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Drosophila, the golden bug, emerges as a tool for human genetics

Key Points

  • Many human disease genes have been highly conserved in Drosophila melanogaster.

  • Genes that specify cell identities during development perform similar functions in D. melanogaster and in vertebrates.

  • Genetic modifier screens in D. melanogaster have identified cellular components that regulate the neurodegenerative effect of cytotoxic, expanded polyglutamine proteins, as well as components of the g-secretase complex, which are defective in patients with Alzheimer disease.

  • D. melanogaster provides an excellent model for understanding the normal control of cellular growth and proliferation as well as of cancerous growth and metastasis.

  • In the future, D. melanogaster should provide a powerful system to address specific questions in human genetics ('closing-the-loop' studies) and to understand the molecular basis of polygenic disorders.

Abstract

Drosophila melanogaster is emerging as one of the most effective tools for analyzing the function of human disease genes, including those responsible for developmental and neurological disorders, cancer, cardiovascular disease, metabolic and storage diseases, and genes required for the function of the visual, auditory and immune systems. Flies have several experimental advantages, including their rapid life cycle and the large numbers of individuals that can be generated, which make them ideal for sophisticated genetic screens, and in future should aid the analysis of complex multigenic disorders. The general principles by which D. melanogaster can be used to understand human disease, together with several specific examples, are considered in this review.

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Figure 1: Comparison of Twist and FGFR signalling in flies and vertebrates.
Figure 2: The Notch signalling pathway.
Figure 3: Examples of second-site modifier screens in Drosophila melanogaster.
Figure 4: The canonical receptor tyrosine kinase (RTK) signalling pathway.
Figure 5: The target of rapamycin (TOR) pathway.
Figure 6: The Drosophila melanogaster wing provides an assay system for several signalling pathways.

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Acknowledgements

I would like to thank the anonymous reviewers and members of the Bier Laboratory for helpful comments, suggestions and discussions.

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DATABASES

OMIM

Alagille syndrome

spondylocostal dysostosis

Huntington disease

spinobulbar muscular atrophy

Parkinson disease

familial Alzheimer disease

Tuberous sclerosis

Entrez Pubmed

TWIST1

PSEN1

PSEN2

FMR1

TSC1

TSC2

HSP40

HSP70

SNCA

PARK2

APP

Flybase

Twist

scribbled

Appl

Fmr1

Tsc1

Tsc2

FURTHER INFORMATION

Ethan Bier's laboratory

Homophila

HapMap

Multiplex in situ hybridization

Glossary

E-VALUES

The likelihood that an observed match between two gene sequences would arise by chance, given the sizes of the databases used for comparison.

METAZOAN

(pl. metazoa) A multicellular organism.

CELL AUTONOMOUS (FUNCTION)

If a gene's activity affects only those cells that express it, its function is cell autonomous; if it affects cells other than (or in addition to) those expressing it, its function is cell non-autonomous.

SECOND-SITE MODIFIER SCREENS

Genetic screens designed to isolate dominant mutations, which are carried out in organisms that are already genetically compromised for a given pathway or process. Such mutations would typically be recessive if generated in a wild-type background, but because the process of interest has been selectively weakened, mutations affecting other components in the pathway now become dominant, making the mutations much easier to identify.

INCLUSION BODIES

Nuclear or cytoplasmic aggregates found in the brains of patients affected by triplet-repeat diseases.

COMPLEX GENETIC TRAIT

A measurable phenotype, such as disease status or a quantitative character, that is influenced by many environmental and genetic factors, and potentially by interactions in and between the factors.

DYSMORPHOLOGIES

Diseases resulting in morphological defects.

CRANIOSYNOSTOSIS

Premature fusion of one or more cranial sutures, often resulting in an abnormal head shape.

SYNDACTYLY

Fused digits.

IMAGINAL DISC

An epithelial sheet of cells that forms as a sac-like infolding of the epithelium in the larva. Small groups of imaginal disc founder cells arise in the embryo. They continue to divide until pupation, when they differentiate into many adult structures (wings, legs, eyes, antennae, genitalia) and then fuse in a quilt-like pattern to construct the adult.

CHAPERONINS

A class of ring-shaped, heat-shock proteins that have a key role in protein folding and protection from stress.

DOMINANT-NEGATIVE ALLELE

A form of mutation that interferes with the function of its wild-type gene product.

APICAL ECTODERMAL RIDGE

The thickening of the ectoderm at the tip of a developing chick limb bud, which is required for bud outgrowth.

EPISTASIS

The situation in which the phenotype caused by a mutation in one gene is masked by a mutation in another gene. Epistatic analysis requires that two mutants have distinguishable phenotypes. It can be used to determine the order of gene function by testing whether the phenotype of the double mutant ab is similar to that of mutant a, or mutant b.

AMYLOID PLAQUES

Extracellular, insoluble aggregations of amyloid β-peptide42 fragment, cleaved from the amyloid precursor protein, that accumulate in the brains of Alzheimer disease patients.

RNA INTERFERENCE

A process by which double-stranded RNA specifically silences the expression of homologous genes through degradation of their cognate messenger RNA.

CLONES

Patches of clonally derived cells in an organism that have been engineered to be genetically distinct from surrounding cells (for example, a homozygous mutant clone in a heterozygous background).

HAPLOTYPE

An experimentally determined profile of genetic markers that is present on a single chromosome of any given individual.

LINKAGE DISEQUILIBRIUM

The condition in which the frequency of a particular haplotype for two loci is significantly greater than that expected from the product of the observed allelic frequencies at each locus.

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Bier, E. Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6, 9–23 (2005). https://doi.org/10.1038/nrg1503

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