Andre Kahles, Dr. rer. nat.

Even in science there is some room for optimism.

Post Doc

E-Mail
andre.kahles@get-your-addresses-elsewhere.inf.ethz.ch
Phone
+41 43 254 0224
Address
Biomedical Informatics Group
Schmelzbergstrasse 26
SHM 26 B 3
8006 Zürich
Room
SHM 26 B 3

My scientific background is in computer science, specifically bioinformatics, where I am most interested in algorithms and data structures that make efficient computation on large, population scale sequencing data sets possible.

I completed my undergraduate training at Friedrich Schiller University in Jena, Germany, and finished my Diplom thesis as a joint work with the Stockholm Bioinformatics Centre in Sweden. In 2009 I joined the Friedrich Miescher Laboratory of the Max Planck Society in Tübingen, Germany, to take up me graduate training. Mostly working on algorithms for genome and transcriptome analysis in model organisms during my time in Tübingen, I moved to the analysis of human transcriptomes when looking into large scale cancer sequencing projects in my second part of the PhD at the Memorial Sloan Kettering Cancer Center in New York City, USA. After graduating in 2014, I stayed two more years in New York, working under a fellowship of the Lucille Castori Center for Microbes, Inflammation and Cancer on efficient data structures for the representation of large collections of mixed sequences, such as whole metagenome sequencing samples. Since 2016 I am a member of the Biomedical Informatics group at ETH, working on graph representations of large sequence sets.

Abstract Cancer is characterised by somatic genetic variation, but the effect of the majority of non-coding somatic variants and the interface with the germline genome are still unknown. We analysed the whole genome and RNA-seq data from 1,188 human cancer patients as provided by the Pan-cancer Analysis of Whole Genomes (PCAWG) project to map cis expression quantitative trait loci of somatic and germline variation and to uncover the causes of allele-specific expression patterns in human cancers. The availability of the first large-scale dataset with both whole genome and gene expression data enabled us to uncover the effects of the non-coding variation on cancer. In addition to confirming known regulatory effects, we identified novel associations between somatic variation and expression dysregulation, in particular in distal regulatory elements. Finally, we uncovered links between somatic mutational signatures and gene expression changes, including TERT and LMO2, and we explained the inherited risk factors in APOBEC-related mutational processes. This work represents the first large-scale assessment of the effects of both germline and somatic genetic variation on gene expression in cancer and creates a valuable resource cataloguing these effects.

Authors Claudia Calabrese, Kjong-Van Lehmann, Lara Urban, Fenglin Liu, Serap Erkek, Nuno Fonseca, Andre Kahles, Leena Helena Kilpinen-Barrett, Julia Markowski, PCAWG-3, Sebastian Waszak, Jan Korbel, Zemin Zhang, Alvis Brazma, Gunnar Raetsch, Roland Schwarz, Oliver Stegle

Submitted bioRxiv

Link DOI

Abstract Most human protein-coding genes are regulated by multiple, distinct promoters, suggesting that the choice of promoter is as important as its level of transcriptional activity. While the role of promoters as driver elements in cancer has been recognized, the contribution of alternative promoters to regulation of the cancer transcriptome remains largely unexplored. Here we show that active promoters can be identified using RNA-Seq data, enabling the analysis of promoter activity in more than 1,000 cancer samples with matched whole genome sequencing data. We find that alternative promoters are a major contributor to tissue-specific regulation of isoform expression and that alternative promoters are frequently deregulated in cancer, affecting known cancer-genes and novel candidates. Noncoding passenger mutations are enriched at promoters of genes with lower regulatory complexity, whereas noncoding driver mutations occur at genes with multiple promoters, often affecting the promoter that shows the highest level of activity. Together our study demonstrates that the landscape of active promoters shapes the cancer transcriptome, opening many opportunities to further explore the interplay of regulatory mechanism and noncoding somatic mutations with transcriptional aberrations in cancer.

Authors Deniz Demircioğlu, Martin Kindermans, Tannistha Nandi, Engin Cukuroglu, Claudia Calabrese, Nuno A. Fonseca, Andre Kahles, Kjong Lehmann, Oliver Stegle, PCAWG-3, PCAWG-Network, Alvis Brazma, Angela Brooks, Gunnar Rätsch, Patrick Tan, Jonathan Göke

Submitted bioRxiv

Link DOI

Abstract To understand the population genetics of structural variants and their effects on phenotypes, we developed an approach to mapping structural variants that segregate in a population sequenced at low coverage. We avoid calling structural variants directly. Instead, the evidence for a potential structural variant at a locus is indicated by variation in the counts of short-reads that map anomalously to that locus. These structural variant traits are treated as quantitative traits and mapped genetically, analogously to a gene expression study. Association between a structural variant trait at one locus, and genotypes at a distant locus indicate the origin and target of a transposition. Using ultra-low-coverage (0.3×) population sequence data from 488 recombinant inbred Arabidopsis thaliana genomes, we identified 6502 segregating structural variants. Remarkably, 25% of these were transpositions. While many structural variants cannot be delineated precisely, we validated 83% of 44 predicted transposition breakpoints by polymerase chain reaction. We show that specific structural variants may be causative for quantitative trait loci for germination and resistance to infection by the fungus Albugo laibachii, isolate Nc14. Further we show that the phenotypic heritability attributable to read-mapping anomalies differs from, and, in the case of time to germination and bolting, exceeds that due to standard genetic variation. Genes within structural variants are also more likely to be silenced or dysregulated. This approach complements the prevalent strategy of structural variant discovery in fewer individuals sequenced at high coverage. It is generally applicable to large populations sequenced at low-coverage, and is particularly suited to mapping transpositions.

Authors Martha Imprialou, André Kahles, Joshua G. Steffen, Edward J. Osborne, Xiangchao Gan, Janne Lempe, Amarjit Bhomra, Eric Belfield, Anne Visscher, Robert Greenhalgh, Nicholas P Harberd, Richard Goram, Jotun Hein, Alexandre Robert-Seilaniantz, Jonathan Jones, Oliver Stegle, Paula Kover, Miltos Tsiantis, Magnus Nordborg, Gunnar Rätsch, Richard M. Clark andRichard Mott

Submitted Genetics

Link DOI

Authors Natalie R. Davidson, ; PanCancer Analysis of Whole Genomes 3 (PCAWG-3) for ICGC, Alvis Brazma, Angela N. Brooks, Claudia Calabrese, Nuno A. Fonseca, Jonathan Goke, Yao He, Xueda Hu, Andre Kahles, Kjong-Van Lehmann, Fenglin Liu, Gunnar Rätsch, Siliang Li, Roland F. Schwarz, Mingyu Yang, Zemin Zhang, Fan Zhang and Liangtao Zheng

Submitted Proceedings of the American Association for Cancer Research Annual Meeting 2017

Link DOI

Abstract Plants use light as source of energy and information to detect diurnal rhythms and seasonal changes. Sensing changing light conditions is critical to adjust plant metabolism and to initiate developmental transitions. Here, we analyzed transcriptome-wide alterations in gene expression and alternative splicing (AS) of etiolated seedlings undergoing photomorphogenesis upon exposure to blue, red, or white light. Our analysis revealed massive transcriptome reprogramming as reflected by differential expression of ∼20% of all genes and changes in several hundred AS events. For more than 60% of all regulated AS events, light promoted the production of a presumably protein-coding variant at the expense of an mRNA with nonsense-mediated decay-triggering features. Accordingly, AS of the putative splicing factor REDUCED RED-LIGHT RESPONSES IN CRY1CRY2 BACKGROUND1, previously identified as a red light signaling component, was shifted to the functional variant under light. Downstream analyses of candidate AS events pointed at a role of photoreceptor signaling only in monochromatic but not in white light. Furthermore, we demonstrated similar AS changes upon light exposure and exogenous sugar supply, with a critical involvement of kinase signaling. We propose that AS is an integration point of signaling pathways that sense and transmit information regarding the energy availability in plants.

Authors Hartmann L, Drewe-Boß P, Wießner T, Wagner G, Geue S, Lee HC, Obermüller DM, Kahles A, Behr J, Sinz FH, Rätsch G, Wachter A

Submitted Plant Cell

Link DOI

Abstract Understanding the occurrence and regulation of alternative splicing (AS) is a key task towards explaining the regulatory processes that shape the complex transcriptomes of higher eukaryotes. With the advent of high-throughput sequencing of RNA (RNA-Seq), the diversity of AS transcripts could be measured at an unprecedented depth. Although the catalog of known AS events has grown ever since, novel transcripts are commonly observed when working with less well annotated organisms, in the context of disease, or within large populations. Whereas an identification of complete transcripts is technically challenging and computationally expensive, focusing on single splicing events as a proxy for transcriptome characteristics is fruitful and sufficient for a wide range of analyses.

Authors Andre Kahles, Cheng Soon Ong, Yi Zhong, Gunnar Rätsch

Submitted Bioinformatics (Oxford, England)

Link Pubmed DOI

Abstract Mapping high-throughput sequencing data to a reference genome is an essential step for most analysis pipelines aiming at the computational analysis of genome and transcriptome sequencing data. Breaking ties between equally well mapping locations poses a severe problem not only during the alignment phase but also has significant impact on the results of downstream analyses. We present the multi-mapper resolution (MMR) tool that infers optimal mapping locations from the coverage density of other mapped reads.

Authors Andre Kahles, Jonas Behr, Gunnar Rätsch

Submitted Bioinformatics (Oxford, England)

Link Pubmed DOI

Abstract Epigenome modulation potentially provides a mechanism for organisms to adapt, within and between generations. However, neither the extent to which this occurs, nor the mechanisms involved are known. Here we investigate DNA methylation variation in Swedish Arabidopsis thaliana accessions grown at two different temperatures. Environmental effects were limited to transposons, where CHH methylation was found to increase with temperature. Genome-wide association studies (GWAS) revealed that the extensive CHH methylation variation was strongly associated with genetic variants in both cis and trans, including a major trans-association close to the DNA methyltransferase CMT2. Unlike CHH methylation, CpG gene body methylation (GBM) was not affected by growth temperature, but was instead correlated with the latitude of origin. Accessions from colder regions had higher levels of GBM for a significant fraction of the genome, and this was associated with increased transcription for the genes affected. GWAS revealed that this effect was largely due to trans-acting loci, many of which showed evidence of local adaptation.

Authors Manu J Dubin, Pei Zhang, Dazhe Meng, Marie Stanislas Remigereau, Edward J Osborne, Francesco Paolo Casale, Philipp Drewe, Andre Kahles, Geraldine Jean, Bjarni Vilhjalmsson, Joanna Jagoda, Selen Irez, Viktor Voronin, Qiang Song, Quan Long, Gunnar Rätsch, Oliver Stegle, Richard M Clark, Magnus Nordborg

Submitted eLife

Link Pubmed DOI

Abstract We present a genome-wide analysis of splicing patterns of 282 kidney renal clear cell carcinoma patients in which we integrate data from whole-exome sequencing of tumor and normal samples, RNA-seq and copy number variation. We proposed a scoring mechanism to compare splicing patterns in tumor samples to normal samples in order to rank and detect tumor-specific isoforms that have a potential for new biomarkers. We identified a subset of genes that show introns only observable in tumor but not in normal samples, ENCODE and GEUVADIS samples. In order to improve our understanding of the underlying genetic mechanisms of splicing variation we performed a large-scale association analysis to find links between somatic or germline variants with alternative splicing events. We identified 915 cis- and trans-splicing quantitative trait loci (sQTL) associated with changes in splicing patterns. Some of these sQTL have previously been associated with being susceptibility loci for cancer and other diseases. Our analysis also allowed us to identify the function of several COSMIC variants showing significant association with changes in alternative splicing. This demonstrates the potential significance of variants affecting alternative splicing events and yields insights into the mechanisms related to an array of disease phenotypes.

Authors Kjong Van Lehmann, Andre Kahles, Cyriac Kandoth, William Lee, Nikolaus Schultz, Oliver Stegle, Gunnar Rätsch

Submitted Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing

Link Pubmed

Abstract We present Oqtans, an open-source workbench for quantitative transcriptome analysis, that is integrated in Galaxy. Its distinguishing features include customizable computational workflows and a modular pipeline architecture that facilitates comparative assessment of tool and data quality. Oqtans integrates an assortment of machine learning-powered tools into Galaxy, which show superior or equal performance to state-of-the-art tools. Implemented tools comprise a complete transcriptome analysis workflow: short-read alignment, transcript identification/quantification and differential expression analysis. Oqtans and Galaxy facilitate persistent storage, data exchange and documentation of intermediate results and analysis workflows. We illustrate how Oqtans aids the interpretation of data from different experiments in easy to understand use cases. Users can easily create their own workflows and extend Oqtans by integrating specific tools. Oqtans is available as (i) a cloud machine image with a demo instance at cloud.oqtans.org, (ii) a public Galaxy instance at galaxy.cbio.mskcc.org, (iii) a git repository containing all installed software (oqtans.org/git); most of which is also available from (iv) the Galaxy Toolshed and (v) a share string to use along with Galaxy CloudMan.

Authors Vipin T Sreedharan, Sebastian J Schultheiss, Geraldine Jean, Andre Kahles, Regina Bohnert, Philipp Drewe, Pramod Mudrakarta, Nico Görnitz, Georg Zeller, Gunnar Rätsch

Submitted Bioinformatics (Oxford, England)

Link Pubmed DOI

Abstract High-throughput RNA sequencing is an increasingly accessible method for studying gene structure and activity on a genome-wide scale. A critical step in RNA-seq data analysis is the alignment of partial transcript reads to a reference genome sequence. To assess the performance of current mapping software, we invited developers of RNA-seq aligners to process four large human and mouse RNA-seq data sets. In total, we compared 26 mapping protocols based on 11 programs and pipelines and found major performance differences between methods on numerous benchmarks, including alignment yield, basewise accuracy, mismatch and gap placement, exon junction discovery and suitability of alignments for transcript reconstruction. We observed concordant results on real and simulated RNA-seq data, confirming the relevance of the metrics employed. Future developments in RNA-seq alignment methods would benefit from improved placement of multimapped reads, balanced utilization of existing gene annotation and a reduced false discovery rate for splice junctions.

Authors Par G Engstrom, Tamara Steijger, Botond Sipos, Gregory R Grant, Andre Kahles, Gunnar Rätsch, Nick Goldman, Tim J Hubbard, Jennifer Harrow, Roderic Guigo, Paul Bertone

Submitted Nature methods

Link Pubmed DOI

Abstract The nonsense-mediated decay (NMD) surveillance pathway can recognize erroneous transcripts and physiological mRNAs, such as precursor mRNA alternative splicing (AS) variants. Currently, information on the global extent of coupled AS and NMD remains scarce and even absent for any plant species. To address this, we conducted transcriptome-wide splicing studies using Arabidopsis thaliana mutants in the NMD factor homologs UP FRAMESHIFT1 (UPF1) and UPF3 as well as wild-type samples treated with the translation inhibitor cycloheximide. Our analyses revealed that at least 17.4% of all multi-exon, protein-coding genes produce splicing variants that are targeted by NMD. Moreover, we provide evidence that UPF1 and UPF3 act in a translation-independent mRNA decay pathway. Importantly, 92.3% of the NMD-responsive mRNAs exhibit classical NMD-eliciting features, supporting their authenticity as direct targets. Genes generating NMD-sensitive AS variants function in diverse biological processes, including signaling and protein modification, for which NaCl stress-modulated AS-NMD was found. Besides mRNAs, numerous noncoding RNAs and transcripts derived from intergenic regions were shown to be NMD responsive. In summary, we provide evidence for a major function of AS-coupled NMD in shaping the Arabidopsis transcriptome, having fundamental implications in gene regulation and quality control of transcript processing.

Authors Gabriele Drechsel, Andre Kahles, Anil K Kesarwani, Eva Stauffer, Jonas Behr, Philipp Drewe, Gunnar Rätsch, Andreas Wachter

Submitted The Plant cell

Link Pubmed DOI

Abstract High-throughput sequencing of mRNA (RNA-Seq) has led to tremendous improvements in the detection of expressed genes and reconstruction of RNA transcripts. However, the extensive dynamic range of gene expression, technical limitations and biases, as well as the observed complexity of the transcriptional landscape, pose profound computational challenges for transcriptome reconstruction.

Authors Jonas Behr, Andre Kahles, Yi Zhong, Vipin T Sreedharan, Philipp Drewe, Gunnar Rätsch

Submitted Bioinformatics (Oxford, England)

Link Pubmed DOI

Abstract Deep transcriptome sequencing (RNA-Seq) has become a vital tool for studying the state of cells in the context of varying environments, genotypes and other factors. RNA-Seq profiling data enable identification of novel isoforms, quantification of known isoforms and detection of changes in transcriptional or RNA-processing activity. Existing approaches to detect differential isoform abundance between samples either require a complete isoform annotation or fall short in providing statistically robust and calibrated significance estimates. Here, we propose a suite of statistical tests to address these open needs: a parametric test that uses known isoform annotations to detect changes in relative isoform abundance and a non-parametric test that detects differential read coverages and can be applied when isoform annotations are not available. Both methods account for the discrete nature of read counts and the inherent biological variability. We demonstrate that these tests compare favorably to previous methods, both in terms of accuracy and statistical calibrations. We use these techniques to analyze RNA-Seq libraries from Arabidopsis thaliana and Drosophila melanogaster. The identified differential RNA processing events were consistent with RT-qPCR measurements and previous studies. The proposed toolkit is available from http://bioweb.me/rdiff and enables in-depth analyses of transcriptomes, with or without available isoform annotation.

Authors Philipp Drewe, Oliver Stegle, Lisa Hartmann, Andre Kahles, Regina Bohnert, Andreas Wachter, Karsten Borgwardt, Gunnar Rätsch

Submitted Nucleic acids research

Link Pubmed DOI

Abstract Deep sequencing of transcriptomes allows quantitative and qualitative analysis of many RNA species in a sample, with parallel comparison of expression levels, splicing variants, natural antisense transcripts, RNA editing and transcriptional start and stop sites the ideal goal. By computational modeling, we show how libraries of multiple insert sizes combined with strand-specific, paired-end (SS-PE) sequencing can increase the information gained on alternative splicing, especially in higher eukaryotes. Despite the benefits of gaining SS-PE data with paired ends of varying distance, the standard Illumina protocol allows only non-strand-specific, paired-end sequencing with a single insert size. Here, we modify the Illumina RNA ligation protocol to allow SS-PE sequencing by using a custom pre-adenylated 3' adaptor. We generate parallel libraries with differing insert sizes to aid deconvolution of alternative splicing events and to characterize the extent and distribution of natural antisense transcription in C. elegans. Despite stringent requirements for detection of alternative splicing, our data increases the number of intron retention and exon skipping events annotated in the Wormbase genome annotations by 127% and 121%, respectively. We show that parallel libraries with a range of insert sizes increase transcriptomic information gained by sequencing and that by current established benchmarks our protocol gives competitive results with respect to library quality.

Authors Lisa M Smith, Lisa Hartmann, Philipp Drewe, Regina Bohnert, Andre Kahles, Christa Lanz, Gunnar Rätsch

Submitted RNA biology

Link Pubmed DOI

Abstract Alternative splicing (AS) generates transcript variants by variable exon/intron definition and massively expands transcriptome diversity. Changes in AS patterns have been found to be linked to manifold biological processes, yet fundamental aspects, such as the regulation of AS and its functional implications, largely remain to be addressed. In this work, widespread AS regulation by Arabidopsis thaliana Polypyrimidine tract binding protein homologs (PTBs) was revealed. In total, 452 AS events derived from 307 distinct genes were found to be responsive to the levels of the splicing factors PTB1 and PTB2, which predominantly triggered splicing of regulated introns, inclusion of cassette exons, and usage of upstream 5' splice sites. By contrast, no major AS regulatory function of the distantly related PTB3 was found. Dependent on their position within the mRNA, PTB-regulated events can both modify the untranslated regions and give rise to alternative protein products. We find that PTB-mediated AS events are connected to diverse biological processes, and the functional implications of selected instances were further elucidated. Specifically, PTB misexpression changes AS of PHYTOCHROME INTERACTING FACTOR6, coinciding with altered rates of abscisic acid-dependent seed germination. Furthermore, AS patterns as well as the expression of key flowering regulators were massively changed in a PTB1/2 level-dependent manner.

Authors Christina Ruhl, Eva Stauffer, Andre Kahles, Gabriele Wagner, Gabriele Drechsel, Gunnar Rätsch, Andreas Wachter

Submitted The Plant cell

Link Pubmed DOI

Authors Nico Görnitz, Georg Zeller, Jonas Behr, Andre Kahles, Pramod Mudrakarta, Soren Sonnenburg, Gunnar Rätsch

Link

Abstract Genetic differences between Arabidopsis thaliana accessions underlie the plant's extensive phenotypic variation, and until now these have been interpreted largely in the context of the annotated reference accession Col-0. Here we report the sequencing, assembly and annotation of the genomes of 18 natural A. thaliana accessions, and their transcriptomes. When assessed on the basis of the reference annotation, one-third of protein-coding genes are predicted to be disrupted in at least one accession. However, re-annotation of each genome revealed that alternative gene models often restore coding potential. Gene expression in seedlings differed for nearly half of expressed genes and was frequently associated with cis variants within 5 kilobases, as were intron retention alternative splicing events. Sequence and expression variation is most pronounced in genes that respond to the biotic environment. Our data further promote evolutionary and functional studies in A. thaliana, especially the MAGIC genetic reference population descended from these accessions.

Authors Xiangchao Gan, Oliver Stegle, Jonas Behr, Joshua G Steffen, Philipp Drewe, Katie L Hildebrand, Rune Lyngsoe, Sebastian J Schultheiss, Edward J Osborne, Vipin T Sreedharan, Andre Kahles, Regina Bohnert, Geraldine Jean, Paul Derwent, Paul Kersey, Eric J Belfield, Nicholas P Harberd, Eric Kemen, Christopher Toomajian, Paula X Kover, Richard M Clark, Gunnar Rätsch, Richard Mott

Submitted Nature

Link Pubmed DOI

Abstract Next-generation sequencing technologies have revolutionized genome and transcriptome sequencing. RNA-Seq experiments are able to generate huge amounts of transcriptome sequence reads at a fraction of the cost of Sanger sequencing. Reads produced by these technologies are relatively short and error prone. To utilize such reads for transcriptome reconstruction and gene-structure identification, one needs to be able to accurately align the sequence reads over intron boundaries. In this unit, we describe PALMapper, a fast and easy-to-use tool that is designed to accurately compute both unspliced and spliced alignments for millions of RNA-Seq reads. It combines the efficient read mapper GenomeMapper with the spliced aligner QPALMA, which exploits read-quality information and predictions of splice sites to improve the alignment accuracy. The PALMapper package is available as a command-line tool running on Unix or Mac OS X systems or through a Web interface based on Galaxy tools.

Authors Geraldine Jean, Andre Kahles, Vipin T Sreedharan, Fabio de Bona, Gunnar Rätsch

Submitted Current protocols in bioinformatics / editoral board, Andreas D. Baxevanis ... [et al.]

Link Pubmed DOI