A Drosophila Genetic Resource of Mutants to Study Mechanisms Underlying Human Genetic Diseases

Abstract

Summary Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X-chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human datasets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health.

Fruit Flies in Biomedical Research

“…This 20% is likely to be too low an estimate as we predict that only 40% of the essential genes have been annotated. If the relationship between lethality and evolutionary conservation that we observe holds true for the rest of the genome that is yet to be explored, we predict that more than 50% of the fly genes that are conserved between fly and human will be essential (Yamamoto et al 2014a).…”

“…We recently created a large collection of X-chromosome lethal mutations in a forward genetic mosaic screen designed to isolate genes that affect many developmental and neurodegenerative processes (Haelterman et al 2014;Yamamoto et al 2014a). The data suggest a number of interesting relationships between essential fly genes and their human homologs.…”

“…These genes are nearly eight times more likely to be linked to human disease than essential fly genes that have a single human homolog (Yamamoto et al 2014a). This enrichment is still three-fold if one analyzes the total number of diseases caused per human gene in this category.…”

“…These include compounds such as juvenile hormone analogs and chitin synthesis inhibitors, processes that have been studied well in Drosophila (De Loof 2008;Moussian 2012). Considering that some fraction of nonconserved genes are also essential for viability in Drosophila (Yamamoto et al 2014a) and that specific nonessential genes are often involved in fitness (Zhang et al 2007), studies of Drosophila genes that do not have obvious direct human homologs remain important.…”

Big Lessons from Tiny Flies:<em> Drosophila Melanogaster </em>as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems

“…The life cycle of Drosophila melanogaster consists of four stages: egg, larva, pupa and fly. The duration of the life cycle is temperature dependent and it is completed in about ten days when the flies are maintained at 25 o C. Drosophila lends itself to large scale genetic screens [3][4][5], cell specific transgene expression [6][7][8] and precise genome editing (reviewed in [9,10]). The availability of this large genetic tool box makes Drosophila an ideal model organism to study conserved biological processes.…”