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Michael Hiller

Publications and source records attributed to Michael Hiller.

11 recordsLinked to original sources
PubMed2026

Lack of Evidence for Gene-Level Convergence Linked to Evolutionary Shifts in Torpor Among Placental Mammals.

Torpor is a key survival strategy that many avian and mammalian lineages evolved in response to challenging environmental conditions. Whether the independent evolution of torpor in different lineages involved changes in the same genes remains poorly understood. Here, we performed comparative screens across 190 placental mammal genomes to comprehensively examine associations between loss, positive selection, and evolutionary rate shifts in individual protein-coding genes and evolutionary shifts in torpor use. We find that gene-torpor associations are highly clade-specific, with no gene being able to explain the majority of torpor shifts across the phylogeny of placental mammals. In contrast, there is more evidence, albeit still limited, for evolutionary convergence at the pathway level. Our results suggest that torpor emerged through several genetic routes in placental mammals, which likely explains the vast diversity of torpor use patterns that can be observed among torpor-capable species today.

Animals↗
PubMed2006

TassDB: a database of alternative tandem splice sites.

Subtle alternative splice events at tandem splice sites are frequent in eukaryotes and substantially increase the complexity of transcriptomes and proteomes. We have developed a relational database, TassDB (TAndem Splice Site DataBase), which stores extensive data about alternative splice events at GYNGYN donors and NAGNAG acceptors. These splice events are of subtle nature since they mostly result in the insertion/deletion of a single amino acid or the substitution of one amino acid by two others. Currently, TassDB contains 114 554 tandem splice sites of eight species, 5209 of which have EST/mRNA evidence for alternative splicing. In addition, human SNPs that affect NAGNAG acceptors are annotated. The database provides a user-friendly interface to search for specific genes or for genes containing tandem splice sites with specific features as well as the possibility to download large datasets. This database should facilitate further experimental studies and large-scale bioinformatics analyses of tandem splice sites. The database is available at http://helios.informatik.uni-freiburg.de/TassDB/.

Alternative Splicing↗
PubMed2006

Using RNA secondary structures to guide sequence motif finding towards single-stranded regions.

RNA binding proteins recognize RNA targets in a sequence specific manner. Apart from the sequence, the secondary structure context of the binding site also affects the binding affinity. Binding sites are often located in single-stranded RNA regions and it was shown that the sequestration of a binding motif in a double-strand abolishes protein binding. Thus, it is desirable to include knowledge about RNA secondary structures when searching for the binding motif of a protein. We present the approach MEMERIS for searching sequence motifs in a set of RNA sequences and simultaneously integrating information about secondary structures. To abstract from specific structural elements, we precompute position-specific values measuring the single-strandedness of all substrings of an RNA sequence. These values are used as prior knowledge about the motif starts to guide the motif search. Extensive tests with artificial and biological data demonstrate that MEMERIS is able to identify motifs in single-stranded regions even if a stronger motif located in double-strand parts exists. The discovered motif occurrences in biological datasets mostly coincide with known protein-binding sites. This algorithm can be used for finding the binding motif of single-stranded RNA-binding proteins in SELEX or other biological sequence data.

Algorithms↗
PubMed2006

Phylogenetically widespread alternative splicing at unusual GYNGYN donors.

BACKGROUND: Splice donor sites have a highly conserved GT or GC dinucleotide and an extended intronic consensus sequence GTRAGT that reflects the sequence complementarity to the U1 snRNA. Here, we focus on unusual donor sites with the motif GYNGYN (Y stands for C or T; N stands for A, C, G, or T). RESULTS: While only one GY functions as a splice donor for the majority of these splice sites in human, we provide computational and experimental evidence that 110 (1.3%) allow alternative splicing at both GY donors. The resulting splice forms differ in only three nucleotides, which results mostly in the insertion/deletion of one amino acid. However, we also report the insertion of a stop codon in four cases. Investigating what distinguishes alternatively from not alternatively spliced GYNGYN donors, we found differences in the binding to U1 snRNA, a strong correlation between U1 snRNA binding strength and the preferred donor, over-represented sequence motifs in the adjacent introns, and a higher conservation of the exonic and intronic flanks between human and mouse. Extending our genome-wide analysis to seven other eukaryotic species, we found alternatively spliced GYNGYN donors in all species from mouse to Caenorhabditis elegans and even in Arabidopsis thaliana. Experimental verification of a conserved GTAGTT donor of the STAT3 gene in human and mouse reveals a remarkably similar ratio of alternatively spliced transcripts in both species. CONCLUSION: In contrast to alternative splicing in general, GYNGYN donors in addition to NAGNAG acceptors enable subtle protein variations.

Alternative Splicing↗
PubMed2005

Single-nucleotide polymorphisms in NAGNAG acceptors are highly predictive for variations of alternative splicing.

Aberrant or modified splicing patterns of genes are causative for many human diseases. Therefore, the identification of genetic variations that cause changes in the splicing pattern of a gene is important. Elsewhere, we described the widespread occurrence of alternative splicing at NAGNAG acceptors. Here, we report a genomewide screen for single-nucleotide polymorphisms (SNPs) that affect such tandem acceptors. From 121 SNPs identified, we extracted 64 SNPs that most likely affect alternative NAGNAG splicing. We demonstrate that the NAGNAG motif is necessary and sufficient for this type of alternative splicing. The evolutionarily young NAGNAG alleles, as determined by the comparison with the chimpanzee genome, exhibit the same biases toward intron phase 1 and single-amino acid insertion/deletions that were already observed for all human NAGNAG acceptors. Since 28% of the NAGNAG SNPs occur in known disease genes, they represent preferable candidates for a more-detailed functional analysis, especially since the splice relevance for some of the coding SNPs is overlooked. Against the background of a general lack of methods for identifying splice-relevant SNPs, the presented approach is highly effective in the prediction of polymorphisms that are causal for variations in alternative splicing.

Alleles↗
PubMed2005

Non-EST based prediction of exon skipping and intron retention events using Pfam information.

Most of the known alternative splice events have been detected by the comparison of expressed sequence tags (ESTs) and cDNAs. However, not all splice events are represented in EST databases since ESTs have several biases. Therefore, non-EST based approaches are needed to extend our view of a transcriptome. Here, we describe a novel method for the ab initio prediction of alternative splice events that is solely based on the annotation of Pfam domains. Furthermore, we applied this approach in a genome-wide manner to all human RefSeq transcripts and predicted a total of 321 exon skipping and intron retention events. We show that this method is very reliable as 78% (250 of 321) of our predictions are confirmed by ESTs or cDNAs. Subsequent analyses of splice events within Pfam domains revealed a significant preference of alternative exon junctions to be located at the protein surface and to avoid secondary structure elements. Thus, splice events within Pfams are probable to alter the structure and function of a domain which makes them highly interesting for detailed biological investigation. As Pfam domains are annotated in many other species, our strategy to predict exon skipping and intron retention events might be important for species with a lower number of ESTs.

Algorithms↗
PubMed2005

Creation and disruption of protein features by alternative splicing -- a novel mechanism to modulate function.

BACKGROUND: Alternative splicing often occurs in the coding sequence and alters protein structure and function. It is mainly carried out in two ways: by skipping exons that encode a certain protein feature and by introducing a frameshift that changes the downstream protein sequence. These mechanisms are widespread and well investigated. RESULTS: Here, we propose an additional mechanism of alternative splicing to modulate protein function. This mechanism creates a protein feature by putting together two non-consecutive exons or destroys a feature by inserting an exon in its body. In contrast to other mechanisms, the individual parts of the feature are present in both splice variants but the feature is only functional in the splice form where both parts are merged. We provide evidence for this mechanism by performing a genome-wide search with four protein features: transmembrane helices, phosphorylation and glycosylation sites, and Pfam domains. CONCLUSION: We describe a novel type of event that creates or removes a protein feature by alternative splicing. Current data suggest that these events are rare. Besides the four features investigated here, this mechanism is conceivable for many other protein features, especially for small linear protein motifs. It is important for the characterization of functional differences of two splice forms and should be considered in genome-wide annotation efforts. Furthermore, it offers a novel strategy for ab initio prediction of alternative splice events.

Alternative Splicing↗
PubMed2004

Widespread occurrence of alternative splicing at NAGNAG acceptors contributes to proteome plasticity.

Splice acceptors with the genomic NAGNAG motif may cause NAG insertion-deletions in transcripts, occur in 30% of human genes and are functional in at least 5% of human genes. We found five significant biases indicating that their distribution is nonrandom and that they are evolutionarily conserved and tissue-specific. Because of their subtle effects on mRNA and protein structures, these splice acceptors are often overlooked or underestimated, but they may have a great impact on biology and disease.

Alternative Splicing↗
PubMed2004

Efficient prediction of alternative splice forms using protein domain homology.

Alternative splicing can yield manifold different mature mRNAs from one precursor. New findings indicate that alternative splicing occurs much more often than previously assumed. A major goal of functional genomics lies in elucidating and characterizing the entire spectrum of alternative splice forms. Existing approaches such as EST-alignments focus only on the mRNA sequence to detect alternative splice forms. They do not consider function and characteristics of the resulting proteins. One important example of such functional characterization is homology to a known protein domain family. A powerful description of protein domains are profile Hidden Markov models (HMM) as stored in the Pfam database. In this paper we address the problem of identifying the splice form with the highest similarity to a protein domain family. Therefore, we take into consideration all possible splice forms. As demonstrated here for a number of genes, this homology based approach can be used successfully for predicting partial gene structures. Furthermore, we present some novel splice form predictions with high-scoring protein domain homology and point out that the detection of splice form specific protein domains helps to answer questions concerning hereditary diseases. Simple approaches based on a BLASTP search cannot be applied here, since the number of possible splice forms increases exponentially with the number of exons. To this end, we have developed an efficient polynomial-time algorithm, called ASFPred (Alternative Splice Form Prediction). This algorithm needs only a set of exons as input.

Algorithms↗