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Ever since the integration of Mendelian genetics into evolutionary biology in the early 20th century, evolutionary geneticists have for the most part treated genes and mutations as generic entities. However, recent observations indicate that all genes are not equal in the eyes of evolution. Evolutionarily relevant mutations tend to accumulate in hotspot genes and at specific positions within genes. Genetic evolution is constrained by gene function, the structure of genetic networks, and population biology. The genetic basis of evolution may be predictable to some extent, and further understanding of this predictability requires incorporation of the specific functions and characteristics of genes into evolutionary theory.

Perhaps the most valuable single set of resources for genetic studies of Drosophila melanogaster is the collection of multiply inverted chromosomes commonly known as balancer chromosomes. Balancers prevent the recovery of recombination exchange products within genomic regions included in inversions and allow perpetual maintenance of deleterious alleles in living stocks and the execution of complex genetic crosses. Balancer chromosomes have been generated traditionally by exposing animals to ionizing radiation and screening for altered chromosome structure or for unusual marker segregation patterns. These approaches are tedious and unpredictable, and have failed to produce the desired products in some species. Here, I describe transgenic tools that allow targeted chromosome rearrangements in Drosophila species. The key new resources are engineered reporter genes containing introns with yeast recombination sites and enhancers that drive fluorescent reporter genes in multiple body regions. These tools were used to generate a doubly inverted chromosome 3R in Drosophila simulans that serves as an effective balancer chromosome.

Key Points Convergent phenotypic evolution often results from similar genetic changes in independent species by a process known as parallel evolution. Sometimes, convergent evolution results from the evolution of a genetic change that is inherited from an ancestral population or from hybridization between species, which, in this Review, are collectively called collateral evolution. Whole-genome sequencing of experimental-evolution populations has provided compelling evidence for the importance of parallel evolution, and parallel evolution at specific genes has also been documented between highly divergent taxa. Collateral evolution by ancestry is likely to be common in species in which a single large population is surrounded by multiple geographical isolates. Collateral evolution by hybridization has been documented only recently and is likely to be widespread in nature. Multiple factors contribute to parallel evolution; it seems that genes which control key developmental decisions and those that interact most immediately with the environment are most likely to contribute to this type of evolution. This Review distinguishes between three distinct routes by which similar genetic changes contribute to convergent evolution and discusses examples from diverse taxa. Convergent genetic evolution might result from the fact that some mutations both minimize pleiotropic effects and maximize adaptation. The evolution of phenotypic similarities between species, known as convergence, illustrates that populations can respond predictably to ecological challenges. Convergence often results from similar genetic changes, which can emerge in two ways: the evolution of similar or identical mutations in independent lineages, which is termed parallel evolution; and the evolution in independent lineages of alleles that are shared among populations, which I call collateral genetic evolution. Evidence for parallel and collateral evolution has been found in many taxa, and an emerging hypothesis is that they result from the fact that mutations in some genetic targets minimize pleiotropic effects while simultaneously maximizing adaptation. If this proves correct, then the molecular changes underlying adaptation might be more predictable than has been appreciated previously.

Transcription activator–like effectors are used for in vivo activation and repression of endogenous promoters and enhancers in the fruit fly. We tested whether transcription activator–like effectors (TALEs) could mediate repression and activation of endogenous enhancers in the Drosophila genome. TALE repressors (TALERs) targeting each of the five even-skipped ( eve ) stripe enhancers generated repression specifically of the focal stripes. TALE activators (TALEAs) targeting the eve promoter or enhancers caused increased expression primarily in cells normally activated by the promoter or targeted enhancer, respectively. This effect supports the view that repression acts in a dominant fashion on transcriptional activators and that the activity state of an enhancer influences TALE binding or the ability of the VP16 domain to enhance transcription. In these assays, the Hairy repression domain did not exhibit previously described long-range transcriptional repression activity. The phenotypic effects of TALER and TALEA expression in larvae and adults are consistent with the observed modulations of eve expression. TALEs thus provide a novel tool for detection and functional modulation of transcriptional enhancers in their native genomic context.

Natural variation in the courtship song of Drosophila is mapped to the intronic insertion of a retroelement at the slowpoke locus, which encodes an ion channel. On a wing and a song An important aspect of courtship behaviour in Drosophila is the male courtship song, generated when the males vibrate their wings. The features of this courtship song and how this varies between Drosophila species have been well-characterized. David Stern and colleagues now map the genetic variation causal for natural variation in courtship song between two wild isolates of D. simulans and D. mauritiana to the insertion of a retroelement at the slowpoke ( slo ) locus, which encodes an ion channel. Animal species display enormous variation for innate behaviours, but little is known about how this diversity arose. Here, using an unbiased genetic approach, we map a courtship song difference between wild isolates of Drosophila simulans and Drosophila mauritiana to a 966 base pair region within the slowpoke ( slo ) locus, which encodes a calcium-activated potassium channel 1 . Using the reciprocal hemizygosity test 2 , we confirm that slo is the causal locus and resolve the causal mutation to the evolutionarily recent insertion of a retroelement in a slo intron within D. simulans . Targeted deletion of this retroelement reverts the song phenotype and alters slo splicing. Like many ion channel genes, slo is expressed widely in the nervous system and influences a variety of behaviours 3 , 4 ; slo -null males sing little song with severely disrupted features. By contrast, the natural variant of slo alters a specific component of courtship song, illustrating that regulatory evolution of a highly pleiotropic ion channel gene can cause modular changes in behaviour.

Back-up enhancers protect phenotype Transcriptional enhancers are segments of regulatory DNA located some distance from the coding region of a gene. Sometimes, several of them can serve apparently redundant functions — driving the production of a gene's messenger RNA at the same stage and place in embryonic development. Frankel et al . now demonstrate in Drosophila that such 'redundant' enhancers (in this case, two enhancers of the embryo-patterning gene shavenbaby ), by contributing higher overall levels of transcription, ensure robustness of phenotypes against both genetic and environmental perturbations; for example, mutations in other genes or temperature changes that would otherwise lead to aberrant development. Transcriptional enhancers are segments of regulatory DNA located some distance from the coding region of a gene, and several of them may sometimes serve apparently redundant functions. These authors demonstrate in Drosophila that such 'redundant' enhancers, by contributing higher overall levels of transcription, ensure robustness of phenotypes against both genetic and environmental perturbations, for example mutations in other genes or temperature changes that would otherwise lead to aberrant development. Genes include cis -regulatory regions that contain transcriptional enhancers. Recent reports have shown that developmental genes often possess multiple discrete enhancer modules that drive transcription in similar spatio-temporal patterns 1 , 2 , 3 , 4 : primary enhancers located near the basal promoter and secondary, or ‘shadow’, enhancers located at more remote positions. It has been proposed that the seemingly redundant activity of primary and secondary enhancers contributes to phenotypic robustness 1 , 5 . We tested this hypothesis by generating a deficiency that removes two newly discovered enhancers of shavenbaby ( svb , a transcript of the ovo locus), a gene encoding a transcription factor that directs development of Drosophila larval trichomes 6 . At optimal temperatures for embryonic development, this deficiency causes minor defects in trichome patterning. In embryos that develop at both low and high extreme temperatures, however, absence of these secondary enhancers leads to extensive loss of trichomes. These temperature-dependent defects can be rescued by a transgene carrying a secondary enhancer driving transcription of the svb cDNA. Finally, removal of one copy of wingless , a gene required for normal trichome patterning 7 , causes a similar loss of trichomes only in flies lacking the secondary enhancers. These results support the hypothesis that secondary enhancers contribute to phenotypic robustness in the face of environmental and genetic variability.

Drosophila melanogaster males perform a series of courtship behaviors that, when successful, result in copulation with a female. For over a century, mutations in the yellow gene, named for its effects on pigmentation, have been known to reduce male mating success. Prior work has suggested that yellow influences mating behavior through effects on wing extension, song, and/or courtship vigor. Here, we rule out these explanations, as well as effects on the nervous system more generally, and find instead that the effects of yellow on male mating success are mediated by its effects on pigmentation of male-specific leg structures called sex combs. Loss of yellow expression in these modified bristles reduces their melanization, which changes their structure and causes difficulty grasping females prior to copulation. These data illustrate why the mechanical properties of anatomy, not just neural circuitry, must be considered to fully understand the development and evolution of behavior. More than 100 years ago, Nobel-prize winning geneticist Thomas Hunt Morgan and his colleagues discovered that some fruit flies inherited genetic mutations that caused their body color to change. The yellow flies had a mutation in one specific gene and these mutants did not only look different from normal flies, they behaved differently too. Specifically, yellow males were far less successful at mating than normal males, demonstrating for the first time that some behaviors had a genetic basis. Since then it has remained a mystery how the genetic mutations that cause yellow coloration in fruit flies lead to unsuccessful mating attempts. Geneticists have long suggested that mutations in insect pigment genes cause changes in the fly’s brain because these pigments are made from dopamine, a chemical messenger that acts in the brain. They proposed that yellow flies must have altered levels of dopamine in their brains which was causing them to fail at mating. To solve this mystery, Massey et al. used a series of genetic experiments and high speed-videos to assess how mutations in male yellow fruit flies affected their mating behavior. The experiments showed that yellow fruit flies mated poorly not because of changes in their brain but because of changes in specialized structures on their legs called sex combs. The yellow males lack melanin pigments in their sex combs, which changes their structure. As a result, the yellow males would court female flies but were then unable to grab and mount them. This explains why yellow flies often fail to mate and why fruit flies have sex combs in the first place. The study reveals the importance of scientists considering that genes that affect behavior may do so by changing anatomy rather than by altering the brain. The results also may benefit those working to control insect pests. For example, they could help insect pest managers to develop strategies that prevent reproduction in other insects that spread disease or destroy crops.

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.

The evolutionary expansion of sensory neuron populations detecting important environmental cues is widespread, but functionally enigmatic. We investigated this phenomenon through comparison of homologous olfactory pathways of Drosophila melanogaster and its close relative Drosophila sechellia , an extreme specialist for Morinda citrifolia noni fruit. D. sechellia has evolved species-specific expansions in select, noni-detecting olfactory sensory neuron (OSN) populations, through multigenic changes. Activation and inhibition of defined proportions of neurons demonstrate that OSN number increases contribute to stronger, more persistent, noni-odour tracking behaviour. These expansions result in increased synaptic connections of sensory neurons with their projection neuron (PN) partners, which are conserved in number between species. Surprisingly, having more OSNs does not lead to greater odour-evoked PN sensitivity or reliability. Rather, pathways with increased sensory pooling exhibit reduced PN adaptation, likely through weakened lateral inhibition. Our work reveals an unexpected functional impact of sensory neuron population expansions to explain ecologically-relevant, species-specific behaviour. Sensory neuron population expansions are common in evolution but of unclear function. Here, the authors show that, in drosophilid olfactory systems, increased sensory neuron number impacts interneuron dynamics, but not sensitivity, to promote olfactory-guided behaviour.

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.