2008 Barcelona - European Society of Human Genetics

Plenary Lectures
ESHG PLENARY LECTURES
PL1.1
Understanding the Influence of Conditional Host-Karyomemicrobiome
interactions in Health and Disease
J. K. Nicholson;
Department of Biomolecular Medicine, Imperial College, London, United Kingdom.
Post-genomic technologies are being widely applied to improve the
understanding of adverse drug reactions and the molecular basis of
human disease . Metabonomics is an approach that enables multivariate
profiling of the integrated metabolic responses of complex systems
to patho-physiological stress, and so involves understanding the way
the whole metabolic regulatory system varies with interventions thus
providing complementary information to genomics and proteomics .
Mammalian biochemistry is strongly influenced by the host karyome
(genome) and gut microbiome symbionts that can alter drug metabolism
and toxicity; the study of these transgenomic interactions is termed
“global systems biology” . Because these interactions are mediated by
a large number of co-metabolic processes the system state integrity
can be evaluated via metabolic profiling of biofluids. With the growing
desire to apply systems biology tools to understanding human disease
processes at the population level where massive cohorts need to be
investigated, it is necessary to use analytical and statistical methods
that report on whole system state non-invasively, hence the attraction
of biofuid analyses described here .
NMR spectroscopy and chromatographic linked MS methods have
been applied to characterize and quantify a wide range of metabolites
in biological fluids and tissues to explore the biochemical consequences
of drug-induced toxicity and human disease . In disease
or toxicity states metabolic profiles and NMR and mass spectra are
changed characteristically in different toxicity or disease conditions
according to the exact site and mechanism of the lesion . The use of
chemometrics allows interrogation of spectroscopic data and can give
direct diagnostic information and aid the detection of novel biomarkers
of disease and the integration of metabolic data with other omics sets .
Such diagnostics can be extremely sensitive for the detection of low
level damage in a variety of organ systems and is potentially a powerful
new adjunct to conventional procedures for disease assessment
and can help explain environment-gene interactions that give rise to
idiosyncratic toxicity of drugs in man . Examples of the application of
metabonomics to personalised healthcare (1) and population screening
to detect new “Metabolome-Wide Associations” with disease risk
factors (2) .
1 . Clayton, T .A . Nicholson, J .K . et al (2006) Pharmaco-metabonomic
phenotyping and personalised drug treatment . Nature 440 (20) 1073-
1077 .
2 . Holmes, E . Nicholson, J .K . et al (2008) Human Metabolic Phenotype
Diversity and its Association with Diet and Blood Pressure . Nature
(in press) .
PL1.2
cell competition, apoptosis and tumour progression in
Drosophila
G. Morata;
Centro de Biologia Molecular Severo Ochoa, CSIC-UAM - Campus de Cantoblanco,
Madrid, Spain.
Larvae homozygous for mutations at the tumour suppressor genes of
Drosophila lethal giant larvae (lgl), scribble (scribb) or disc large (dlg)
develop extensive neoplastic tumours that affect principally the central
nervous system and the imaginal discs . Thus the lack of any of these
products is sufficient to transform normal imaginal cells into tumorous
cells . However, imaginal cells mutant for any of these genes are unable
to develop a tumour if they are surrounded by non-tumour cells .
We have been studying the behaviour of clones of lgl mutant cells
in the wing disc to study the interactions between tumour and nontumour
cells. We find that as a rule lgl clones are eliminated from the
wing disc by a process akin to cell competition: they enter apoptosis
mediated by the JNK pathway and the interactions leading to the disappearance
of the mutant cells take place at the border of the clones .
We have also found that when these cells contain an additional factor
conferring a high proliferation rate, the lgl mutant cells are transformed
into “supercompetitors”, which are able to eliminate surrounding non-
tumour cells and give rise to invasive neoplastic tumours that colonise
the entire disc
PL1.3
Human evolution: palaeontology and ancient DNA
J. L. Arzuaga;
Centro de evolucion y comportamientos humanos, Instituto de salud de la Universidad
Carlos III, Madrid, Spain.
PL2.1
mutations in the pericentrin (PcNt) gene cause primordial
dwarfism
A. Rauch 1 , C. T. Thiel 1 , U. Wick 1 , Y. J. Crow 2 , D. Schindler 3 , A. Ekici 1 , C.
Zweier 1 , A. J. van Essen 4 , T. O. Goecke 5 , L. Al-Gazali 6 , K. H. Chrzanowska 7 ,
H. G. Brunner 8 , K. Becker 9 , C. J. Curry 10 , B. Dallapiccola 11 , K. Devriendt 12 , E.
Kinning 13 , A. Megarbane 14 , P. Meinecke 15 , R. K. Semple 16 , A. Toutain 17 , R. Hennekam
18 , R. Trembath 19 , H. G. Dörr 20 , A. Reis 1 ;
1 Insitute of Human Genetics, Erlangen, Germany, 2 Leeds Institute of Molecular
Medicine, Leeds, United Kingdom, 3 Insitute of Human Genetics, Würzburg,
Germany, 4 Department of Genetics, Groningen, The Netherlands, 5 Insitute of
Human Genetics, Düsseldorf, Germany, 6 Faculty of Medicine, Al-Ain, United
Arab Emirates, 7 Department of Medical Genetics, Erlangen, Poland, 8 Department
of Human Genetics, Nijmegen, The Netherlands, 9 North Wales Clinical
Genetics Service, Rhyl, United Kingdom, 10 Genetic Medicine Central California,
San Francisco, CA, United States, 11 IRCCS-CSS, Rome, Italy, 12 Centre for Human-Genetics,
Leuven, Belgium, 13 Department of Clinical Genetics, Leicester,
United Kingdom, 14 Unité de Génétique Médicale, Beirut, Lebanon, 15 Abteilung
für Medizinische Genetik, Hamburg, Germany, 16 Department of Clinical Biochemistry,
Cambridge, United Kingdom, 17 Department of Genetics, Tours,
France, 18 Department of Clinical Genetics, London, United Kingdom, 19 Department
of Medical and Molecular Genetics, London, United Kingdom, 20 Department
of Pediatrics and Adolescent Medicine, Erlangen, Germany.
The growth of an individual grossly depends on regulation of cell size
and cell division and dysfunction of the pathways involved not only
results in somatic undergrowth but contributes to a wide variety of
pathological conditions .
Using positional cloning, we found in a total of 25 patients that biallelic
loss-of-function mutations in the pericentrin (PCNT) gene cause microcephalic
osteodysplastic primordial dwarfism type Majewski II (MOPD
II, MIM 210720) . Adults with this rare inherited condition belong to the
shortest of the short having a height of about 100 centimeters and a
brain size comparable to that of a three-month old baby, but are of
near-normal intelligence . Truncal obesity, type 2 diabetes and a high
risk of stroke have been noted in older individuals with MOPD II .
PCNT is known to mediate nucleation of microtubules by anchoring
the γ-tubulin ring complex, thus initiating the assembly of the mitotic
spindle apparatus . We show that PCNT mutations cause absence of
the protein resulting in disorganized mitotic spindles, premature sister
chromatid separation and missegregation of chromosomes in patient
cells. Our findings thus characterize MOPD II as a distinct clinical entity
linking a key protein of the centrosome to dwarfism and a high risk
of diabetes and stroke .
Similarities between MOPD II individuals and the Late Pleistocene
hominid fossils from the island of Flores, Indonesia, also known as
“hobbits”, suggest that these do not represent a diminutive, smallbrained
new species, Homo floresiensis, but are pathological modern
humans .
Rauch et al . 2008, Science Feb 8, 319:816-9 .
PL2.2
meta-analysis of genome-wide association data and large-scale
replication identifies several additional susceptibility loci for
type 2 diabetes
E. Zeggini 1 , R. Saxena 2 , L. J. Scott 3 , B. F. Voight 2 , for the DIAGRAM Consortium;
1 University of Oxford, Oxford, United Kingdom, 2 Harvard and Massachusetts
Institute of Technology, Cambridge, MA, United States, 3 University of Michigan,
Ann Arbor, MI, United States.
Genome-wide association (GWA) studies have identified multiple new
loci at which common variants modestly but reproducibly contribute to
risk of type 2 diabetes (T2D) . However, established variants, common
and rare, explain only a small proportion of the heritability of T2D . To
increase the power to discover alleles of modest effect, we performed