2009 Vienna - European Society of Human Genetics

Concurrent Symposia
s01.1
Genome variation, gene regulation, and human disease
S. McCarrol;
Broad Institute , Program in Medical and Population Genetics, Cambridge, MA,
United States.
No abstract received as per date of printing. Please see www.eshg.
org/eshg2009 for updates.
s01.2
New methods for detecting rare variants associations
A. Kong;
deCODE genetics, Reykjavik, Iceland.
No abstract received as per date of printing. Please see www.eshg.
org/eshg2009 for updates.
s01.3
Rare and common variants in human disease
D. Goldstein;
Duke University, Center for Human Genome Variation, Durham, NC, United
States.
There are now several confirmed common variants that influence
common diseases, responses to infection, and responses to drugs.
For most common diseases however all common variants identified
explain only a few percent of the known heritability, and many of the
signals emerging from genome wide association studies have yet to be
tracked to single common variants, raising the possibility that in some
cases the signals emerge from associated sets of rare variants. Here
I argue that progress in identifying the so called ‘missing heritability’
for many human traits will be facilitated using an extreme phenotype
whole-genome sequencing paradigm. I illustrate the basic structure
and motivation for this approach using examples from our work on host
determinants of control of HIV-1
s02.1
Non-coding antisense RNAs epigenetically regulate
transcription in human cells
K. V. Morris;
Department of Molecular and Experimental Medicine, The Scripps Research
Institute, La Jolla, CA, United States.
Small RNA targeting of promoters in human cells has been shown to
modulate transcriptional gene silencing. While the mechanism involved
in transcriptional gene silencing has been shown to require Argonaute
1 (Ago-1), Histone Deactylase 1 (HDAC-1), and DNA methyltransferase
3a (DNMT3a), the endogenous RNA trigger directing these proteins
to targeted promoters in human cells had remained unknown. We
present evidence here suggesting that non-coding antisense RNAs
function in human cells as effector molecules driving transcriptional
gene silencing. The antisense non-coding RNAs guide epigenetic remodeling
complexes to target promoters in an Ago-1 mediated manner.
When these regulatory antisense non-coding RNAs are degraded
using RNA interference there is a concomitant activation of the sense/
mRNA promoter which is under the regulatory control of the particular
antisense RNA. The data presented here suggests that in human cells,
bidirectional transcription is an endogenous gene regulatory mechanism
whereby antisense non-coding RNAs direct epigenetic regulatory
complexes to the corresponding sense promoters, resulting in RNA
directed epigenetic gene regulation. These observations support the
notion that epigenetic silencing of tumor suppressor genes may be the
result of an imbalance in bidirectional transcription levels. This imbalance
allows the unchecked antisense RNA to direct silent state epigenetic
marks to the sense promoter, resulting in stable transcriptional
gene silencing.
s02.2
the role of microRNAs in brain tumors
D. Beier1 , J. Y. Zhu2 , A. Eichner2 , C. Beier1 , G. Meister2 ;
1Neurologische Universitätsklinik im Bezirksklinikum, Regensburg, Germany,
2Center for integrated protein Sciences Munich (CIPSM), Laboratory of RNA
Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
MicroRNAs (miRNAs) are fundamental regulators of gene expression
that direct processes as diverse as cell metabolism, lineage specification
or cell differentiation. Consistently, miRNAs are frequently misexpressed
in cancer. In several cancer types including breast cancer
and glioblastoma, a minor cell population with stem cell-like properties
has been identified and these cells have been termed cancer stem
cells. Here we report the miRNA expression profile of glioblastoma
stem cells. We find that both miR-9 as well as its corresponding miR-
9* are highly abundant in cancer stem cell-containing cell populations.
Inhibition of both miRNAs leads to reduced tumor growth in vitro and
in nude mice. We further find that inhibition of miR-9/9* leads to enhanced
neuronal differentiation and therefore miR-9/9* inhibit differentiation
of glioblastoma stem cells and maintain their ‘stemness’. Since
tumor stem cells are difficult to target and very often survive therapy,
our findings could be the basis for novel therapeutic strategies.
s02.3
mRNA splicing and disease
U. Fischer;
Department of Biochemistry at the Biocentre, University of Würzburg, Würzburg,
Germany.
Mutations that affect pre-mRNA processing are the cause for many
genetic diseases. Most such mutations target cis-acting regulatory
sequences in a given transcript, thus preventing its proper maturation.
Only recently however, mutations in trans-acting factors involved
in pre-mRNA processing have likewise been linked to disease. One
prominent example is spinal muscular atrophy (SMA) a monogenic,
neuromuscular disorder caused by reduced levels of functional survival
motor neuron (SMN) protein. This ubiquitous factor is part of a
complex that mediates the formation of spliceosomal snRNPs. The detailed
biochemical investigation of SMN under normal conditions and
in SMA has provided clues of how mutations in factors with general
functions elicit tissue specific phenotypes.
s03.1
Predictive Genetic testing for cardiovascular Diseases: impact
on carrier children.
E. M. A. Smets 1 , T. M. Meulenkamp 1 , M. M. H. Stam 1 , A. Tibben 2 , E. D. Mollema
3 , I. M. van Langen 3 , A. Wiegman 4 , G. M. de Wert 5 , I. D. de Beaufort 6 , A. A.
M. Wilde 7 ;
1 Medical Psychology, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands, 2 Center for Human and Clinical Genetics,
Leiden University Medical Center, Leiden, The Netherlands, 3 Clinical Genetics,
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands,
4 Pediatric Lipid Clinic, Emma’s Children Hospital, Academic Medical
Center/University of Amsterdam, Amsterdam, The Netherlands, 5 Health Ethics
and Philosophy, Faculty of Medicine, Maastricht University, Maastricht, The
Netherlands, 6 Health care ethics at the Erasmus Medical Center of Erasmus
University, Rotterdam, The Netherlands, 7 Cardiology, Academic Medical Center/University
of Amsterdam, Amsterdam, The Netherlands.
Familial Hypercholesterolemia, Hypertrophic Cardiomyopathy and
Long QT Syndrome are genetic cardiovascular conditions which may
lead to sudden cardiac death at a young age. Preventive measures
include lifestyle modifications, medications and/or cardiac devices.
Identification of carrier children can protect them for the potentially life
threatening consequences at a young age, but may at the same time
have negative consequences.
Our study aimed to explore a) the manner in which children perceive
their carrier status, b) the impact on their daily lives and c) the strategies
used to cope with these consequences and d) how their quality of
life compares to the quality of life of other children their age.
Children (aged 8-18) who tested positive for LQTS (n=11), HCM (n=6)
or FH (n=16) and their parents participated in semi-structured audiotaped
interviews. Children’s health-related quality of life was assessed
with a children and parent version self-report questionnaire.
The children were overall quite articulate about the disease they were
tested for, including its mode of inheritance. They expressed positive
future health perceptions, but feelings of controllability varied. Adherence
and side-effects were significant themes with regard to medication-use.
Refraining from activities and maintaining a non-fat diet were
themes concerning lifestyle modifications. Some children spontaneously
reported worries about the possibility of dying and frustration
about being different from peers. Children coped with these worries by
expressing faith in the effectiveness of medication, trying to be similar
to peers or, in contrast, emphasizing their ‘being different’. Children
generally appeared effective in the way they coped with their carrier
status and its implications. However, children who tested positive for