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Scientific Background
Successful reconstruction of ancestral sequences involves several phases. The
first phase is computational reconstruction of ancestral sequences over a phylogeny
based upon a multiple sequence alignment. In the absence of any experimentation,
this may offer valuable clues to understanding the sequence-function relationship.
A second phase is experimental expression of synthesized ancestral proteins
and measurement of changes in function compared with proteins in extant species.
To access this, we need to understand what can go wrong. This includes flaws
of the ancestral sequence reconstruction process and their effects on protein
structure and function. More optimistically, we also can discuss what can go
right, our vision for the future. What types of questions can be addressed using
these approaches? What applications might we expect to see in industries, like
the pharmaceutical industry? Answering these questions depends upon the integration
of interdisciplinary knowledge involving bioinformatics, computational molecular
evolution, experimental functional genomics, biochemistry, and protein structural
analysis.
Ultimately, ancestral sequence reconstruction is a method to correlate the evolution
of protein sequence with the evolution of protein function. As the protein sequence
evolves on branches of a phylogenetic tree while the function is evolving under
selective pressure, the residues driving this functional evolution can be pinpointed.
Such methods significantly reduce the signal-noise ratio in detecting point
mutations with important phenotypic (biochemical) effects. Studying nature in
this way can be turned around into a design principle for identifying important
positions (and the amino acids to occupy them) to modify the behaviors of proteins
for various industrial (including pharmaceutical and biotechnological) applications.
Workshop Ambitions
So far, most of the expertise in this area has been in North America, especially
on the experimental side. This ESF workshop aims to link together European researchers
in this important area (as well as transferring knowledge from American researchers
to Europe). An interesting development is the initiation of a project to use
ancestral sequence reconstruction in the drug design process by NovoNordisk,
a Danish pharmaceutical company. Janos Kodra, the lead researcher on the project,
will be invited to speak. Three of the leading young North American researchers
in this field will also be invited.
The workshop aims at bringing together researchers with expertise in bioinformatics
and models of sequence evolution, in expression, in understanding the impact
of sequence evolution on protein structure and finally in understanding the
impact of sequence evolution on biochemical phenotype. A first step is the integration
of knowledge in a workshop like this that brings together such a diversity of
knowledge. Most importantly, researchers in this workshop are actively involved
in reconstructing different proteins (translation proteins, steroid receptors,
visual pigments, kinases, transporters, and signal transduction regulators )
and can gain from the experience of others and from experts in related areas
of knowledge, like protein structure determination or protein expression.
Oxford University Press has agreed to work with us on publishing a volume based
upon such an exploratory workshop.
Venue:
Kristineberg, Sweden
29-30 March, 2005
Confirmed Speakers to date:
David Ardell (Uppsala University, Sweden)
Belinda Chang (University of Toronto, Canada)
Alan Cooper (Oxford University, UK)
Nicolas Galtier (University of Montpellier II, France)
Eric Gaucher
(University of Florida, USA)
Richard Goldstein
(National Institute of Medical Research, UK)
Martijn Huynen (University of Nijmegen, Netherlands)
Janos Kodra (Novo Nordisk, Denmark)
Pietro Lio (Cambridge University, UK)
Andrei Lupas
(Max Planck Institute for Developmental Biology, Germany)
David Liberles
(University of Bergen, Norway)
Giorgio Matassi (Stazione Zoologica "Anton Dohrn", Naples, Italy)
Michel Milinkovitch (Free University of Brussels, Belgium)
Pierre Pontarotti (University of Provence, France)
Tal Pupko (Tel Aviv University, Israel)
Denis Shields (Royal College of Surgeons, Ireland)
Joe Thornton (University of Oregon, USA)
Ziheng Yang
(University College London, UK) TBC
Registration is now closed.