Figure 1: Antisense transcription enables local dispersion of regulatory signals via bidirectional promoters (Xu et al., 2011, Molecular Systems Biology)
Figure 2: Reciprocal allele-specific RNAi identifies the mosquito gene TEP1 as a major contributor to resistance to malaria parasites (Blandin et al., 2009, Science)
Figure 3: High-resolution map of meiotic recombination identifies hotspots of crossovers and non-crossovers (Mancera et al., 2008, Nature)
The Steinmetz group bridges diverse domains of genome science, from deciphering the structure and function of genomes to the application of these insights in understanding diseases.
Previous and current research
One of the most daunting challenges in medicine is the complex nature of most common diseases (including cancer, diabetes, and heart disease) due to interactions between multiple genetic variants and environmental influences. 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 underlying factors, and quantify their contributions. We investigate variation at the level of the genome, transcriptome and proteome, which we integrate with higher-level phenotypes. We also use the resulting molecular networks to predict and evaluate intervention points that enable modulation of phenotype.
To this end, we are using budding yeast and human cell culture as model systems for functional genomics. Using the strand-specific yeast tiling microarray that we developed, we have discovered pervasive transcription of the genome and shown that much of this transcription originates from bidirectional promoters, which enable the spread of regulatory signals via antisense transcription (figure 1). We are currently carrying out functional and mechanistic studies of these non-coding RNAs as well as developing new sequencing-based technologies to define transcriptome architecture. Furthermore, we have dissected the genetic architecture of complex traits such as high-temperature growth in yeast as well as mosquito resistance to the malaria parasite (figure 2) and are continuing with further traits such as drug resistance. To clarify the process of trait inheritance, we have generated a high-resolution map of meiotic recombination in yeast (figure 3) and are now studying this process in humans via whole genome sequencing.
Future projects and goals
We are developing new technologies to carry out rapid, high-resolution dissection of the genetic and environmental factors underlying complex traits; we will combine this knowledge with other ‘omic’ measurements that will allow the computational prediction of phenotype from genotype. We will continue testing novel genetic and chemical therapeutics in experimental models of mitochondrial and neurodegenerative diseases. Furthermore, we have begun working with patientderived iPS cells to measure the phenotypic consequences of disease-associated alleles using whole genome sequencing, transcriptome profiling, and RNAi. 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.
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