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141 Publications

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    05/01/19 | Pleiotropic effects of ebony and tan on pigmentation and cuticular hydrocarbon composition in Drosophila melanogaster.
    Massey JH, Akiyama N, Bien T, Dreisewerd K, Wittkopp PJ, Yew JY, Takahashi A
    Frontiers in Physiology. 05/2019;10:518. doi: 10.3389/fphys.2019.00518

    Pleiotropic genes are genes that affect more than one trait. For example, many genes required for pigmentation in the fruit fly also affect traits such as circadian rhythms, vision, and mating behavior. Here, we present evidence that two pigmentation genes, and , which encode enzymes catalyzing reciprocal reactions in the melanin biosynthesis pathway, also affect cuticular hydrocarbon (CHC) composition in females. More specifically, we report that loss-of-function mutants have a CHC profile that is biased toward long (>25C) chain CHCs, whereas loss-of-function mutants have a CHC profile that is biased toward short (<25C) chain CHCs. Moreover, pharmacological inhibition of dopamine synthesis, a key step in the melanin synthesis pathway, reversed the changes in CHC composition seen in mutants, making the CHC profiles similar to those seen in mutants. These observations suggest that genetic variation affecting and/or activity might cause correlated changes in pigmentation and CHC composition in natural populations. We tested this possibility using the Genetic Reference Panel (DGRP) and found that CHC composition covaried with pigmentation as well as levels of and expression in newly eclosed adults in a manner consistent with the and mutant phenotypes. These data suggest that the pleiotropic effects of and might contribute to covariation of pigmentation and CHC profiles in .

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    03/08/19 | Neural evolution of context-dependent fly song.
    Ding Y, Lillvis JL, Cande J, Berman GJ, Arthur BJ, Long X, Xu M, Dickson BJ, Stern DL
    Current Biology : CB. 2019 Mar 08;29(7):1089-99. doi: 10.1016/j.cub.2019.02.019

    It is unclear where in the nervous system evolutionary changes tend to occur. To localize the source of neural evolution that has generated divergent behaviors, we developed a new approach to label and functionally manipulate homologous neurons across Drosophila species. We examined homologous descending neurons that drive courtship song in two species that sing divergent song types and localized relevant evolutionary changes in circuit function downstream of the intrinsic physiology of these descending neurons. This evolutionary change causes different species to produce divergent motor patterns in similar social contexts. Artificial stimulation of these descending neurons drives multiple song types, suggesting that multifunctional properties of song circuits may facilitate rapid evolution of song types.

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    12/13/18 | Gene flow mediates the role of sex chromosome meiotic drive during complex speciation.
    Meiklejohn CD, Landeen EL, Gordon KE, Rzatkiewicz T, Kingan SB, Geneva AJ, Vedanayagam JP, Muirhead CA, Garrigan D, Stern DL, Presgraves DC
    eLife. 2018 Dec 13;7:. doi: 10.7554/eLife.35468

    During speciation, sex chromosomes often accumulate interspecific genetic incompatibilities faster than the rest of the genome. The drive theory posits that sex chromosomes are susceptible to recurrent bouts of meiotic drive and suppression, causing the evolutionary build-up of divergent cryptic sex-linked drive systems and, incidentally, genetic incompatibilities. To assess the role of drive during speciation, we combine high-resolution genetic mapping of X-linked hybrid male sterility with population genomics analyses of divergence and recent gene flow between the fruitfly species, and . Our findings reveal a high density of genetic incompatibilities and a corresponding dearth of gene flow on the X chromosome. Surprisingly, we find that a known drive element recently migrated between species and, rather than contributing to interspecific divergence, caused a strong reduction in local sequence divergence, undermining the evolution of hybrid sterility. Gene flow can therefore mediate the effects of selfish genetic elements during speciation.

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    10/05/18 | Correlated evolution of two copulatory organs via a single cis-regulatory nucleotide change.
    Nagy O, Nuez I, Savisaar R, Peluffo AE, Yassin A, Lang M, Stern DL, Matute DR, David JR, Courtier-Orgogozo V
    Current Biology : CB. 2018 Oct 05;28(21):3450-7. doi: 10.1016/j.cub.2018.08.047

    Diverse traits often covary between species [1-3]. The possibility that a single mutation could contribute to the evolution of several characters between species [3] is rarely investigated as relatively few cases are dissected at the nucleotide level. Drosophila santomea has evolved additional sex comb sensory teeth on its legs and has lost two sensory bristles on its genitalia. We present evidence that a single nucleotide substitution in an enhancer of the scute gene contributes to both changes. The mutation alters a binding site for the Hox protein Abdominal-B in the developing genitalia, leading to bristle loss, and for another factor in the developing leg, leading to bristle gain. Our study suggests that morphological evolution between species can occur through a single nucleotide change affecting several sexually dimorphic traits. VIDEO ABSTRACT.

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    07/11/18 | Evolution of a central neural circuit underlies Drosophila mate preferences.
    Seeholzer LF, Seppo M, Stern DL, Ruta V
    Nature. 2018 Jul 11;559(7715):564-9. doi: 10.1038/s41586-018-0322-9

    Courtship rituals serve to reinforce reproductive barriers between closely related species. Drosophila melanogaster and Drosophila simulans exhibit reproductive isolation, owing in part to the fact that D. melanogaster females produce 7,11-heptacosadiene, a pheromone that promotes courtship in D. melanogaster males but suppresses courtship in D. simulans males. Here we compare pheromone-processing pathways in D. melanogaster and D. simulans males to define how these sister species endow 7,11-heptacosadiene with the opposite behavioural valence to underlie species discrimination. We show that males of both species detect 7,11-heptacosadiene using homologous peripheral sensory neurons, but this signal is differentially propagated to P1 neurons, which control courtship behaviour. A change in the balance of excitation and inhibition onto courtship-promoting neurons transforms an excitatory pheromonal cue in D. melanogaster into an inhibitory cue in D. simulans. Our results reveal how species-specific pheromone responses can emerge from conservation of peripheral detection mechanisms and diversification of central circuitry, and demonstrate how flexible nodes in neural circuits can contribute to behavioural evolution.

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    12/09/17 | Optogenetic dissection of descending behavioral control in Drosophila.
    Cande J, Namiki S, Qiu J, Korff W, Card GM, Shaevitz JW, Stern DL, Berman GJ
    eLife. 2018:e34275. doi: 10.7554/eLife.34275

    In most animals, the brain makes behavioral decisions that are transmitted by descending neurons to the nerve cord circuitry that produces behaviors. In insects, only a few descending neurons have been associated with specific behaviors. To explore how descending neurons control an insect's movements, we developed a novel method to systematically assay the behavioral effects of activating individual neurons on freely behaving terrestrial D. melanogaster. We calculated a two-dimensional representation of the entire behavior space explored by these flies and we associated descending neurons with specific behaviors by identifying regions of this space that were visited with increased frequency during optogenetic activation. Applying this approach across a large collection of descending neurons, we found that (1) activation of most of the descending neurons drove stereotyped behaviors, (2) in many cases multiple descending neurons activated similar behaviors, and (3) optogenetically-activated behaviors were often dependent on the behavioral state prior to activation.

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    04/02/18 | Accurate and sensitive quantification of protein-DNA binding affinity.
    Rastogi C, Rube HT, Kribelbauer JF, Crocker J, Loker RE, Martini GD, Laptenko O, Freed-Pastor WA, Prives C, Stern DL, Mann RS, Bussemaker HJ
    Proceedings of the National Academy of Sciences of the United States of America. 2018 Apr 02;115(16):E3692-701. doi: 10.1073/pnas.1714376115

    Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. Mutations in TF binding sites are increasingly found to be associated with human disease, yet we currently lack robust methods to predict these sites. Here, we developed a versatile maximum likelihood framework named No Read Left Behind (NRLB) that infers a biophysical model of protein-DNA recognition across the full affinity range from a library of in vitro selected DNA binding sites. NRLB predicts human Max homodimer binding in near-perfect agreement with existing low-throughput measurements. It can capture the specificity of the p53 tetramer and distinguish multiple binding modes within a single sample. Additionally, we confirm that newly identified low-affinity enhancer binding sites are functional in vivo, and that their contribution to gene expression matches their predicted affinity. Our results establish a powerful paradigm for identifying protein binding sites and interpreting gene regulatory sequences in eukaryotic genomes.

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    03/13/18 | Comprehensive analysis of a cis-regulatory region reveals pleiotropy in enhancer function.
    Preger-Ben Noon E, Sabarís G, Ortiz DM, Sager J, Liebowitz A, Stern DL, Frankel N
    Cell Reports. 2018 Mar 13;22(11):3021-3031. doi: 10.1016/j.celrep.2018.02.073

    Developmental genes can have complex cis-regulatory regions with multiple enhancers. Early work revealed remarkable modularity of enhancers, whereby distinct DNA regions drive gene expression in defined spatiotemporal domains. Nevertheless, a few reports have shown that enhancers function in multiple developmental stages, implying that enhancers can be pleiotropic. Here, we have studied the activity of the enhancers of the shavenbaby gene throughout D. melanogaster development. We found that all seven shavenbaby enhancers drive expression in multiple tissues and developmental stages. We explored how enhancer pleiotropy is encoded in two of these enhancers. In one enhancer, the same transcription factor binding sites contribute to embryonic and pupal expression, revealing site pleiotropy, whereas for a second enhancer, these roles are encoded by distinct sites. Enhancer pleiotropy may be a common feature of cis-regulatory regions of developmental genes, and site pleiotropy may constrain enhancer evolution in some cases.

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    12/01/17 | Editorial overview: Making evolutionary sense of everything.
    Stern DL, Haag E
    Current Opinion in Genetics & Development. 2017 Dec;47:iv-vi. doi: 10.1016/j.gde.2017.11.005
    11/02/17 | Nuclear microenvironments modulate transcription from low-affinity enhancers.
    Tsai A, Muthusamy AK, Alves MR, Lavis LD, Singer RH, Stern DL, Crocker J
    eLife. 2017 Nov 02;6:. doi: 10.7554/eLife.28975

    Transcription factors bind low-affinity DNA sequences for only short durations. It is not clear how brief, low-affinity interactions can drive efficient transcription. Here we report that the transcription factor Ultrabithorax (Ubx) utilizes low-affinity binding sites in the Drosophila melanogastershavenbaby (svb) locus and related enhancers in nuclear microenvironments of high Ubx concentrations. Related enhancers colocalize to the same microenvironments independently of their chromosomal location, suggesting that microenvironments are highly differentiated transcription domains. Manipulating the affinity of svb enhancers revealed an inverse relationship between enhancer affinity and Ubx concentration required for transcriptional activation. The Ubx cofactor, Homothorax (Hth), was co-enriched with Ubx near enhancers that require Hth, even though Ubx and Hth did not co-localize throughout the nucleus. Thus, microenvironments of high local transcription factor and cofactor concentrations could help low-affinity sites overcome their kinetic inefficiency. Mechanisms that generate these microenvironments could be a general feature of eukaryotic transcriptional regulation.

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