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Genetics and the Evolution of Animal Form

Research Summary

Sean Carroll is interested in understanding how animals develop and evolve.

Many animals are built from reiterated parts, such as the segments and appendages of arthropods and the somites and vertebrae of vertebrates. During evolution there has been a trend toward the divergence of the number, morphology, and function of these parts, both within and between animal taxa. Deciphering the genetic regulatory mechanisms that control the formation, number, and ultimate morphology of body parts is therefore crucial to understanding the dual mysteries of the development and evolution of animal design.

The fruit fly Drosophila melanogaster has emerged as a key model system for elucidating the genetics and molecular biology of animal development. Advances in our knowledge of how this complex animal develops have made possible comparative studies to identify common features of animal design and to determine how morphological diversity evolves. Our laboratory and many others have worked toward a detailed mechanistic understanding of some of the major features of Drosophila development. This has provided the foundation for our study of the genetic and developmental basis of animal diversity, as well as new insights into animal origins and relationships. This approach has resulted in a deeper understanding of how developmental genes and patterning mechanisms evolve. Most importantly, this body of work has uncovered some of the first direct evidence for the central role of changes in gene cis-regulatory sequences in the evolution of body plans and body parts and in the origin of new structures and pattern elements.

The Evolution of Animal Form
How do body plans and body parts evolve? Differences in morphology are, of course, the developmental products of genetic differences between animals, but for a very long time it was not understood how many or what kinds of differences underlie changes in body patterns. Early investigations into the nature of genetic evolution proposed two potential mechanisms for the origin of new features: gene duplication and divergence, and regulatory changes in gene expression.

With an expanding understanding of the genes that control body pattern in model animals, it is now possible to investigate the genetic basis of morphological diversity in related animals. The major architectural differences between insects and other arthropods involve variations in the number, type, and pattern of segments and body appendages. Comparisons of how genes are used in different animals, such as diverse insects, centipedes, and crustacea, have revealed the primacy of regulatory changes in the generation of morphological diversity. Regulatory changes in developmental programs are by far the more common mechanism in the evolution of body plans and body parts than is the evolution of new genes. However, we have also found, quite unexpectedly, that functional changes have occurred in certain Hox proteins in the course of arthropod evolution.

The Central Role of Cis-Regulatory Sequences in the Evolution of Development and Form
A major challenge has been to elucidate at a molecular level how genetic regulatory circuits evolve and to understand the roles of selection and genetic variation in their evolution. Molecular studies of Hox-regulated target genes suggest that these changes occur through accumulation of mutations in regulatory DNA sequences. Because it is very difficult to dissect these mechanisms over great taxonomic distances, we have bridged this gulf between large-scale evolutionary change and the evolutionary mechanisms operating within species by developing several experimental models of the evolution of characters among closely related Drosophila species, primarily models involving pigmentation of the body and wings as general models for the evolution of form. This body of work, which has examined numerous cases of divergence over a range of taxonomic distances, has demonstrated the key role of mutations in the modular, cis-regulatory elements (enhancers) of developmentally-regulated genes in the evolution of gene regulation and form.

Melanic pigmentation patterns differ widely across Drosophila species, from no pigment to complex patterns of stripes and spots, to ubiquitous black coloration. We have identified several of the key genes and molecular genetic mechanisms that have contributed to such diversity. One of the most remarkable trends in the evolution of pigmentation patterns is the repeated, independent occurrence of similar patterns on fly bodies and wings. We have uncovered instances where similar patterns have evolved independently (parallel evolution) via changes at the same gene as well as via different loci. The examples offer some unique insights into mechanisms that shape what patterns are most readily produced.

One of the major forces appears to be the existence of evolutionarily stable "prepatterns" of transcription factor distribution. Regulatory proteins that serve in one or more regulatory circuits can be exploited in the generation of new and complex patterns. And the similarity of "cryptic" prepatterns among related species makes the evolution of similar overt patterns more probable.

Another important dimension of animal diversity reflected in pigmentation is sexual dimorphism. We have elucidated part of the genetic regulatory circuit that controls sexually dimorphic abdominal pigmentation and traced the evolution of this circuit through the evolution of the Drosophila subfamily. Our studies suggest that the expression of Hox proteins constitutes another cryptic set of prepatterns. Moreover, these studies illustrate how more complex Hox-regulated traits diverge at higher taxonomic levels.

The pervasive role of cis-regulatory sequence evolution in the evolution of morphological traits has raised a host of new questions about the process of regulatory evolution. For example, how many mutations are involved in the functional divergence of cis-regulatory elements? How quickly can such mutations arise and sweep through a population? And, how few mutations can give rise to new features of gene expression? Detailed examinations of accessible models are revealing that many mutations often contribute to functional divergence, but that such variation is widely available in populations.

Gene Evolution and the Origins of Novelty
The evolution of regulatory sequences appears to be the major mechanism underlying the evolution of animal form. However, several genetic mechanisms—including the evolution of protein-coding sequences and gene duplication, as well as the evolution of regulatory sequences—are sources of variation in all species and contribute to organismal adaptation. We are keen to understand, in general, the contribution of these mechanisms to evolution and adaptation, and the origin of novel properties. We are exploring a number of different biological models to understand the origin of novel gene functions.

For several decades, much attention has been placed on gene duplication as a source of new gene functions. More recently, however, it has become appreciated that after gene duplication, the resulting duplicates are often "subfunctionalized" and accumulate complementary mutations: the two genes together perform the function formerly carried out by a single ancestral gene. Gene duplication, therefore, is only a necessary contributor to adaptation if it enables previously unfavored mutations to evolve. We have identified one such instance in a bifunctional yeast gene where gene duplication enabled the two functions to become independently encoded and regulated and where most of the adaptive divergence between the two duplicates involved regulatory sequences. Our findings suggest that coding sequences and regulatory sequences that harbor more than one function may require duplication in order for an individual function to evolve.

As of April 29, 2016

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Genetics, Molecular Biology