Gene-Environment Interaction: The Big Picture

The goal of our research is to understand how genes and the environment work together to regulate morphology and how this regulation evolves. A major problem in evolutionary biology is explaining how genetic variation is transformed into phenotypic variation. The integration of evolutionary with developmental biology has revealed how heritable changes in gene expression during development can alter phenotype. However, this is only half the story – phenotype is also influenced by the environment. The next step is therefore to understand how the environment influences the developmental process by which genotype becomes phenotype, integrating evo-devo with physiology. Gene-environment interactions mold the phenotypes of all living things and uncovering the mechanism of these interactions is fundamental to understanding phenotypic variation, both adaptive and maladaptive.

Research in the Shingleton lab addresses a number of different aspects of gene-environment interactions, largely focusing on the environmental regulation of body and trait size, and how this regulation evolves. Because gene-environment interactions involve dialogue among multiple levels of biological organization our research is correspondingly integrative, synthesizing multiple disciplines, from molecular and developmental genetics to physiology, bioinformatics and evolutionary biology.

Below are some of the projects being conducted in the laboratory.

Allometry: The Developmental Regulation and Evolution of Scaling

Biological diversity is dominated by variation in shape. This is perhaps no more apparent than in one of the most successful metazoan taxa, the insects. From a very simple body plan (head, thorax, abdomen, a pair of antenna, two pairs of wings and three pairs of legs) comes myriad forms, from bees to beetles, and fleas to flies. Much of this diversity is a result of variation in the relative, rather than the absolute, size of the insect body parts. This variation can be illustrated as a plot of the relative size of two structures among members of a population of animals (Figure 1A). This is called a static allometry. When we think about variation in shape, we are often thinking about variation in static allometry (even though we might not realize it!).

Static allometries can vary in their intercepts and slope. Differences in intercept reflect a difference in relative trait size across the full range of body sizes. A simple example is the difference in the relative wing size between bees and butterflies (Figure 1B). Differences in slope reflect differences in how relative trait size changes with overall body size.  For example, traits with low allometric slopes – called hypoallometry –  are more-or-less the same size in large and small individuals. A good example of this is the relationship between brain size and body size in humans (Figure 1C). In contrast, traits with high allometric slopes –called hyperallometry – are proportionally larger in large individuals. A good example of this is the relationship between antler size and body size in male elk (Figure 1D).

  Figure 1:  Potential changes in static allometry.  A:  Static allometry describes the relationship between trait size and body size across the range of body sizes observed in a species or population.  B:  Differences in the intercept of static allometries capture differences in relative trait size and body proportion across all body sizes, for example the differences in relative wing size between bees and butterflies.  C:  Traits with a low allometric slopes are more-or-less the same size across all body sizes and so are proportionally larger in smaller individuals, for example brain size in humans.  D:  Traits with high allometric slopes are proportionally larger in large individuals, for example antler size in male elk.

Figure 1: Potential changes in static allometry. A: Static allometry describes the relationship between trait size and body size across the range of body sizes observed in a species or population. B: Differences in the intercept of static allometries capture differences in relative trait size and body proportion across all body sizes, for example the differences in relative wing size between bees and butterflies. C: Traits with a low allometric slopes are more-or-less the same size across all body sizes and so are proportionally larger in smaller individuals, for example brain size in humans. D: Traits with high allometric slopes are proportionally larger in large individuals, for example antler size in male elk.

We have a good idea why some traits are hypoallometric to body size while others are hyperallometric to body size. For example,  brains are important organs, and development has likely evolved to ensure that conditions that result in a reduction in adult size (for example malnutrition during childhood) retard the growth of the body more than the growth of the brain. However, we have no idea how this is achieved.

In fruit flies, it is not the brain that is hypoallometric to body size, but the male genitals. Consequently smaller male flies tend to have proportionally larger genitals than larger male flies (Figure 2). Over the past few years we have begun to understand the developmental mechanisms that regulate this phenomenon. Our research shows  that differences in the way the insulin-signaling pathway regulates the growth of the genitals compared to other organs is key. Thus the insulin-signaling pathway, which plays a major roles in longevity, diabetes, and the regulation of cell, organ and body size, is centrally involved in regulating allometry. 

  Figure 2:   The scaling realtionship between wing and body size and genital and body size in male  Drosophila

Figure 2:  The scaling realtionship between wing and body size and genital and body size in male Drosophila

If trait-specific differences in insulin-regulated growth accounts for differences in scaling among traits within a body, perhaps genetic variation in the same mechanism can generate differences in scaling for the same trait among individuals in a population. This variation could then be naturally selected to generate evolved changes in morphological scaling. We are currently testing this exciting hypothesis, using a combination of mathematical modeling, population genetics and artificial selection.

You can follow the progress of our research in these papers:

Dreyer, A.P., Shingleton, A.W. 2018. Insulin-insensitivity in male genitalia maintains reproductive success in Drosophila. In review.

Shingleton , A.W., Frankino, W.A. 2018. The (ongoing) problem of relative growth. Current Opinion in Insect Science. 25. 9-19

 Shingleton, A.W., Masandika, J. R., Thorsen, L.S., Zhu, Y., Mirth, C.K. 2017. The sex-specific effects of diet quality versus quantity on size and shape in Drosophila melanogaster. Royal Society Open Science. 4: 170375.

Dreyer, A.P., Saleh Ziabari, O., Swanson, E.M., Chawla, A., Frankino, W.A., Shingleton, A.W. 2016. Cryptic individual scaling relationships and the evolution of morphological scaling. Evolution . 70: 1703-1706.

Stillwell, R.C., Shingleton, A.W., Dworkin, I., Frankino, W.A. 2016. Tipping the scales: Evolution of the allometric slope independent of average trait size. Evolution. 7: 433-444

Shingleton, A.W., Frankino, W.A. 2013. New perspectives on the evolution of exaggerated traits. BioEssay, 35, 100-107

Shingleton, A.W., Tang, H.Y. 2012. Plastic flies: The regulation and evolution of trait variability in Drosophila. Fly, 6, 1-3

Tang, H., Smith-Caldas, M.S.R., Driscoll, M.V., Salhadar, S. & Shingleton, A.W. 2011. FOXO regulates organ-specific phenotypic plasticity in DrosophilaPLoS Genetics, 7, e1002373

Dreyer, A.P., Shingleton, A.W. 2011. The effect of genetic and environmetal variation on genital size in male Drosophila: Canalized but developmentally unstable. PLoS One, 6, e28278

Shingleton, A.W., Estep, C.M., Driscoll, M.V., Dworkin, I. 2009. Many ways to be small: Different environmental regulators of size generate different scaling relationships in Drosophila melanogaster. Proceedings of the Royal Society, London. Series B, 276, 2625-2633

Frankino, W.A., Emlen, D.J. & Shingleton, A.W. 2009. Experimental approaches to studying the evolution of morphological allometries: The shape of things to come. in "Experimental Evolution(T. Garland & M.R. Rose, Eds), University of California Press, Berkley.

Shingleton, A.W., Mirth, C.K. & Bates, P.W. 2008Developmental model of static allometry in holometabolous insects. Proceedings of the Royal Society, London. Series B, 275, 1875-1885

Shingleton, A.W., Frankino, W.A., Flatt, T. Nijhout, H.F. & Emlen, D.J. 2007.Size and Shape: The regulation of static allometry in insects, BioEssays, 29 (6), 536-548

Shingleton, A.W., Das, J., Vinicius, L. & Stern, D.L. 2005. The temporal requirements for insulin signaling during development in Drosophila, PLoS Biology, 3 (9)

What Controls Body and Organ Size?

An important aspect of the control of allometry is the control of body size.  In holometabolous insects (insects that form pupae), final body size is regulated by the point in development when a larva decides to stop growing and begin to pupate. This decision is made when the larvae reaches a particular size, called the critical size. We are interested in how an insect knows when it has reached critical size. Early research suggested that damage to the developing organs in a fly (called imaginal discs) can delay development. This suggests that the imaginal discs may need to be at a certain size for a fly to reach critical size and initiate metamorphosis. We have been using various physical and genetic methods to alter the growth of imaginal discs and see how this affects critical size. Our data indicate that the imaginal discs do indeed help regulate critical size and the timing of metamorphosis. Even more excitingly, we have discovered that slowing the growth of one imaginal disc slows the growth of all other organs in the body. This suggests that body and organ size is controlled by a complex set of signals by which growing organs 'talk' to one another. On going work in the lab is directed to identifying the nature of these signals.

Gokhale, R.H., Hayashi, T., Mirque, C.D., Shingleton, A.W. 2016. Intra-organ growth coordination in Drosophila is mediated by systemic ecdysone signaling. Developmental Biology418: 135-145.

Herbosa, L., Oliviera, M.M., Talamillo, Pérez, C., González, M., Martín, D., Sutherland, J.D., Shingleton, A.W., Mirth, C.K., Barrio, R. 2015. Ecdysone promotes growth of imaginal discs through the regulation of Thor in D. melanogaster. Scientific Reports. online ahead of print.

Oliveira, M.M., Shingleton, A.W., Mirth, C.K. 2014. Tissue pattern is not tightly coordinated with whole body development. PLoS Genetics. 10(6): e1004408

Mirth, C.K., Tang, H., Makohon-Moore, S., Salhadar, S., Gokhale, R.H., Riddiford, L.M., Shingleton, A.W., 2014. Juvenile hormone regulates body size and perturbs insulin-signaling in Drosophila. Proceedings of the National Academy of Sciences, USA, doi: 10.1073/pnas.1313058111

Callier, V., Shingleton, A.W., Brent, C.S., Ghosh, S.M., Kim, J., Harrison, J.F., 2013. The role of reduced oxygen in the developmental physiology of growth and metamorphosis initiation in Drosophila melanogaster. The Journal of Experimental Biology, 216, 4334-4340.

Parker, N.F. & Shingleton, A.W. 2011. The coordination of growth among Drosophila organs in response to localized growth perturbation. Developmental Biology, 357, 318-325

 Shingleton, A.W. 2011. The regulation and evolution of growth and body size. in"Mechanisms of Life History Evolution" (T. Flatt & A. Heyland, Eds), OUP

Stieper, B.C., Kupershtok, M., Driscoll, M.V. & Shingleton, A.W. 2008. Imaginal disc growth regulates the timing of metamorphosis in Drosophila melanogaster. Developmental Biology321, 18-26

Shingleton, A.W. 2005, Body-Size Regulation: Combining Genetics and Physiology, Current Biology, 15 (20), R825-R827