Figure 1: Extensive variation in transcript start and end sites revealed by TIF-Seq, a novel technique for transcript isoform profiling (Pelechano et al., Nature 2013)
Figure 2: Gene-environment interactions reveal causal pathways (A-B) that mediate genetic effects on phenotype (Gagneur et al., PLOS Genetics 2013)
The Steinmetz group develops and applies interdisciplinary, genome-wide technologies to study genome regulation, the genetic basis of complex phenotypes and the genetic and molecular systems underpinning disease.
Previous and current research
One of the most daunting obstacles in biomedicine is the complex nature of most phenotypes (including cancer, diabetes, heart disease and some forms of rare disease) due to interactions between multiple genetic variants and environmental influences. A central challenge is to understand how genetic (ie, SNPs and indels) and environmental (ie, drug) perturbations affect health, wellness and disease. Our research is directed at understanding such complex traits. To do so, we develop novel genomic approaches to investigate the molecular processes that link genotype to phenotype, identify the causal underlying factors, and quantify their contributions. We investigate inter-individual variations at the level of the genome, transcriptome, and proteome, which we integrate with higher-level phenotypes. Our projects are mainly in the following areas:
Functions and mechanisms of transcription: We have developed several technologies to characterise and quantify transcriptome architecture as well as its functional impact. In particular, we are interested in the function and regulation of non-coding RNAs, antisense transcription, and the molecular phenotypes that arise from pervasive transcription. Recently, we discovered extensive variation in the start and end sites of transcript molecules produced by each gene by developing a novel technique to map full-length transcript isoforms genome-wide (figure 1).
Quantitative genetics: We have piloted new technologies to dissect the genetic basis of complex, multifactorial phenotypes. We are interested in studying how genetic variation is inherited through recombination, the consequences of genetic variation, learning to predict phenotype from genotype, and integrating multiple layers of molecular data in order to define intervention points that can be targeted to modulate phenotypes of interest (figure 2).
Disease models: We have used multiple model systems, primarily yeast and human cells, to characterize the genetic and cellular systems affected in particular diseases and assess potential therapeutic strategies. We are applying personalised functional genomics to study diseases in patient-derived cells using systematic and targeted approaches, to unravel mechanisms and discover novel treatments (see video).
Future projects and goals
We are integrating multiple layers of genomic information in order to understand how the genome is read for function, leading to inter-individual differences. Using novel algorithms, intervention points can be identified from such data that can be targeted to modulate phenotypes of interest. We are also following up on our studies of transcriptional regulation through targeted investigations of the interplay between epigenetics and transcription, the functional consequences of complex transcriptome architecture, and its contribution to single-cell heterogeneity. Ultimately, by integrating genetics, genomics, systems biology, and computational modelling, we aim to develop approaches that unravel disease mechanisms and predict effective therapeutics, enabling personalised and preventive medicine.
The Steinmetz lab operates in an integrated manner across sites in Heidelberg, Germany, and at Stanford University in the US.
|ERC ADVANCED INVESTIGATOR|