Sunday June 2, 2013
Organized by IBM Research –
Haifa and Edmond J. Safra Center for Bioinformatics at
Tel-Aviv University
You are cordially invited to participate in a one-day leadership seminar on clinical genomic analysis, to be held Sunday, June 2, 2013, from 9:30 to 17:00 at the IBM research lab, on the University of Haifa campus in Haifa, Israel. Lunch and light refreshments will be served. Participation is free.
This full-day workshop will provide a forum for the research and development communities from both academia and industry to share their work, exchange ideas, and discuss issues, problems, and works-in-progress. The forum will also address future research directions and trends in the area of personalized healthcare and the use of "omics" and Big Data technologies for optimizing the individual care.
This year, we will devote a panel discussion to a current challenge in the healthcare world - genomic medicine.
Student authors are asked to submit an abstract for poster presentation before May 23, 2013.
Please confirm your participation by May 23, via the seminar registration page.
Program
09:30 |
Registration |
---|---|
10:00 |
Opening Remarks, |
10:10 |
The Molecular Basis for Chromosomal Instability
in Early Stages of Cancer Development,
Abstract: Chromosomal instability is a hall
mark of cancer. In early stages of cancer
development the instability is caused by stress on
the DNA replication. However, the molecular basis
for this replication perturbation remained
unknown. We have studied the replication dynamics
in cells enforced to proliferate by aberrant
activation of the Rb-E2F pathway, due to
over-expression of the viral (HPV-16 E6/E7) or
cellular (cyclin E) oncogenes. This enforced cell
proliferation with an insufficient pool of
nucleotides to support normal DNA replication
resulting in replication perturbation, DNA damage
and genome instability. Importantly, an exogenous
supply of nucleosides rescued the replication
stress, decreased the replication-induced DNA
damage and reduced transformation. Increased
transcription of nucleotide biosynthesis genes,
mediated by expressing the transcription factor
c-Myc, increased the nucleotide pool and also
rescued the replication-induced DNA damage. Hence,
the low-nucleotide pool is a result of unbalanced
activation of nucleotide biosynthesis genes.
Tumorigenicity is driven by alterations in cellular and environmental factors. We further analyzed the effect of folate, an environmental factor essential for nucleotide biosynthesis, on the early stages of cancer. We show that suboptimal levels of folate, which are associated with increased risk of cancer development, lead to concentration-dependent replication-induced DNA damage. Importantly, folate deficiency significantly enhances the replication stress caused by aberrant oncogene expression, leading to significantly increased DNA damage and tumorigenic potential. These findings shed new light on the combined effect of cellular and environmental factors on cancer and indicate that the extent of nucleotide-driven replication stress is a key regulator of tumorigenicity.
Bio: TBD
|
10:40 |
Cancer is Associated with Pervasive Positive
Selection on Globally Expressed Genes,
Abstract: Cancer is, at the cellular level,
an evolutionary, adaptive process in which cells
acquire new proliferative and invasive
capabilities. The cancer evolutionary process
depends on genetic variation that is generated by
somatic mutation. While, much focus has been given
to identifying specific positively selected cancer
'driver' mutations, not much is currently
understood about the more general dynamics of how
natural selection affects cancer somatic
mutations. We have been using extensive data of
somatic substitutions from a large number of
breast tumors, gathered by the Cancer Genome Atlas
project, to characterize the intensity with which
purifying and positive selection affect somatic
mutations during the evolution of these tumors. We
demonstrate that breast tumor somatic mutations
are subject to extremely relaxed purifying
selection. At the same time, BRCA somatic
mutations are also strongly influenced by positive
selection, which affects most strongly genes that
are globally expressed across tissues.
Bio: TBD
|
11:05 |
Personalized Medicine — the Future is
Already Here,
Abstract: TBD
Bio: TBD
|
11:30 |
Break |
12:00 |
Solving the Puzzle — the Pathogenic
Effect of Copy Number Variation from the Array
to the Patient and Back,
Abstract: In the past two decades
chromosomal micro arrays (CMA) have emerged as a
powerful tool for identifying novel genomic
syndromes. This technology (using different
platforms) allows the identification of
sub-microscopic chromosomal deletions and
duplications that are 100 times smaller than those
detected by the traditional karyotype. Our one
decade experience utilizing this technology both
in the prenatal and postnatal settings, clearly
suggests that changes in the dosage of the DNA
material makes up part of the normal variation in
the general healthy population, as well as being a
common cause for numerous syndromes.
The challenges related to the "learning curve" primarily regards our need to differ pathogenic vs non-pathogenic copy number variants (CNVs) identified by CMA. The relationship of genotype to phenotype for CNVs is rarely as simple as the dominant and recessive patterns described by Mendel, with some known and others ever defined. The puzzle is just beginning to reveal its full magnitude. The clinical usage of CMA technology as a routine tool for the work-up of patients, families and during pregnancies is essential both for researchers and clinicians attempting to interpret the potential pathogenicity of each identified CNV. In the genomic era, when new technologies such as massive parallel sequencing emerge, insights from CMA is becoming a powerful diagnostic tool aiming to affect treatment modalities of human diseases.
Bio: TBD
|
12:30 |
Challenges in Designing Pharmacogenomics
Studies,
Abstract: In this talk I will review
various possible designs for clinical trials
involving genetic markers, and address their
advantages and disadvantages. I will also discuss
the possibility of combining a PGx trial within a
"regular" clinical trial, and the additional
considerations needed for such a trial.
Bio: TBD
|
12:55 |
Panel: Genomic Medicine, |
13:30 |
Lunch and Poster Session |
14:45 |
Information Stored in Small RNAs,
Abstract: Understanding viral infections in
clinical samples is critical for effective patient
health care. The study of a transcriptome is a
powerful tool for perfecting gene expression and
RNA-based regulation in any organism. Our
laboratory uses massive parallel sequencing
technologies (Deep sequencing or Next Generation
Sequencing) that generate billions of reads per
experiment, to study the RNA-mediated regulatory
mechanisms during cellular processes. We are
currently focusing on emerging principles
controlling non-coding RNA-mediated regulatory
mechanisms during pathogenesis caused by viral
infection. Understanding the impact of this
regulation on viral life cycles together with host
interactions, might provide insight into future
novel targets for intervention. Our genome-wide
analyses will bring us closer towards having a
full non-coding RNA 'signature map' during
infection from both the viral and host
perspectives. These findings will make significant
contribution in the field of systems
pathogenicity.
Bio: TBD
|
15:15 |
Post-Translational Modification (PTM)
Profiling: From Global Patterns to Mechanistic
Insight of Ubl Regulation,
Abstract: The ubiquitin and ubiquitin-like
(Ubl) modification pathways regulate various
aspects of cellular and physiological processes in
health and disease. However, studies mapping
different targets of Ubls on a genome-wide scale
are still lacking. We developed a novel
high-throughput method for detection of
post-translational modifications using an
activity-based assay. We employed the PTM
profiling approach to identify the substrates of
ubiquitin and six additional Ubl modifiers (e.g.
Ubiquitin, SUMO, NEDD8, FAT10, UFM1 and ISG15) in
mitosis. We identified over 1500 potential targets
(known as well as novel ones) of ubiquitin and Ubl
modifications. Our analysis revealed highly
independent target specificities for the different
Ubl modifiers where between 100-200 specific
proteins distinctly classify each of these
pathways (i.e. were reactive exclusively toward
one Ubl). We mapped different molecular functions
and biological processes to each Ubl pathway and
revealed novel specialized roles in various
biological processes.
Interestingly, FAT10 exhibited the most significant effect in target modification upon release from mitotic arrest. Indeed, we found that inhibiting the FAT10 pathway resulted in a mitotic arrest that ultimately lead to cell death. This data is supported by upregulation of FAT10 in different types of cancer, suggesting an underappreciated and important role in mitotic regulation and malignancy. Finally, PTM profiling establishes a broadly-applicable and systematic approach to study regulation of PTMs in the context of human diseases and offers a new molecular dimension for clinical diagnostics.
Bio: TBD
|
15:40 |
Break |
16:10 |
A Tangle of SNPs and Infectious Diseases in
Human and Animal Health,
Abstract: Since last two decades plethora
of the data is generated on gene polymorphism and
point mutations. Special attention has been given
to search any linkage between susceptibility to
infectious diseases and single nucleotide
polymorphisms (SNPs) in genes of immune system
like Toll like receptors (TLRs), MHC genes,
defensins, complement system etc. The first part
of the presentation will be dedicated to a review
of known SNPs in various genes of immune system
and their linkage to the susceptibility to
infectious diseases. The second part will be
focused on novel mutations in the Toll like
receptor -1 (TLR1) and TLR2 of human and animal,
responsible for increase in the susceptibility to
mycobacterial infection. Human and animal TLR1
consist of 20 Lucine rich repeats (LRRs) that take
part in the mycobacterial antigen recognition. The
central region of the extracellular domain of
human TLR1 (LRR9 to LRR12) is necessary for the
sensing of bacterial lipopeptides. We observed
that the central part of TLR1 ectodomain (LRR9 to
LRR11) is more irregular and prone to missense
mutations. Further we showed that novel mutation
Val220Met in LRR10 motif at the 9th amino acid
position disrupts hydrogen bonds in the LRR loop
structure that cause reduced recognition of
mycobacteria. In the case of TLR2, the TIR domain
is crucial as it forms a TIR-TIR dimerized
platform (TLR1-TLR2 and TLR2-TLR6), which promotes
homotypic protein-protein interactions and further
downstream signaling necessary to fight against
mycobacteria. We found that homozygous 670Leu
mutation causes impaired dimerization of TLR2-TIR
domain with its counterparts and thus cause abrupt
downstream signaling. Mapping of such mutations in
the population, finding their linkage with various
infectious diseases and summarizing plethora of
the generated data from such experiments in a
systematic way is challenging but make a
worthwhile contribution to clinical
immonogenetics.
Bio: TBD
|
16:35 |
Cellular Mechanisms of Epilepsy: Chemical
Synapses and Gap Junctions,
Abstract: During brief epileptic bursts,
principal neurons fire together for tens to
hundreds of milliseconds, producing a large
extracellular potential ("field"). Superimposed on
this large field are high-frequency oscillations,
from ~100 to several hundred Hz. Two distinctive
means of coupling between neurons cooperate to
generate the event. Recurrent excitatory synaptic
connections shape the overall event, but gap
junction coupling (between pyramidal cells)
produces the fast oscillations. I will describe
the dissection of the cellular mechanisms via in
vitro experiments (on rodent and human tissue) and
via computer modeling and network theory.
Experimentally, the fast oscillations can be
evoked alone, during blockade of chemical
synapses; but blockade of gap junctions abolishes
BOTH the fast oscillations and the larger burst.
Other lines of evidence pointing toward a critical
role for gap junctions in epilepsy-related very
fast oscillations are these: a) large-scale
spatial patterns of cortical fast oscillations,
resembling an excitable medium; b) the existence
of "glissandi" (~30 to >150 Hz) oscillations in
epileptic tissue, with chemical synapses blocked;
c) recent data showing that fast ripples (>250 Hz)
in resected human tissue persist without chemical
synapses. These data suggest that a targeted
manipulation of selected gap junctions might
prevent certain seizure events.
Bio: TBD
|
17:05 |
Concluding Remarks, |
Navigation
Workshop Organizers
-
Ya'ara Goldschmidt
IBM Research - Haifa
- Ron Shamir
- Eran Halperin
- Saharon Rosset
- Ranit Aharonov
Tel-Aviv University
Tel-Aviv University
Tel-Aviv University