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

Concurrent Symposia
S17. Towards a gene expression map of human brain
development
S. Lindsay 1 , L. Puelles 2 , D. Vouyiouklis 1 , M. Muiras 1 , S. Woods 3 , M. Atkinson 4 ,
D. Davidson 5 , T. Strachan 1 , R. A. Baldock 5 ;
1 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne,
United Kingdom, 2 University of Murcia, Murcia, Spain, 3 PEALS Institute, Newcastle
University, Newcastle upon Tyne, United Kingdom, 4 National e-Science
Centre, University of Edinburgh, Edinburgh, United Kingdom, 5 MRC Human
Genetics Unit, Edinburgh, United Kingdom.
Discoveries of human-specific gene expression or gene regulation
or gene content are being made at an accelerating pace and have
sparked interest in molecular answers to the question of “what makes
us human”. Studies of the human brain and its development are expected
to provide at least some of these answers.
Characterising gene expression patterns is a crucial step towards understanding
the molecular determinants of development and the roles
of genes in disease. However, human brain development involves
transformations from a simple tube to a highly organised and complex
3-dimensional (3-D) structure. We have used a recently developed
method, optical projection tomography (OPT), to generate digital 3-D
models of early human brain development. These models can be used
both as frameworks, on to which normal or experimental gene expression
data can be mapped, and as objects, which provide a valuable
means for visual interpretation and overview of complex morphological
data and within which morphological relationships can be investigated
in silico. Together these models, mapped gene expression patterns
and the sophisticated software to manipulate and analyse them are
being expanded towards the generation of an electronic atlas of human
brain development (www.ncl.ac.uk/EADHB). This should be a
mechanism for systematically correlating human gene expression results
with corresponding data in mouse and provide a scientific basis
for extrapolation from mouse model to human disease which is crucial
if we are to safely use the mouse (or other animal models) to investigate
the mechanisms underlying human disorders and for testing
therapeutic agents or interventions.
More generally, human developmental studies bring with them ethical
and technical challenges and will need a large-scale, trans-national
effort in order to make the maximum effective use of the limited human
tissue (suitable for gene expression studies) that is being collected.
DGEMap (Developmental Gene Expression Map) is an EU-funded
Design Study with a multidisciplinary team which aims to define the
molecular genetic & informatics technologies and the organisational &
collaborative structures necessary for a new research infrastructure to
meet these challenges within an appropriate ethical framework (www.
dgemap.org)
S18. Genetic and genomic studies of patterning in the human
cerebral cortex
X. Piao, T. Sun, B. Chang, C. A. Walsh;
Division of Genetics, Children’s Hospital Boston, Howard Hughes Medical Institute,
Beth Israel Deaconess Medical Center, and Departments of Neurology
and Pediatrics, Harvard Medical School, Boston, MA, United States.
The human cerebral cortex is distinguished from that of other species
by its remarkable size, its subdivision into lobes and regions with distinct
functions, and the relative specialization of the left and right hemispheres
for complementary functions, with the left usually dominant
for language and mathematical ability. Remarkably, genetic malformations
of human cerebral cortex can affect different cortical regions
preferentially, potentially identifying genes involved in generating areaspecific
patterns in human cortex. Mutations in GPR56, which encodes
an unusual G-protein coupled receptor, cause a recessively inherited
disorder that preferentially affects the frontal lobe (bilateral frontoparietal
polymicrogyria), and specific GPR56 alleles cause remarkably
localized frontal defects. Understanding the regulation of GPR56 expression
may reveal additional factors that pattern the cortex. In order
to identify genes with potential differences in expression between left
and right hemisphere, we used SAGE to compare right and left perisylvian
cortex at 12-14 weeks gestation, and found substantial numbers
of genes with differential levels of expression, notably LMO4. We
are presently extending these studies to earlier developmental ages.
Finally, a recently described human brain malformation preferentially
disrupts the right perisylvian region but not the left, suggesting a gene
that may be involved in hemisphere-specific development. Supported
by the NINDS, HHMI, the NLM Family Foundation and the Simons
Foundation. C.A.W. is an Investigator of the Howard Hughes Medical
Institute.
S19. Signalling Pathways Deduced from a Global Analysis of
Spatial Gene Expression Patterns
A. Visel 1 , J. Carson 2 , J. Oldekamp 1 , M. Warnecke 1 , V. Jakubcakova 1 , X. Zhou 1 ,
C. Shaw 3 , G. Alvarez-Bolado 1 , G. Eichele 1 ;
1 Genes and Behavior Department, MPI Biophysical Chemistry, Göttingen, Germany,
2 Biological Monitoring and Modeling Department, Pacific Northwest National
Laboratory, Richland, WA, United States, 3 Department of Molecular and
Human Genetics, Baylor College of Medicine, Houston, TX, United States.
Automated in situ hybridization (ISH) permits construction of comprehensive
atlases of gene expression patterns in mammals. When
web-accessible, such atlases become searchable digital expression
maps of individual genes and offer an entryway to elucidate genetic
interactions and signaling pathways. An atlas housing ~1,000 spatial
gene expression patterns of the mid-gestation mouse embryo was
generated. Patterns were textually annotated using a controlled vocabulary
comprising 90 anatomical features. Hierarchical clustering
of annotations was carried out using distance scores calculated from
the similarity between pairs of patterns across all anatomical structures.
This ordered hundreds of complex expression patterns into a
matrix that reflected the embryonic architecture and the relatedness
of patterns of expression. Clustering yielded twelve distinct groups of
expression pattern. Because of similarity of expression patterns within
a group, members of this group may be components of regulatory cascades.
We focused on group 7 which is composed of 80 genes, many
of which encoded regulatory proteins such as Pax6, an evolutionary
conserved transcriptional master mediator of the development. By
combining ISH on Pax6-deficient embryos, bioinformatics-driven Pax6
binding site selection, and Pax6 binding site validation by means of
electromobility shift assays, we identify numerous new genes that are
transcriptionally regulated by Pax6 in the developing neocortex. Hence
cluster analysis of annotated gene expression patterns derived from
ISH is a novel approach to unravel components of signaling cascades
regulating critical aspects of mammalian development, physiology and
pathophysiology.
S20. New mechanisms of human genetic disease
M. De Gobbi 1 , V. Viprakasit 2 , J. Hughes 1 , C. Fisher 1 , V. J. Buckle 1 , H. Ayyub 1 ,
R. J. Gibbons 1 , D. Vernimmen 1 , Y. Yoshinaga 3 , P. de Jong 3 , J. F. Chen 4 , E. M.
Rubin 4 , W. G. Wood 1 , D. Bowden 5 , D. R. Higgs 1 ;
1 MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine,
Oxford, United Kingdom, 2 Department of Pediatrics, Mahidol University, Bangkok,
Thailand, 3 BACPAC Resources, Oakland Research Institute, Oakland,
CA, United States, 4 Genome Science, Genomic Division, Lawrence Berkeley
National Laboratory, CA, United States, 5 Clinical Genetics Laboratory, Monash
Medical Centre, Clayton, Australia.
We describe a new mechanism underlying human genetic disease by
identifying a gain of function regulatory SNP (rSNP) that causes a form
of alpha thalassaemia which occurs at polymorphic frequencies in
Melanesia. Association studies localised the mutation to a 168kb segment
of the genome including the alpha globin locus but conventional
analyses failed to detect any molecular defect. After re-sequencing
this region and using a combination of chromatin immunoprecipitation
and expression analysis on a tiled oligonucleotide array, a regulatory
SNP (rSNP) was identified in a nondescript region of the genome lying
between the alpha globin genes and their highly conserved, remote,
upstream regulatory elements. The rSNP creates a new promoter-like
element which interferes with normal activation of all downstream alpha-like
genes. This not only demonstrates a new mechanism of human
genetic disease but also illustrates an important general strategy
for distinguishing between neutral and functionally important rSNPs.
S21. Chromosome dynamics in cytokine gene expression
C. Spilianakis, T. Town, R. A. Flavell;
Department of Immunobiology, Yale University School of Medicine, New Haven,
CT, United States.
In the last few years, we have found that regulatory elements on one
chromosome associate with genes on another chromosome. The system
that we study is the differentiation of naïve, precursor CD4 T cells
into different kinds of effector helper T cells. We first observed inter-