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Human Molecular Genetics Pages 1745-1754  
Drosophila-related expressed sequences
Expressed Sequence Tags (ESTs):An Overview
ESTs And Human Diseases
Drosophila Melanogaster: An Ideal Model Organism
Drosophila-Related Expressed Sequences
Mapping Of Dres In Humans And Mice
Systematic Expression Studies Of Dres Genes
Dres Database
Acknowledgements
References

Drosophila-related expressed sequences

Drosophila-related expressed sequences

Sandro Banfi, Giuseppe Borsani, Alessandro Bulfone, Andrea Ballabio*

Telethon Institute of Genetics and Medicine (TIGEM), San Raffaele Biomedical Science Park, via Olgettina 58, Milan 20132, Italy

Received July 3, 1997

The study of model organisms has been instrumental towards the elucidation of the basic mechanisms of human biology. Drosophila melanogaster has been the target of extensive genetic analyses over the past 90 years and a notable amount of information is known about its gene structure, gene regulation and gene function. The vast gene resource generated by the expressed sequence tags (ESTs) efforts was exploited to identify, using a bioinformatic approach, novel human and murine gene transcripts homologous to Drosophila mutantgenes. A systematic characterization of these genes, named Drosophila-related expressed sequences (DRES), was performed including genomic mapping in human and mouse and detailed study of their expression pattern by RNA in situ hybridization experiments. Comparison between DRES genes and their putative partners in Drosophila contributes to the understanding of their function in mammals and to the discovery of their possible role in disease.

EXPRESSED SEQUENCE TAGS (ESTs):AN OVERVIEW

The identification of all human genes represents one of the most important aims of the Human Genome Project. It is anticipated that this goal will be achieved in its entirety by the year 2005 through the complete sequencing of the whole human genome. However, in the past 6-7 years, a `shortcut' approach was devised which allowed the scientific community to have access to partial sequence information for a significant number of human genes. This approach was represented by the random sequencing of human cDNA clones which generated the so-called expressed sequence tags (ESTs) (1). A considerable number of reports describing the generation of ESTs from different tissue sources, and even different organisms have been published (2-6).

It was evident that ESTs colinear with genomic DNAs could be easily converted into sequence-tagged sites (STSs) (7) and, therefore, function as landmarks of an expression map of the human genome (1,8). The 3[prime] untranslated region (3[prime]UTR), which usually lacks introns, was the ideal site for the generation of cDNA-specific STSs. This observation led to a rapid shifting of EST generation from random-primed to directionally-cloned oligodT-primed cDNA libraries. Another advantage of the unidirectional libraries is an easier identification of ESTs corresponding to the 5[prime] end of the clone, which more likely corresponds to protein coding sequences of the gene. The exponential accumulation of ESTs deposited in the public databases led to the creation in 1993 of dbEST (Table 1), a separate division of GenBank for ESTs (9).

In October 1994, the Merck-funded EST project spurred a tremendous increase in the number of ESTs deposited in dbEST. This project was carried out by the Genome Sequencing Center at Washington University in St Louis, MO, in collaboration with the IMAGE consortium (10). Most of the cDNA clones sequenced were derived from normalized and arrayed libraries from several human tissues (11). In the course of this project, more than 480 000 ESTs (as of May 14, 1997, http://genome.wustl.edu/est/est_status/est_status.html) produced both from the 5[prime] and the 3[prime] ends of cDNA clones were added to dbEST. This number represents a significant percentage of the total number of public human ESTs, which, as of June 13, 1997, is composed of almost 740 000 entries. The debate over the percentage of human genes which is represented in dbEST is still open. To provide an estimate of the total number of human genes represented in dbEST, Boguski and Schuler (12) at NCBI tried to identify and cluster ESTs belonging to the same human transcript. The results of this computational analysis, which is periodically performed, are stored in the UniGene database that, as of July 1997, contains more than 45 000 clusters. Even taking into consideration the limitations of this computational procedure, there is a general agreement that >50% of all human genes are already present in the public databases, at least as an EST.

ESTs AND HUMAN DISEASES

How is the availability of this enormous amount of information affecting the strategies aimed at the identification of genes involved in human diseases? First of all, it is interesting to note that >80% of positionally cloned genes mutated in human disease states are represented by exact matches with one or more ESTs in dbEST (as of June 1996) (13). There are in fact several examples of human disease genes identified through the screening of EST databases. In 1996, Nigro et al., by sequence homology analysis of dbEST, identified [delta]-sarcoglycan ([delta]-SG), the fourth member of the human SG subcomplex of dystrophin-associated glycoproteins, (14). The three previously known members of this family, [gamma]-SG, [alpha]-SG and [beta]-SG, were found to be responsible for three different forms of limb-girdle muscular dystrophy, LGMD2C, LGMD2D and LGMD2E, respectively. The regional assignment of the EST corresponding to 5q33 suggested that this gene could be involved in LGMD2F, which was previously mapped to the same locus (15). Indeed, mutations in [delta]-SG were found in LGMD2F patients (14). Other notable examples in which the identification of an EST was instrumental in the isolation of a disease gene are represented by the cloning of the genes responsible for hereditary non-polyposis colon cancer (16) and peroxisome biogenesis disorders (17).

Table 1. . List of World Wide Web (WWW) uniform resource locators (URLs) for various resources described in the text
Resources URLs
The Genome Database http://gdbwww.gdb.org/
Human Genome Project Resources http://gdbwww.gdb.org/gdb/hgpResources.html
dbEST http://www.ncbi.nlm.nih.gov/dbEST/index.html
The I.M.A.G.E. Consortium http://www-bio.llnl.gov/bbrp/image/image.html
WashU-Merck Human EST Project http://genome.wustl.edu/est/esthmpg.html
WashU-HHMI Mouse EST Project http://genome.wustl.edu/est/mouse_esthmpg.html
UniGene http://www.ncbi.nlm.nih.gov/Schuler/UniGene
XREF db http://www.ncbi.nlm.nih.gov/XREFdb/
Online Mendelian Inheritance in Man http://www3.ncbi.nlm.nih.gov/omim/
The Human Gene Map http://www.ncbi.nlm.nih.gov/SCIENCE96/
FlyBase http://flybase.bio.indiana.edu:80/
The Drosophila related expressed sequences homepage http://www.tigem.it/LOCAL/drosophila/dros.html
DRES search engine =http://gcg.tigem.it/DRES/dresearch.html
DRES db http://www.tigem.it/LOCAL/drosophila/html/drostable.html

The identification of each of these disease genes has relied on a common strategy, namely the so-called positional candidate gene approach (18) which has become the most effective gene identification strategy thanks to the EST efforts. This strategy relies on a combination of positional and functional data, i.e., the colocalization of a disease locus and a gene whose predicted function is highly suggestive for a causative role in the disease phenotype. We are, in fact, not very far from the scenario in which all human genes will be identified and placed on the chromosome map. In such an ideal situation, the identification of a disease gene would be largely a computer-based exercise in which it is possible to query the genomic region where the disease gene of interest has been assigned, and to select the most attractive candidate in the list of genes mapped to the same region. This strategy could also be applied in the opposite direction: the chromosomal assignment of a gene could be correlated with the list of disease loci mapped to the same genomic region. The latter approach is more suitable for the systematic analysis of a large number of genes as candidates for human inherited disorders. For instance, Neri et al. undertook a large-scale survey of cDNA containing CAG/CTG repeats to identify new candidate genes for inherited neurodegenerative disorders (19).

Comparative genomics represents another promising strategy to assess the function of genes (20) and ultimately to determine their role in both physiological and pathological conditions (16,21-24). In recent years, several human disease genes have been identified on the basis of their similarity to genes mutated in model organisms (16,21).

The complete sequencing of the genome of several organisms (25-27), together with a systematic functional analysis of the genes identified, is facilitating the cross-reference between genes mutated in model organisms and their homologs in man (23).

DROSOPHILA MELANOGASTER: AN IDEAL MODEL ORGANISM

The fruitfly Drosophila melanogaster is one of the most valuable organisms in biological research. This is probably due to the fact that only Drosophila, more than other model organisms, is well-suited for the application of the tools of genetics, biochemistry, molecular biology, electrophysiology and other biological techniques.

Over the past 90 years, most of the knowledge about genetic phenomena such as mutation, recombination and others has been obtained by using Drosophila as a model organism (28). In addition, Drosophila mutants display various and interesting phenotypes. The feasibility of performing systematic genetic screens in Drosophila provides a powerful tool to identify genes involved in essential developmental processes, without any prior knowledge about the biochemical nature of the process itself. Furthermore, molecular genetic analysis is facilitated by the small size of Drosophila genome, which is [sim]1/20 the size of the human genome, and contains [sim]12 000 genes (24).

More than 11 000 genetic loci and 38 000 alleles have been identified to date; for a significant number of them, the genes responsible have been molecularly cloned, using techniques such as chromosome walking and transposon tagging. All this information has been deposited in Flybase, a comprehensive database containing information on the genetics and molecular biology of this organism (29,30).

The identification of additional Drosophila mutant genes and the dissection of their biological functions will be greatly enhanced by the ongoing effort of the Drosophila Genome Project which includes the mapping and sequencing of the entire Drosophila genome as well as the generation of several thousand ESTs (31).

DROSOPHILA-RELATED EXPRESSED SEQUENCES

The remarkable amount of information available makes Drosophila one of the most valuable model organisms to study the function of genes conserved during evolution. There is a considerable number of genes which are highly conserved between humans and Drosophila and play a similar biological role in the two species. More interestingly, the phenotypes caused by mutations in some of these genes can be very similar or affect related systems and organs in both man and fly (32-34). Perhaps the most notable example is represented by the eyeless gene whose human homolog, PAX6, plays a causative role in autosomal dominant aniridia (32).


Figure 1 The goliath-related human gene family. A TBLASTN search against dbEST using as query the Drosophila goliath protein sequence (M97204) reveals the presence of at least four different human cDNAs related to the same Drosophila protein. The sequence accession numbers of the human ESTs are indicated, as well as the DRES numbers (in parentheses).


Therefore, in theory, the systematic identification of human genes similar to genes involved in the generation of mutant phenotypes in Drosophila could provide us with a number of promising candidate genes for human diseases. Furthermore, comparing these novel human genes with genes that have been well characterized in the fly facilitates the process of deciphering their function in mammals. On the basis of this hypothesis we decided to undertake this strategy. While waiting for the complete recognition of all human genes via large scale sequencing approaches, the most obvious reservoir of human transcribed sequences is represented by the EST data. In October 1995, to evaluate the feasibility of this approach, we started to query dbEST using the text query interface available at the NCBI entering the names of some selected Drosophila mutant genes as keywords. As hoped, we were encouraged to observe that a significant percentage of our searches identified human ESTs showing a remarkable similarity to the Drosophila gene product used as query. This was possible since EST sequences in dbEST are periodically run through a BLAST homology search (35) against non-redundant sequence databases, and the best matches for each entry are included in the EST record. These findings stimulated us to pursue an exhaustive search. Introducing all of the Drosophila mutant genes reported at the time in FlyBase as queries, within a few weeks we ended up with 66 uncharacterized human cDNAs which we named DRES (Drosophila-related expressed sequences). The significance of the similarity between each DRES and its Drosophila counterpart was confirmed by performing a BLASTX search against a non-redundant protein database using the human EST as query (36).


Figure 2 Characterization of DRES9 and DRES10 (PPEF): two human cDNAs highly similar to Drosophila retinal degeneration B (rdgB) and C (rdgC) genes, respectively. A BLASTX analysis against a non-redundant protein database reveals significant homology between DRES9 (EST R56391) and Drosophila rdgB protein (a) and between DRES10 (EST H18854) and Drosophila rdgC protein (b). Mapping assignment of DRES9 and DRES10 (PPEF) to the 11q13 (c) and Xp22 (d) regions, respectively, where several loci for human retinopathies (indicated on the right of each chromosome ideogram) have been mapped. (e) and (f) Expression patterns of Dres9 and Dres10, as revealed by RNA in situ hybridization in a 14.5 day old mouse embryo (autoradiography of sagittal sections). Dres9 is remarkably expressed in the eye and at lower levels in the telencephalic cortex (e), while Dres10 (Ppef) shows expression restricted to the trigeminal ganglion and the dorsal root ganglia (f).


Obviously, we were aware that the list of DRES genes identified was not comprehensive, as our search was based exclusively on keywords. For this reason, we adopted a more systematic approach based on an automated dbEST searching procedure. We ran a series of TBLASTN searches using all of the Drosophila melanogaster protein entries as query sequences and dbEST (dynamically translated in all six reading frames) as the target database. We organized the collection of TBLASTN output results in a searchable database named DRES search engine (37).

One of the main advantages of this `TBLASTN-based' procedure is the possibility of performing a periodic analysis of dbEST, thanks to the automation of the entire process. Furthermore, it allows a more immediate identification of DRES members of putative gene families. One example is represented by the putative human GOLIATH gene family: the TBLASTN search versus dbEST performed using the Drosophila Goliath protein as query reveals the presence of at least four different human cDNAs (DRES58, 119, 120 and 121) showing a significant similarity to their Drosophila counterpart (Fig. 1). Similar is the case of the three human cDNAs homologous to the Drosophila eyes absent gene (38); each of these human transcripts is represented in dbEST by at least one EST entry. The presence of multiple human genes related to only one Drosophila sequence has been described several times (24,39,40) and may partially explain the significant difference in the number of genes estimated in the two species [12 000 in Drosophila versus 70 000 in man (24)].

MAPPING OF DRES IN HUMANS AND MICE

The combination of the keyword-based and DRES search engine strategies allowed us to identify 121 DRES (as of May 1997). The degree of similarity between these human cDNAs and their Drosophila counterparts is in all cases highly significant (with P values ranging from 1.4e-70 to 1.1e-06), which suggests the possibility of a conserved function of these genes during evolution.

DRES may thus be considered candidate genes for human disorders whose phenotype resembles that observed in Drosophila. In order to test this hypothesis, the next obvious step is the regional mapping of these transcripts. At the time we started the project (October 1995), very few data on EST mapping were available. For this reason, we decided to map the first set of DRES identified, using a combined approach including both fluorescence in situ hybridization (FISH) and radiation hybrid mapping. Subsequently, a large-scale EST mapping Consortium was started to systematically map by radiation hybrids the EST clusters generated by UniGene, providing the public databases with the regional mapping information for more than 17 000 putative human transcripts (41). Therefore, the screening of databases storing EST mapping information, such as UniGene, now constitutes a preliminary and obligatory step in our DRES mapping strategy. Mapping data for 11 DRES have been obtained simply by screening UniGene and similar databases. In addition, we have determined the regional assignment of 98 DRES using the experimental approach described above. Identification of YAC clones corresponding to each DRES gene is also in progress: this information will provide more precise map assignments, as well as possible physical links with polymorphic markers in the region.

The mapping data are particularly important for the evaluation of DRES as candidate genes for human disorders. DRES may be considered positional candidate genes for human diseases mapped to the corresponding genomic region. This hypothesis is particularly intriguing when the phenotype of the Drosophila mutant resembles the phenotype of the human disease. There are several such examples among DRES genes: two of them are represented by DRES9 and DRES10, which are significantly similar to the Drosophila proteins retinal degeneration B (rdgB) (42) and retinal degeneration C (rdgC) (43), respectively (Fig. 2a and b). These two genes determine light-induced retinal degeneration in the fly (44). We have regionally mapped DRES9 to 11q13 (Fig. 2c) where the loci responsible for at least four types of retinopathies have been mapped, namely Bardet-Biedl syndrome type 1 (BBS1) (45), vitelliform macular dystrophy (VMD2) (46), vitreoretinopathy (VRNI) (47), and exudative vitreoretinopathy-1 (48). Similarly, DRES10 was mapped to Xp22 (Fig. 2d), the region known to harbor the locus for X-linked juvenile retinoschisis (49). Based on the sequence homology and mapping assignment, both these human cDNAs could be considered very strong candidates for human retinopathies (see below).

The identification of DRES genes responsible for human disorders can be difficult for several reasons. Firstly, most of the standard procedures used for mutation detection require the determination of the genomic structure of the gene under examination, which is a time-consuming process. Secondly, in many cases, candidate diseases are clinically heterogeneous, which hampers the collection of an appropriate subset of patients to be tested. Thirdly, many genetic diseases either have not been mapped yet or have not been assigned with sufficient accuracy to a given chromosomal region. Nevertheless, the involvement of DRES genes in human disorders has already been demonstrated in a few instances. A novel homeobox-containing gene with significant similarity to the Drosophila Goosecoid (DRES112) has been found to be mutated in Rieger syndrome, an autosomal dominant disorder characterized by ocular anterior chamber anomalies, dental hypoplasia and cranofacial dysmorphism (50). Furthermore, DRES43 corresponds to DPC4, a gene mutated in patients with pancreatic carcinomas carrying deletions of the 18q21 region (51); this finding suggests that DRES genes can also be involved in somatic mutations.

Murine homologs of DRES genes (Dres) could also represent candidates for mouse mutant phenotypes, both spontaneous or induced. Accordingly, we decided to determine the mapping assignment of Dres cDNAs in the mouse genome in order to anchor their location to existing genetic maps. To systematically identify murine Dres genes, besides using standard experimental approaches such as library screening and PCR-based techniques, we took advantage of the presence of over 190 000 mouse ESTs in dbEST, mainly generated by the WashU-HHMI Mouse EST Project. This expanding resource allows us to perform in many cases a bioinformatic identification of murine Dres, simply by running a BLASTN search against dbEST using human DRES nucleotide sequences as queries. These cDNAs are currently used for mapping experiments through the analysis of strain-specific polymorphisms on interspecific backcross DNA panels. The mapping assignment of Dres genes will provide a catalog of positional candidates for mouse mutant phenotypes. This catalog will be more and more valuable as the number of regionally mapped murine mutant phenotypes increases. The ongoing large scale systematic generations of mouse mutants represents promising strategies towards this goal (52).


Figure 3 The Drosophila-Related Expressed Sequence homepage (http://www.tigem.it/LOCAL/drosophila/dros.html) allows easy retrieval of all data generated by the DRES project and contains links to the DRES database and the DRES search engine pages.

SYSTEMATIC EXPRESSION STUDIES OF DRES GENES

In addition to sequence homology, a homologous pattern of gene expression is a common criterion used to diagnose the phylogenetic descent of two genes and their functional conservation. In fact, genes that are themselves homologous may be involved in disparate and non-homologous developmental processes and be expressed in non-homologous structures. One paradigmatic example is represented by EYA1, a human homolog of the Drosophila eyes absent, a gene required in the fly for survival and differentiation of eye progenitor cells. Mutations in the EYA1 gene have been found in patients with branchio-oto-renal (BOR) syndrome (38), a genetic disorder characterized by branchial arch and renal anomalies, as well as hearing impairment. EYA1 does not seem to play any role in the development of the eye in mammals, which is confirmed by the lack of expression in the eye (38) and by the absence of any ocular abnormalities in BOR patients.

Taking into account these considerations, we decided to perform a detailed and systematic study of the expression of DRES genes in mammals, both during development and in adult tissues. Towards this goal, we decided to use RNA in situ hybridization, a technique which allows very accurate analysis of the spatial and temporal pattern of expression of gene transcripts. We are carrying out this analysis on mouse embryonic and adult tissue sections using as probes the murine homologs of DRES. An example of the usefulness of the expression studies of Dres genes is represented by the analysis of the expression of Dres9 and Dres10 (Fig. 2).

RNA in situ hybridization studies performed on mouse embryo tissue sections at various developmental stages revealed that Dres9, similar to its Drosophila rdgB counterpart, is expressed at very high levels in the neural retina (53) (Fig. 2E). This finding supports the possible involvement of DRES9 in human retinopathies, which was also suggested by its mapping assignment (Fig. 2C). Conversely, Dres10, unlike its putative Drosophila homolog rdgC, was not found to be expressed in retina in all stages examined but was highly and exclusively expressed in sensory neurons of the peripheral nervous system (Fig. 2F). DRES10 has been identified in our laboratory also by a positional cloning effort from the Xp22 region and termed PPEF (54). Mutation analysis of the PPEF gene excluded it from being a candidate for retinoschisis, which is not surprising considering its expression pattern in mouse.

These systematic expression studies will provide useful information on the putative function of DRES genes in vertebrates and their possible involvement in human inherited disorders. Moreover, the correlation with the expression pattern of the corresponding Drosophila genes will be helpful in assessing a conserved function of these genes during evolution. More specific insights into the biological role of these transcripts in mammals will be derived by the study of knockout mice carrying null mutations of Dres genes.

In summary, the suggestion of the involvement of a given DRES in human and/or mouse inherited disorders arises from the global evaluation of sequence homology and mapping assignment data, integrated with the analysis of their expression patterns.

DRES DATABASE

We created the DRES database (DRES db) (Table 1) containing findings generated at TIGEM integrated with information retrieved from external databases such as GenBank, FlyBase, Unigene, OMIM, etc. The data are accessible through interactive World Wide Web on the DRES homepage (Fig. 3).

For each DRES, the following types of data are available:

(i) GenBank accession number: a direct link to dbEST at NCBI allows the retrieval of all relevant information on the cDNA clone from which the EST was originally generated.

(ii) Drosophila gene and gene symbol: all available information for every Drosophila gene can be retrieved from FlyBase, including a detailed description of the Drosophila phenotype integrated with molecular biology data and bibliographic references.

(iii) Drosophila sequence accession number: a hypertext link to the Drosophila sequence deposited in public databases.

(iv) BlastX P value: a link to the BLASTX output obtained using each DRES as query sequence against a non-redundant protein database. This allows a visualization of the degree of homology between the human and the Drosophila sequences.

(v) UniGene entry: this link makes it possible to determine whether a given DRES is present in a UniGene cluster.

(vi) Additional sequence information: in this field, all additional sequence data generated on DRES can be retrieved, including human and/or murine full-length transcripts.

(vii) Mapping data: this field contains all DRES mapping information generated as previously described, including FISH and radiation hybrids, as well as mapping data generated by other genome centers. In addition, a direct link to the gene map of the OMIM database allows the retrieval of all human diseases mapped to the corresponding genomic region.

(viii) Expression data (to be implemented): a link to the Gene Expression Database (GXD) (55) will allow the retrieval of video frames generated for any relevant in situ hybridization experiment.

The DRES database constitutes a valuable tool which facilitates both the evaluation of DRESs as candidate genes for human diseases and the understanding of their biological role in mammals.

ACKNOWLEDGEMENTS

We wish to thank Gyorgy Simon and Alessandro Guffanti for bioinformatic support, Massimo Zollo and the Tigem Sequencing Core and Melissa Smith for preparation of this manuscript. The financial support of the Italian Telethon Foundation (Grant n. B.37) is gratefully acknowledged.

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* To whom correspondence should be addressed. Tel: +39 2 2156 0206; Fax: +39 2 2156 0220; Email: ballabio@tigem.it

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