Hans Rudolf Lehrach

Max Planck Institute for Molecular Genetics | MOLGEN · Department of Vertebrate Genomics

Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by haemolytic anaemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other o...

Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed a pre-clinical platform generating...

Clinical data of the OT cohort.

List of deleted genes in the OT cohort.

Comparison of mutations between 5 PDX derived from 150_MET2.

Assignment of OT samples to molecular groups.

Functional annotation of the OT_NMF and OT_C clusters.

Gene signatures related to drug sensitivity in patient derived models.

Classification of responders and non-responders for 5-FU treatment.

Combined list of alterations in the OT cohort.

Supplementary Figures and Supplementary Tables

Discordant SNVs and indels in matched patient and model pairs.

Drug sensitivity data.

Summary of SciClone clonality analysis.

Expression values of differentially expressed genes in 151_MET_CELL1 Wnt -negative, -low, -high sorted fractions and unsorted cells.

Classification of responders and non-responders for cetuximab treatment.

Copy Number Variations (CNVs) in the OT cohort.

Gene signatures used for the classification of OT primary tumour samples and models.

Values of mean pattern matrices and enrichment scores (ES) of single sample gene set enrichment analysis (ssGSEA).

List of identified gene fusions in the OT cohort.

Background Human endogenous retroviruses (HERVs) constitute 8% of the human genome and contribute substantially to the transcriptome. HERVs have been shown to generate RNAs that modulate host gene expression. However, experimental evidence for an impact of these regulatory transcripts on the cellular phenotype has been lacking. ResultsWe characteri...

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14⁺ monocytes, CD16⁺ neutrophils, and naive CD4⁺ T cells) from up to 197...

Crossover sample information and correlation coefficient before and after batch correction in crossover samples of RNA-seq and 450K methylation array. In Chip-seq, as ComBat cannot be applied, we used a normalization method based on library size.

Table S4. Canonical Pathways Enrichment for Genes under Genetic and Epigenetic Control, Related to Figures 2, 3, and 4 For ‘Epigenetic’ rows show genes identified by the variance decomposition analysis as having a significant epigenetic contribution independent from cis-genetic effects. Genetic rows detail genes identified as having a significant...

Table S3. Overview of Genes Identified as Having a Significant Epigenetic 0r Genetic Contribution in Three Cell Types, Related to Figures 2, 3, 4, 5, and 6 For each cell type, we report whether a given gene was associated as carrying a genetic or epigenetic feature in each of the following analyses: VD=Variance Decomposition, further divided in ep...

Table S5. Summary of Colocalization Results in the Genetic Association of Autoimmune Diseases and Molecular Traits, Related to Figure 7 List of lead QTLs (gene, PSI, DNA methylation and histone modifications) loci that colocalize a variant associated with selected autoimmune diseases [multiple sclerosis (MS), Celiac disease (CEL), rheumatoid arthr...

Table S1. Donor Characteristics and Per-Sample Data Quality Metrics, Related to Figure 1 Details of donor characteristics (gender, smoking status past and present and age bin), identification (ID) code and donation date along with FACS purity results by cell type and sample quality metrics for each assay. Missing data are indicated by ‘no data’, ‘...

Table S6. Genetically Controlled Gene-Histone Mark Peaks Validated by Orthogonal Allelic Correlation, Related to Figures 3, 5, and 6

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14(+) monocytes, CD16(+) neutrophils, and naive CD4(+) T cells) from up t...

This work was predominantly funded by the EU FP7 High Impact Project BLUEPRINT (HEALTH-F5-2011-282510) and the Canadian Institutes of Health Research (CIHR EP1-120608). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 282510 (BLUEPRINT), the Eur...

The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comp...

Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET fusions activated mitogen-activated protein kinase...

A central challenge in pharmaceutical research is to investigate genetic variation in response to drugs. The Collaborative Cross (CC) mouse reference population is a promising model for pharmacogenomic studies because of its large amount of genetic variation, genetic reproducibility, and dense recombination sites. While the CC lines are phenotypica...

Every human is unique. We differ in our genomes, environment, behavior, disease history, and past and current medical treatment—a complex catalog of differences that often leads to variations in the way each of us responds to a particular therapy. We argue here that true personalization of drug therapies will rely on “virtual patient” models based...

Proper patient-tailoring strategy and the validation of novel therapeutic targets remain enormous challenges during drug discovery processes. Patient-derived three-dimensional organoid cell culture models possess great potential to associate compound sensitivity and disease complexity in order to provide a key missing link between compound screenin...

Background: Knowledge in the era of Omics and Big Data has been increasingly conceptualized as a public good. Sharing of de-identified patient data has been advocated as a means to increase confidence and public trust in the results of clinical trials. On the other hand, research has shown that the current research and development model of the bio...

Objective: Colorectal cancer (CRC) is the third most common cause of cancer related death and the third most frequently diagnosed cancer entity worldwide with more than one million new cases each year. Some eukaryotic translation initiation factors (eIFs) are increased in CRC compared to precursor lesions and normal mucosa. eIFs are involved in the...

We report the sequence sof �244 human Y chromosomes randomly ascertained from 26 worldwide populations by the �1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants con...

Proper patient-tailoring strategy and the validation of novel therapeutic targets remain enormous challenges during drug discovery processes. Patient-derived three-dimensional organoid cell culture models possess great potential to associate compound sensitivity and disease complexity in order to provide a key missing link between compound screenin...

Growing evidence supports a subpopulation of cancer stem cells (CSCs) as both the drivers of tumor growth and the source of relapse following treatment. The identification of genes and pathways required for the survival of CSCs may therefore lead to better treatment outcomes. Here, as part of the OncoTrack* consortium, we report the use of 3D in vi...

Recent data support a hierarchical model of colon cancer in which tumor growth is driven by a subpopulation of cancer stem cells (CSCs) that may also be the source of relapse following treatment. Elucidation of the cellular heterogeneity within a tumor would therefore facilitate better characterization of patient subtypes and lead to more personali...

Recent data support a hierarchical model of colon cancer in which tumor growth is driven by a subpopulation of cancer stem cells (CSCs) that may also be the source of relapse following treatment. Elucidation of the cellular heterogeneity within a tumor would therefore facilitate better characterization of patient subtypes and lead to more personali...

Combined transcriptome and whole genome sequencing of the same ultra-low input sample down to single cells is a rapidly evolving approach for the analysis of rare cells. Besides stem cells, rare cells originating from tissues like tumor or biopsies, circulating tumor cells and cells from early embryonic development are under investigation. Herein w...

Unlabelled: Deletions at the C-terminus of the proto-oncogene protein c-Src kinase are found in the viral oncogene protein v-Src as well as in some advanced human colon cancers. They are associated with increased kinase activity and cellular invasiveness. Here, we analyzed the mRNA expression signature of a constitutively active C-terminal mutant...

Objective Monoclonal Anti-citrullinated protein autoantibodies ACPA target different proteins and their role in RA is still largely unknown. We analysed the susceptibility of PWD Musmusculusmusculus subspecies, separated from Musmusculusdomesticus about one million years ago to collagen antibody-induced arthritis (CAIA) and the role of ACPA antibod...

Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subg...

A substantial fraction of phenotypic differences between closely related species are likely caused by differences in gene regulation. While this has already been postulated over 30 years ago, only few examples of evolutionary changes in gene regulation have been verified. Here we identified and investigated binding sites of the transcription factor...

Despite the approval of numerous molecular targeted drugs, long-term antiproliferative efficacy is rarely achieved and therapy resistance remains a central obstacle of cancer care. Combined inhibition of multiple cancer-driving pathways promises to improve antiproliferative efficacy. HIF-1 is a driver of gastric cancer and considered to be an attra...

Despite the approval of numerous molecular targeted drugs, long-term antiproliferative efficacy is rarely achieved and therapy resistance remains a central obstacle of cancer care. Combined inhibition of multiple cancer-driving pathways promises to improve antiproliferative efficacy. HIF-1 is a driver of gastric cancer and considered to be an attra...

Non-alcoholic fatty liver disease (NAFLD) is a consequence of sedentary life style and high fat diets with an estimated prevalence of about 30% in western countries. It is associated with insulin resistance, obesity, glucose intolerance and drug toxicity. Additionally, polymorphisms within, e.g., APOC3, PNPLA3, NCAN, TM6SF2 and PPP1R3B, correlate w...

Despite a growing body of knowledge on the mechanisms underlying the onset and progression of cancer, treatment success rates in oncology are at best modest. Current approaches use statistical methods that fail to embrace the inherent and expansive complexity of the tumor/patient/drug interaction. Computational modeling, in particular mechanistic m...

Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subg...

We investigated parent-of-origin and allele-specific expression effects on obesity and hepatic gene expression in reciprocal crosses between the Berlin Fat Mouse Inbred line (BFMI) and C57Bl/6NCrl (B6N). We found that F1-males with a BFMI mother developed 1.8 times more fat mass on a high fat diet at 10 weeks than F1-males of a BFMI father. The ph...

Next Generation Sequencing has proven to be an exceptionally powerful tool in the field of genomics and transcriptomics. With recent development it is nowadays possible to analyze ultra-low input sample material down to single cells. Nevertheless, investigating such sample material often limits the analysis to either the genome or transcriptome. We...

Background: We investigated parent-of-origin and allele-specific expression effects on obesity and hepatic gene expression in reciprocal crosses between the Berlin Fat Mouse Inbred line (BFMI) and C57Bl/6NCrl (B6N). Results: We found that F1-males with a BFMI mother developed 1.8 times more fat mass on a high fat diet at 10 weeks than F1-males o...

Every patient is different - his/her genomes, environment, disease history and exposure to drugs. Tumours, in particular, are often heterogeneous in their genetic make-up and their response to drugs, both within and between samples. Classic clinical trials basically ignore this complexity or, as in stratified medicine, attempt to reduce it to an an...

The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received funding from the European Commission for 41/2 years. The objectives of the project revolved around technological developments in nucleic acid analysis. The project partners have discovered, created and developed a huge body of insights into nucleic acid ana...

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-covera...

The biological processes that keep us healthy or cause disease, as well as the mechanisms of action of possible drugs are inherently complex. In the face of this complexity, attempts at discovering new drugs to treat diseases have alternated between trial-and-error (typically on experimental systems) and grand simplification, usually based on much...

Colon cancer is a heterogeneous tumour entity. Growing evidence supports a subpopulation of cancer stem cells (CSCs) as both the drivers of tumour growth and the source of relapse following treatment. Elucidation of the cellular heterogeneity within a tumour would therefore facilitate better characterization of patient subtypes and lead to more per...

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of...

We investigated to which extent polymorphisms of an individual affect the proteomic network. Consomic mouse strains (CS) were used to study the trans-effect of the cis-variant (polymorphic) proteins of the strain PWD/Ph on the proteins of the host strain C57BL/6J. The cardiac proteome of ten CSs was analyzed by 2-DE and MS. Cis-variant PWD proteins...

To fully understand human biology and link genotype to phenotype, the phase of DNA variants must be known. Here we present a comprehensive analysis of haplotype-resolved genomes to assess the nature and variation of haplotypes and their pairs, diplotypes, in European population samples. We use a set of 14 haplotype-resolved genomes generated by fos...

Background Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result...

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Traditionally, tumors have been classified based on their tissue of origin and their histopathological characteristics and consequently patients are divided into groups where they are treated identically despite substantial differences in genetic profiles. Identification of gene...

Colon cancer is a heterogeneous disease. Growing evidence supports a subpopulation of cancer stem cells (CSCs) as both the drivers of tumour growth and the source of relapse following treatment. Elucidation of the cellular heterogeneity within a tumour would therefore facilitate better characterization of patient subtypes and lead to more personali...