European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Concurrent Symposia 11
at E13.5 similar to those seen in DS and NFATc mutant mice. Mathematical
modelling of the NFAT pathway, which includes positive and
negative feedback loops, predicts that a 1.5-fold increase in DSCR1
and DYRK1a levels will reduce NFAT activity and alter the expression
of target genes. These studies raise the question that perturbation of
the NFAT genetic circuit by increased dosage of these genes may explain
many of the developmental phenotypes in DS. More generally
this suggests that developmental defects may arise from the specific
susceptibilities of genetic regulatory circuits.
1. Arron, J. R. et al. NFAT dysregulation by increased dosage of
DSCR1 and DYRK1A on chromosome 21. Nature (2006).
2. Graef, I. A., Chen, F. & Crabtree, G. R. NFAT signaling in vertebrate
development. Curr Opin Genet Dev 11, 505-12. (2001).
S28. The Tc1 mouse, an aneuploid mouse with a human
chromosome that models aspects of Down syndrome
A. O’Doherty 1,2 , S. Ruf 1,2 , C. Mulligan 3 , V. Hildreth 4 , M. L. Errington 2 , S. Cooke 2 ,
S. Sesay 2 , S. Modino 5 , L. Vanes 2 , D. Hernandez 1,2 , J. M. Linehan 1 , P. Sharpe 5 ,
S. Brandner 1 , T. V. P. Bliss 2 , D. J. Henderson 4 , D. Nizetic 3 , V. L. J Tybulewicz 2 ,
E. M. C. Fisher 1 ;
1 Department of Neurodegenerative Disease, Institute of Neurology, London,
United Kingdom, 2 National Institute for Medical Research, Mill Hill, London,
United Kingdom, 3 Centre for Haematology, Institute of Cell and Molecular Science,
Barts and The London - Queen Mary’s School of Medicine, London,
United Kingdom, 4 Institute of Human Genetics, University of Newcastle upon
Tyne, International Centre for Life, Newcastle upon Tyne, London, United Kingdom,
5 Department of Craniofacial Development, Kings College London, Guy’s
Hospital, London, United Kingdom.
Down syndrome (DS) arises from trisomy human chromosome 21
(Hsa21) and is the most common known genetic cause of mental retardation,
and also results in increased susceptibility for other disorders,
such as heart defects. DS is a complex genetic disorder likely involving
several ‘major effect’ dosage sensitive genes on Hsa21 and their
interaction with the rest of genome/environment. To help towards our
understanding of DS we generated a mouse model in which an almost
complete Hsa21 segregates through the germline. This trans-species
aneuploid mouse strain, ‘Tc1’, has widespread novel phenotypes including
in behaviour, synaptic plasticity, cerebellar neuronal number,
heart development and mandible size, that relate to human DS. Transchromosomic
mouse lines such as Tc1 could be useful genetic tools
for dissecting other human aneuploidies and syndromes arising from
dosage sensitivity of multiple genes.
S29. Polymorphic miRNA-mediated gene regulation:
contribution to phenotypic variation and disease
M. Georges;
Unit of Animal Genomics, Department of Animal Production, Liège, Belgium.
The expression level of at least one third of mammalian genes is posttranscriptionally
fine-tuned by ∼ 1,000 microRNAs assisted by the RNA
silencing machinery comprising tens of components. Polymorphisms
and mutations in the corresponding sequence space (machinery, miR-
NA precursors and target sites) are likely to make a significant contribution
to phenotypic variation including disease susceptibility. We
herein review basic miRNA biology in animals, survey the available
evidence for DNA sequence polymorphisms affecting miRNA-mediated
gene regulation and hence phenotype, and discuss their possible
importance in the determinism of complex traits.
S30. Epigenetics and X-inactivation
P. Navarro, C. Chureau, L. Duret, P. Avner, C. Rougeulle;
Unité de Génétique Moléculaire Murine, Institut Pasteur, Paris, France.
Some 150 years after the emergence of genetics, epigenetic mechanisms
are increasingly understood to be fundamental players in phenotype
transmission and development. In addition, epigenetic alterations
are now linked to several human diseases, including cancers. A
common feature of many epigenetic phenomena, for which X-chromosome
inactivation (XCI) is the paradigm, is the implication of non-coding
RNAs. The X-inactivation centre, which controls the initiation of
X-inactivation, hosts several such non-coding RNAs, of which at least
two play essential roles in the process in the mouse. The Xist gene produces
a nuclear RNA that, when expressed in sufficient amount, coats
the chromosome in cis and induce its silencing. Tsix, a transcript antisense
to Xist, is a negative regulator of its sense counterpart, whose
chromatin-remodelling activities have been shown by us and others to
be important for the epigenetic programming of Xist expression.
Although X-chromosome inactivation has been adopted as a dosage
compensation mechanism in all therian mammals, phenotypic
divergences are known to exist between species and to correlate with
genotypic differences, in which non-coding RNAs are particularly concerned.
As essential as it is in placental mammals, Xist was recently
found to have no homolog in marsupials and to be derived from a protein-coding
gene with ancestral functions unrelated to X-inactivation.
Likewise Tsix, which is clearly involved in some aspect of X-inactivation
in the mouse, has seen its existence in human actively debated.
The observation that X chromosome inactivation can be achieved in
different species through distinct pathways, most of which remaining to
be deciphered, underlies the mechanistic plasticity of epigenetic processes
during evolution.
S31. DNA methylation signatures in colorectal cancer
J. Rodriguez 1 , J. Frigola 1 , R. Mayor 1 , L. Vives 2 , M. Jordà 1 , M. A. Peinado 2 ;
1 Institut d’Investigacio Biomèdica de Bellvitge (IDIBELL), L’Hospitalet, Barcelona,
Spain, 2 Institut de Medicina Predictiva i Personalitzada del Càncer
(IMPPC), Badalona, Barcelona, Spain.
Cancer cells are characterized by a generalized disruption of the DNA
methylation pattern involving an overall decrease in the level of 5methylcytosine
together with regional hypermethylation of particular
CpG islands. The extent of both DNA hypomethylation and hypermethylation
in the tumor cell is likely to reflect distinctive biological and clinical
features. We have analyzed DNA methylation profiles in sporadic
colorectal carcinomas, synchronous adenoma-carcinoma pairs and
their matching normal mucosa using different techniques. All tumors
displayed altered patterns of DNA methylation in reference to normal
tissue. Genome-wide hypomethylation and hypermethylation associate
with different features in colorectal tumorigenesis suggesting that
DNA hypermethylation and hypomethylation are independent processes
and play different roles in colorectal tumor progression. While
hypermethylation is associated with patient’s sex, tumor staging, and
specific gene hypermethylation, hypomethylation is an early event, associated
with chromosomal instability and poor prognosis.
S32. Testing and estimation of genotype and haplotype effects in
case/control and family-based association studies
H. Cordell;
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne,
United Kingdom.
A variety of methods are used for the analysis of data generated in
genetic association studies. Most methods focus on the detection of
genetic effects using case/control or family (pedigree) data, although
arguably a more interesting question, once a region of disease association
has been identified, is to estimate the relevant genotypic or
haplotypic effects and to perform tests of complex null hypotheses
such as the hypothesis that some loci, but not others, are associated
with disease. We previously developed a regression-based approach
(Cordell and Clayton 2002; Cordell et al. 2004) that provides a unified
framework for detection or estimation of effects using case/control or
family data. This approach allows genotype and haplotype analysis
at an arbitrary number of linked and unlinked multiallelic loci, as well
as modelling of more complex effects such as gene-gene interactions
(epistasis), gene-environment interactions, parent-of-origin and maternal
genotype effects. In practice, many genetic studies contain moderate
to large amounts of missing genotype data, either arising from
individuals who have not been fully genotyped, or from the inability to
infer phase (alleles received in coupling from a single parent), given
unphased genotype data. We have recently been exploring different
approaches to deal with this missing data problem in the context of
case/control (Cordell 2006) or family (Croiseau et al. 2007) data. In
particular, multiple imputation approaches, in which the missing data
is repeatedly filled in using the correct posterior probability distribution
(given the observed data), appear to represent a promising approach
that has some advantages over missing data likelihood methods with
regards to model flexibility and ease of use.