involve a plethora of trans-regulators, transcription factors and signaling pathways, which control the spatial, temporal, and even sex-specific patterns of trait-building realizator gene expression. These patterns of gene expression emerge from GRN transcription factors interacting with binding sites in the cis-regulatory elements (CREs) of their direct target genes. Since many trans-regulators and realizator genes are older than the traits they regulate, trait evolution occurs through changes in the uses of these ancestral genes. This project’s overarching goal is to understand how a trait emerged and was modified by changes to a GRN’s trans-regulators and realizator genes. The evolution of a GRN for a rapidly evolving trait present in an experimentally tractable animal model species, and closely-related emerging model species will be examined. The proposed studies will focus on how the male-specific pattern of abdominal pigmentation emerged in the fruit fly lineage of D. melanogaster and how it was modified in the montium lineage. In the first Aim, the breadth of trans-regulators in the D. melanogaster GRN will be mapped, and determine which of these genes have conserved or evolved expressions in species with the ancestral and modified trait phenotypes. The second aim will determine how trans-regulator and realizator gene expressions evolved through CRE evolution. The third aim will directly test the phenotypic consequences of GRN modifications through genetic engineering performed in emerging model species.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
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0.969 |