A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster

Abstract

We performed a systematic analysis of 929 human disease gene entries associated with at least one mutant allele in the Online Mendelian Inheritance in Man (OMIM) database against the recently completed genome sequence of Drosophila melanogaster. The results of this search have been formatted as an updateable and searchable on-line database called Homophila. Our analysis identified 714 distinct human disease genes (77% of disease genes searched) matching 548 unique Drosophila sequences, which we have summarized by disease category. This breakdown into disease classes creates a picture of disease genes that are amenable to study using Drosophila as the model organism. Of the 548 Drosophila genes related to human disease genes, 153 are associated with known mutant alleles and 56 more are tagged by P-element insertions in or near the gene. Examples of how to use the database to identify Drosophila genes related to human disease genes are presented. We anticipate that cross-genomic analysis of human disease genes using the power of Drosophila second-site modifier screens will promote interaction between human and Drosophila research groups, accelerating the understanding of the pathogenesis of human genetic disease. The Homophila database is available at http://homophila.sdsc.edu.

Figure 1

How to query the Homophila database. (A) Schematic of a Homophila query. The user enters the text query in the form of human disease name, Online Mendelian Inheritance in Man (OMIM) number, fly gene name, or keyword search through the human disease entry box. The database then opens a window with information on the disease name, and human and fly genes that match the key word query. The user then can examine the details of an individual human to Drosophila BLAST comparison to get more information on the specific BLAST score, alignment, and other hits to this gene. In addition, P-element information is found at this level. (B) Example Homophila query using the keyword “neuropathy”. The user enters the key word and the database will return any human entry or Drosophila gene description that contains the key word. In this case, there are several human neuropathies listed, including a gene for peripheral neuropathy, which is a transcription factor (Krox20). By clicking the “details” button in this first window, one can examine the particular BLAST comparisons of the human genes to Drosophila genes as well as the P-element information. By scrolling down in this window, one can look at particular alignments between the query sequence and its Drosophila matches. In this case, the human Krox20 matches Drosophila stripe gene most strongly in the DNA-binding domains, but also retains some overall sequence similarity in other domains as can clearly be seen on the color graphical alignment of similar sequences.

Figure 1

How to query the Homophila database. (A) Schematic of a Homophila query. The user enters the text query in the form of human disease name, Online Mendelian Inheritance in Man (OMIM) number, fly gene name, or keyword search through the human disease entry box. The database then opens a window with information on the disease name, and human and fly genes that match the key word query. The user then can examine the details of an individual human to Drosophila BLAST comparison to get more information on the specific BLAST score, alignment, and other hits to this gene. In addition, P-element information is found at this level. (B) Example Homophila query using the keyword “neuropathy”. The user enters the key word and the database will return any human entry or Drosophila gene description that contains the key word. In this case, there are several human neuropathies listed, including a gene for peripheral neuropathy, which is a transcription factor (Krox20). By clicking the “details” button in this first window, one can examine the particular BLAST comparisons of the human genes to Drosophila genes as well as the P-element information. By scrolling down in this window, one can look at particular alignments between the query sequence and its Drosophila matches. In this case, the human Krox20 matches Drosophila stripe gene most strongly in the DNA-binding domains, but also retains some overall sequence similarity in other domains as can clearly be seen on the color graphical alignment of similar sequences.

Figure 1

How to query the Homophila database. (A) Schematic of a Homophila query. The user enters the text query in the form of human disease name, Online Mendelian Inheritance in Man (OMIM) number, fly gene name, or keyword search through the human disease entry box. The database then opens a window with information on the disease name, and human and fly genes that match the key word query. The user then can examine the details of an individual human to Drosophila BLAST comparison to get more information on the specific BLAST score, alignment, and other hits to this gene. In addition, P-element information is found at this level. (B) Example Homophila query using the keyword “neuropathy”. The user enters the key word and the database will return any human entry or Drosophila gene description that contains the key word. In this case, there are several human neuropathies listed, including a gene for peripheral neuropathy, which is a transcription factor (Krox20). By clicking the “details” button in this first window, one can examine the particular BLAST comparisons of the human genes to Drosophila genes as well as the P-element information. By scrolling down in this window, one can look at particular alignments between the query sequence and its Drosophila matches. In this case, the human Krox20 matches Drosophila stripe gene most strongly in the DNA-binding domains, but also retains some overall sequence similarity in other domains as can clearly be seen on the color graphical alignment of similar sequences.

Figure 2

Number of Drosophila sequences related to human disease genes as a function of E-value. A graph of the percent of human disease genes with similar sequences in Drosophila as a function of E-value. Black-filled bars indicate the percent of human Locuslink entries (929 total) with matches to Drosophila sequences. White-filled bars indicate the percent of unique Drosophila sequences that match one or more human disease gene sequences. Note that even at E-values of ≤10⁻⁴⁰, 54% of human disease genes have matches to Drosophila sequences.

Figure 3

Relationship of a components position in the bone morphogenetic protein (BMP) pathway to human disease phenotypes. In general, there is a relationship between the position of a component in signaling pathway to the disease phenotype resulting from inactivation of that component. An example of this trend is the BMP pathway. Mutations in components acting at the start of the BMP signal transduction cascade such as a particular BMP ligand (e.g., Drosophila Dpp = Human BMP4/BMP2) or a specialized BMP type I receptor (Drosophila Saxophone = type I receptor for the Screw and Glass Bottom Boat ligands) result in specific developmental defects (e.g., brachydactyly). Mutations acting on subsequent steps in the BMP pathway, which mediate the effects of several converging upstream inputs such as the universal type II BMP receptor (e.g., Drosophila Punt = type II receptor mediating all BMP signaling) or the cytoplasmic/nuclear SMAD transducer (e.g., Drosophila Medea = Human SMAD4) result in generalized misregulation of cellular growth control and cancer (e.g., colorectal or pancreatic cancer).