Dataset Information

The haplolethal region at the 16F gene cluster of Drosophila melanogaster: structure and function.

ABSTRACT: Extensive aneuploid analyses had shown the existence of a few haplolethal (HL) regions and one triplolethal region in the genome of Drosophila melanogaster. Since then, only two haplolethals, 22F1-2 and 16F, have been directly linked to identified genes, dpp and wupA, respectively. However, with the possible exception of dpp, the actual bases for this dosage sensitivity remain unknown. We have generated and characterized dominant-lethal mutations and chromosomal rearrangements in 16F and studied them in relation to the genes in the region. This region extends along 100 kb and includes at least 14 genes. The normal HL function depends on the integrity of a critical 4-kb window of mostly noncoding sequences within the wupA transcription unit that encodes the muscle protein troponin I (TNI). All dominant lethals are breakpoints within that window, which prevent the functional expression of TNI and other adjacent genes in the proximal direction. However, independent mutations in these genes result in recessive lethal phenotypes only. We propose that the HL at 16F represents a long-range cis regulatory region that acts upon a number of functionally related genes whose combined haploidy would yield the dominant-lethal effect.

SUBMITTER: Prado A

PROVIDER: S-EPMC1460474 | biostudies-other | 1999 Jan

REPOSITORIES: biostudies-other

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The haplolethal region at the 16F gene cluster of Drosophila melanogaster: structure and function.

Prado A A Canal I I Ferrús A A

Genetics 19990101 1

Extensive aneuploid analyses had shown the existence of a few haplolethal (HL) regions and one triplolethal region in the genome of Drosophila melanogaster. Since then, only two haplolethals, 22F1-2 and 16F, have been directly linked to identified genes, dpp and wupA, respectively. However, with the possible exception of dpp, the actual bases for this dosage sensitivity remain unknown. We have generated and characterized dominant-lethal mutations and chromosomal rearrangements in 16F and studied ...[more]

PMID: 9872957

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Project description:Using a complete set of RING domains from Drosophila melanogaster, all the solved RING domains and cocrystal structures of RING-containing ubiquitin-ligases (RING-E3) and ubiquitin-conjugating enzyme (E2) pairs, we analyzed RING domains structures from their primary to quarternary structures. The results showed that: i) putative orthologs of RING domains between Drosophila melanogaster and the human largely occur (118/139, 84.9%); ii) of the 118 orthologous pairs from Drosophila melanogaster and the human, 117 pairs (117/118, 99.2%) were found to retain entirely uniform domain architectures, only Iap2/Diap2 experienced evolutionary expansion of domain architecture; iii) 4 evolutionary structurally conserved regions (SCRs) are responsible for homologous folding of RING domains at the superfamily level; iv) besides the conserved Cys/His chelating zinc ions, 6 equivalent residues (4 hydrophobic and 2 polar residues) in the SCRs possess good-consensus and conservation- these 4 SCRs function in the structural positioning of 6 equivalent residues as determinants for RING-E3 catalysis; v) members of these RING proteins located nucleus, multiple subcellular compartments, membrane protein and mitochondrion are respectively 42 (42/139, 30.2%), 71 (71/139, 51.1%), 22 (22/139, 15.8%) and 4 (4/139, 2.9%); vi) CG15104 (Topors) and CG1134 (Mul1) in C3HC4, and CG3929 (Deltex) in C3H2C3 seem to display broader E2s binding profiles than other RING-E3s; vii) analyzing intermolecular interfaces of E2/RING-E3 complexes indicate that residues directly interacting with E2s are all from the SCRs in RING domains. Of the 6 residues, 2 hydrophobic ones contribute to constructing the conserved hydrophobic core, while the 2 hydrophobic and 2 polar residues directly participate in E2/RING-E3 interactions. Based on sequence and structural data, SCRs, conserved equivalent residues and features of intermolecular interfaces were extracted, highlighting the presence of a nucleus for RING domain fold and formation of catalytic core in which related residues and regions exhibit preferential evolutionary conservation.

Project description:BACKGROUND:While the genomes of hundreds of organisms have been sequenced and good approaches exist for finding protein encoding genes, an important remaining challenge is predicting the functions of the large fraction of genes for which there is no annotation. Large gene expression datasets from microarray experiments already exist and many of these can be used to help assign potential functions to these genes. We have applied Support Vector Machines (SVM), a sigmoid fitting function and a stratified cross-validation approach to analyze a large microarray experiment dataset from Drosophila melanogaster in order to predict possible functions for previously un-annotated genes. A total of approximately 5043 different genes, or about one-third of the predicted genes in the D. melanogaster genome, are represented in the dataset and 1854 (or 37%) of these genes are un-annotated. RESULTS:39 Gene Ontology Biological Process (GO-BP) categories were found with precision value equal or larger than 0.75, when recall was fixed at the 0.4 level. For two of those categories, we have provided additional support for assigning given genes to the category by showing that the majority of transcripts for the genes belonging in a given category have a similar localization pattern during embryogenesis. Additionally, by assessing the predictions using a confidence score, we have been able to provide a putative GO-BP term for 1422 previously un-annotated genes or about 77% of the un-annotated genes represented on the microarray and about 19% of all of the un-annotated genes in the D. melanogaster genome. CONCLUSIONS:Our study successfully employs a number of SVM classifiers, accompanied by detailed calibration and validation techniques, to generate a number of predictions for new annotations for D. melanogaster genes. The applied probabilistic analysis to SVM output improves the interpretability of the prediction results and the objectivity of the validation procedure.

Dataset Information

The haplolethal region at the 16F gene cluster of Drosophila melanogaster: structure and function.

Publications

The haplolethal region at the 16F gene cluster of Drosophila melanogaster: structure and function.

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