Dissecting complex traits using the Drosophila Synthetic Population Resource

Long, Anthony D.; Macdonald, Stuart J.; King, Elizabeth G.

doi:10.1016/j.tig.2014.07.009

Cited by 84 publications

(110 citation statements)

References 53 publications

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“…polyallelism, genetic heterogeneity) by forward genetic approaches is difficult in spite of their suspected importance in human disease (McClellan and King 2010). Indeed, detecting multiallelism requires a multiple-parent QTL scheme, and this has only been recently implemented in a handful of model organisms (Huang et al 2011;Long et al 2014a). Furthermore, GWAS studies typically underestimate the contributions of mixed alleles (Thornton et al 2013).…”

Section: How When and Why Ligand Genes Are Likely Drivers Of Pattermentioning

confidence: 99%

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

Martin

Courtier‐Orgogozo

2017

Diversity and Evolution of Butterfly Wing Patterns

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What types of genetic changes underlie evolution? Secreted signaling molecules (syn. ligands) can induce cells to switch states and thus largely contribute to the emergence of complex forms in multicellular organisms. It has been proposed that morphological evolution should preferentially involve changes in developmental toolkit genes such as signaling pathway components or transcription factors. However, this hypothesis has never been formally confronted to the bulk of accumulated experimental evidence. Here we examine the importance of ligandcoding genes for morphological evolution in animals. We use Gephebase (http:// www.gephebase.org), a database of genotype-phenotype relationships for evolutionary changes, and survey the genetic studies that mapped signaling genes as causative loci of morphological variation. To date, 19 signaling genes represent 20% of the cases where an animal morphological change has been mapped to a gene (80/391). This includes the signaling gene Agouti, which harbors multiple cis-regulatory alleles linked to color variation in vertebrates, contrasting with the effects of coding variation in its target, the melanocortin receptor MC1R. In sticklebacks, genetic mapping approaches have identified 4 signaling genes out of 14 loci associated with lake adaptations. Finally, in butterflies, a total of 18 allelic variants of the WntA Wnt-family ligand cause color pattern adaptations related to wing mimicry, both within and between species. We discuss possible hypotheses explaining these cases of natural replication (genetic parallelism) and conclude that signaling ligand loci are an important source of sequence variation underlying morphological change in nature.

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Section: How When and Why Ligand Genes Are Likely Drivers Of Pattermentioning

confidence: 99%

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

Martin

Courtier‐Orgogozo

2017

Diversity and Evolution of Butterfly Wing Patterns

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“…A promising example of a community-wide effort is the Arabidopsis 1001 Genomes Project, in which ecologically diverse A. thaliana lines sampled from across the ancestral species range are being sequenced to catalyze functional dissection of genetic variation [54]. This and other mapping resources for model organism communities [55, 54, 28, 56, 48, 49, 57] not only enable mapping of phenotypic differences in parental lines, but can unmask cryptic variation that provides a powerful complement to laboratory mutagenesis (e.g. [58, 59]).…”

Section: Capturing Natural Functional Variation In Model Organismsmentioning

confidence: 99%

The Power of Natural Variation for Model Organism Biology

2016

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Genetic background effects have long been recognized, and in some cases studied, but they are often viewed as a nuisance by molecular biologists. We suggest that genetic variation represents a critical frontier for molecular studies today. Human genetics has seen a surge of interest in genetic variation and its contributions to disease, but insights into disease mechanisms are difficult since information about gene function is lacking. In contrast, model organism genetics has excelled at revealing molecular mechanisms of cellular processes, but often de-emphasizes genetic variation and its functional consequences. We argue that model organism biology would benefit from incorporating natural variation, both to capture how well laboratory lines exemplify the species they represent and to inform on molecular processes and their variability. Such a synthesis would also greatly expand the relevance of model systems for studies of complex trait variation, including disease.

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“…The D. melanogaster and C. elegans communities have developed numerous strain resources with divergent genetic backgrounds, including wild isolates with whole-genome sequence data [28–30] and recombinant inbred lines (RILs) generated by crossing distinct genetic backgrounds [31–33]. Across both species, drug responses generally affect fitness, including offspring production, growth rate, and viability.…”

Section: The Effect Of Genetic Background On Chemotherapeutic Drug Rementioning

confidence: 99%

Natural diversity facilitates the discovery of conserved chemotherapeutic response mechanisms

Zdraljevic

Andersen

2017

Current Opinion in Genetics & Development

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Organismal fitness depends on adaptation to complex niches where chemical compounds and pathogens are omnipresent. These stresses can lead to the fixation of alleles in both xenobiotic responses and proliferative signaling pathways that promote survival in these niches. However, both xenobiotic responses and proliferative pathways vary within and among species. For example, genetic differences can accumulate within populations because xenobiotic exposures are not constant and selection is variable. Additionally, neutral genetic variation can accumulate in conserved proliferative pathway genes because these systems are robust to genetic perturbations given their essential roles in normal cell-fate specification. For these reasons, sensitizing mutations or chemical perturbations can disrupt pathways and reveal cryptic variation. With this fundamental view of how organisms respond to cytotoxic compounds and cryptic variation in conserved signaling pathways, it is not surprising that human patients have highly variable responses to chemotherapeutic compounds and to the activities of proliferative pathways. These different patient responses result in the low FDA-approval rates for chemotherapeutics and underscore the need for new approaches to understand these diseases and therapeutic interventions. Model organisms, especially the classic invertebrate systems of Caenorhabditis elegans and Drosophila melanogaster, can be used to combine studies of natural variation across populations with responses to both xenobiotic compounds and chemotherapeutics targeted to conserved proliferative signaling pathways.

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Dissecting complex traits using the Drosophila Synthetic Population Resource

Cited by 84 publications

References 53 publications

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

The Power of Natural Variation for Model Organism Biology

Natural diversity facilitates the discovery of conserved chemotherapeutic response mechanisms

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