Movies for the human genome

Europe consortium captures gene disruption on film

Movies for the human genome

mitocheck-divide.jpg
Functional analysis of spindle phenotypes. Left panel: Phenotypic time curves (mitotic delay [green], binuclear [purple], polylobed [pale blue], grape [dark blue], cell death [red]) for 9 corresponding RNAi experiments from the primary screen. Right panel: Confocal still images from movies of HeLa cells stably expressing GFP-tubulin (green) and H2B-mcherry (red) after RNAi knockdown show mitotic phenotypes in the first (b, d, g) cell cycle or mitotic consequences in the following one (a, c, e, f, h-j)

At its outset, one aim of the Human Genome Project was to identify all the genes in the human genome, so as to enable systematic approaches to understanding gene function. Today, a decade on from the human draft sequence, a global scan of all 21,000 human genes identifies many ways that human genes are involved in cell biological processes such as cell division and migration - the basic stuff of life.

The data have been developed using the freely available human genome sequence: as with the public release of that sequence, the consortium that produced the current results has made them freely available to the research community.

The Mitocheck Consortium developed high-throughput systems to disrupt the working of each gene and to study the consequences for cell behaviour using time-lapse microscopy: this 'Candid Camera' of the cell caught how cells respond to gene disruption.

The team produced about 190,000 movies.

"This work is the fruit of an innovative European collaboration in functional genomics, bringing multiple large-scale experimental strategies to bear on a key component of basic biology: how cells manage the doubling of their DNA when they divide. Because of its scale it would not have been possible without new software and analysis tools."

Dr Richard Durbin, a researcher at the Wellcome Trust Sanger Institute

To carry out biology on this scale, the team developed automated systems to inhibit gene function and to study the effects on cell behaviour such as migration, division. The observations were supported by newly developed computer programmes to report the cell observations.

The team studied almost two billion cell nuclei.

Cell division is often poorly captured in studies of mutation, in part simply because it is such a short part of a cell's life. However this vital part of a cell's - and our - life is ideally captured by time-lapse microscopy. The study found almost 600 genes that could be involved in these basic functions.

The system uses reduction in gene activity caused by siRNAs - small, interfering RNAs designed to match and thus interfere with the sequence of one specific gene. The elegant high throughput platform that EMBL scientists developed to silence all of an organism's genes in a fast and systematic manner is itself proving a boon to the scientific community.

"A year after we developed these new siRNA microarrays they're already in use by over 10 research groups from across Europe."

Dr Rainer Pepperkok, who led the method's development at EMBL

The team have yet to uncover exactly how these genes act at the molecular level - a task which will be tackled by a follow-up project called MitoSys. All data from this follow-up work will also be made freely available online, creating what Professor Ellenberg describes as a 'one-stop-shop' for mitosis research.

"Without mitosis, nothing happens in life, really and when mitosis goes wrong, you get defects like cancer."

Jan Ellenberg, who led the study at EMBL

Notes to Editors
Publications
  • Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes.

    Neumann B, Walter T, Hériché JK, Bulkescher J, Erfle H et al.

    Nature 2010;464;7289;721-7

Data availability

Data are available from the Mitocheck consortium as a resource to the community at http://www.mitocheck.org.

Funding

This project was funded by grants by the European Commission, by the German Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network, by the Landesstiftung Baden Wuerttemberg and by the Wellcome Trust.

Participating Centres
  • MitoCheck Project Group, Gene Expression and Cell Biology/Biophysics Units, Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
  • Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany
  • ETH Zurich, Institute of Biochemistry, ETH-Hoenggerberg, Zurich, Switzerland
  • Leica Microsystems CMS GmbH, Mannheim, Germany
  • European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge, UK
  • Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany
  • Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
  • Institute for Molecular Pathology, Vienna, Austria.
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