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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 9, Number 7, November 2008
Contents
Comprehensive Resources for Tomato Functional Genomics Based
on the Miniature Model Tomato Micro-Tom Pp. 436-443
C. Matsukura, K. Aoki, N. Fukuda, T. Mizoguchi,
E. Asamizu, T. Saito, D. Shibata and H. Ezura
[Abstract]
Molecular Genetics of Alcohol Dependence
and Related Endophenotypes Pp. 444-451
Y.L. Strat, N. Ramoz, G. Schumanna and
P. Gorwood
[Abstract]
Molecular Cytogenetics and Cytogenomics
of Brain Diseases Pp. 452-465
I.Y. Iourov, S.G. Vorsanova and
Y.B. Yurov
[Abstract]
Clinical Utility of Microarrays: Current
Status, Existing Challenges and Future Outlook Pp.
466-474
X. Li, R.J. Quigg, J. Zhou, W. Gu, P.N.
Rao and E.F. Reed
[Abstract]
Genetics and Molecular Biology of Tuberous
Sclerosis Complex Pp. 475-487
V. Napolioni and P. Curatolo
[Abstract]
Pan-Vertebrate Toll-Like Receptors During
Evolution Pp. 488-493
H. Oshiumi, A. Matsuo, M. Matsumoto and
T. Seya
[Abstract]
Gene Expression Profiling as a Tool for
Positional Cloning of Genes-Shortcut or the Longest Way Round
Pp. 494-499
L.W. Rosenlöf
[Abstract]
Hsp90 Affecting Chromatin Remodeling
Might Explain Transgenerational Epigenetic Inheritance in
Drosophila Pp. 500-508
D.M. Ruden and X. Lu
[Abstract]
Abstracts
[Back to top]
Comprehensive Resources for Tomato Functional
Genomics Based on the Miniature Model Tomato Micro-Tom
C. Matsukura, K. Aoki, N. Fukuda, T. Mizoguchi,
E. Asamizu, T. Saito, D. Shibata and H. Ezura
Tomato (Solanum lycopersicum L., Solanaceae)
is an excellent model plant for genomic research of solanaceous
plants, as well as for studying the development, ripening,
and metabolism of fruit. In 2003, the International Solanaceae
Project (SOL, www.sgn.cornell.edu) was initiated by members
from more than 30 countries, and the tomato genome-sequencing
project is currently underway. Genome sequence of tomato obtained
by this project will provide a firm foundation for forthcoming
genomic studies such as the comparative analysis of genes
conserved among the Solanaceae species and the elucidation
of the functions of unknown tomato genes. To exploit the wealth
of the genome sequence information, there is an urgent need
for novel resources and analytical tools for tomato functional
genomics. Here, we present an overview of the development
of genetic and genomic resources of tomato in the last decade,
with a special focus on the activities of Japan SOL and the
National Bio-Resource Project in the development of functional
genomic resources of a model cultivar, Micro-Tom.
[Back to top]
Molecular Genetics of Alcohol Dependence and Related Endophenotypes
Y.L. Strat, N. Ramoz, G. Schumanna and
P. Gorwood
Alcohol dependence is a worldwide public health problem,
and involves both environmental and genetic vulnerability
factors. The heritability of alcohol dependence is rather
high, ranging between 50% and 60%, although alcohol dependence
is a polygenic, complex disorder.
Genome-wide scans on large cohorts of multiplex families,
including the collaborative study on genetics of alcoholism
(COGA), emphasized the role of many chromosome regions and
some candidate genes. The genes encoding the alcohol-metabolizing
enzymes, or those involved in brain reward pathways, have
been involved. Since dopamine is the main neurotransmitter
in the reward circuit, genes involved in the dopaminergic
pathway represent candidates of interest. Furthermore, gamma-amino-butyric
acid (GABA) neurotransmitter mediates the acute actions of
alcohol and is involved in withdrawal symptomatology. Numerous
studies showed an association between variants within GABA
receptors genes and the risk of alcohol dependence.
In accordance with the complexity of the “alcohol dependence”
phenotype, another field of research, related to the concept
of endophenotypes, received more recent attention. The role
of vulnerability genes in alcohol dependence is therefore
re-assessed focusing on different phenotypes and endophenotypes.
The latter include brain oscillations, EEG alpha and beta
variants and alpha power, and amplitude of P300 amplitude
elicited from a visual oddball task.
Recent enhancement on global characterizations of the genome
by high-throughput approach for genotyping of polymorphisms
and studies of transcriptomics and proteomics in alcohol dependence
is also reviewed.
[Back to top]
Molecular Cytogenetics and Cytogenomics of Brain Diseases
I.Y. Iourov, S.G. Vorsanova and
Y.B. Yurov
Molecular cytogenetics is a promising field of biomedical
research that has recently revolutionized our thinking on
genome structure and behavior. This is in part due to discoveries
of human genomic variations and their contribution to biodiversity
and disease. Since these studies were primarily targeted at
variation of the genome structure, it appears apposite to
cover them by molecular cytogenomics. Human brain diseases,
which encompass pathogenic conditions from severe neurodegenerative
diseases and major psychiatric disorders to brain tumors,
are a heavy burden for the patients and their relatives. It
has been suggested that most of them, if not all, are of genetic
nature and several recent studies have supported the hypothesis
assuming them to be associated with genomic instabilities
(i.e. single-gene mutations, gross and subtle chromosome imbalances,
aneuploidy). The present review is focused on the intriguing
relationship between genomic instability and human brain diseases.
Looking through the data, we were able to conclude that both
interindividual and intercellular genomic variations could
be pathogenic representing, therefore, a possible mechanism
for human brain malfunctioning. Nevertheless, there are still
numerous gaps in our knowledge concerning the link between
genomic variations and brain diseases, which, hopefully, will
be filled by forthcoming studies. In this light, the present
review considers perspectives of this dynamically developing
field of neurogenetics and genomics.
[Back to top]
Clinical Utility of Microarrays: Current Status, Existing
Challenges and Future Outlook
X. Li, R.J. Quigg, J. Zhou, W. Gu, P.N.
Rao and E.F. Reed
Microarray-based clinical tests have become powerful
tools in the diagnosis and treatment of diseases. In contrast
to traditional DNA-based tests that largely focus on single
genes associated with rare conditions, microarray-based tests
are ideal for the study of diseases with underlying complex
genetic causes. Several microarray based tests have been translated
into clinical practice such as MammaPrint and AmpliChip CYP450.
Additional cancer-related microarray-based tests are either
in the process of FDA review or under active development,
including Tissue of Tumor Origin and AmpliChip p53. All diagnostic
microarray testing is ordered by physicians and tested by
a Clinical Laboratories Improvement Amendment-certified (CLIA)
reference laboratory. Recently, companies offering consumer
based microarray testing have emerged. Individuals can order
tests online and service providers deliver the results directly
to the clients via a password-protected secure website.
Navigenics, 23andMe and deCODE Genetics represent pioneering
companies in this field. Although the progress of these microarray-based
tests is extremely encouraging with the potential to revolutionize
the recognition and treatment of common diseases, these tests
are still in their infancy and face technical, clinical and
marketing challenges. In this article, we review microarray-based
tests which are currently approved or under review by the
FDA, as well as the consumer-based testing. We also provide
a summary of the challenges and strategic solutions in the
development and clinical use of the microarray-based tests.
Finally, we present a brief outlook for the future of microarray-based
clinical applications.
[Back to top]
Genetics and Molecular Biology of Tuberous Sclerosis Complex
V. Napolioni and P. Curatolo
Tuberous Sclerosis Complex is a multisystem disorder
exhibiting a wide range of manifestations characterized by
tumour-like lesions called hamartomas in the brain, skin,
eyes, heart, lungs and kidneys. Tuberous Sclerosis Complex
is genetically determined with an autosomal dominant inheritance
and is caused by inactivating mutations in either the TSC1
or TSC2 genes. TSC1/2 genes play a fundamental role in the
regulation of phosphoinositide 3-kinase (PI3K) signalling
pathway, inhibiting the mammalian target of rapamycin (mTOR)
through activation of the GTPase activity of Rheb. Mutations
in TSC1/2 genes impair the inhibitory function of the hamartin/tuberin
complex, leading to phosphorylation of the downstream effectors
of mTOR, p70 S6 kinase (S6K), ribosomal protein S6 and the
elongation factor binding protein 4E-BP1, resulting in uncontrolled
cell growth and tumourigenesis.
Despite recent promising genetic, diagnostic, and therapeutic
advances in Tuberous Sclerosis Complex, continuing research
in all aspects of this complex disease will be pivotal to
decrease its associated morbidity and mortality. In this review
we will discuss and analyse all the important findings in
the molecular pathogenesis of Tuberous Sclerosis Complex,
focusing on genetics and the molecular mechanisms that define
this multisystemic disorder.
[Back to top]
Pan-Vertebrate Toll-Like Receptors During Evolution
H. Oshiumi, A. Matsuo, M. Matsumoto and
T. Seya
Human toll-like receptors (TLRs) recognize pathogen-associated
molecular patterns (PAMPs) to raise innate immune responses.
The human TLR family was discovered because of its sequence
similarity to fruit fly (Drosophila) Toll, which
is involved in an anti-fungal response. In this review, we
focus on the origin of the vertebrate TLR family highlighted
through functional and phylogenetic analyses of TLRs in non-mammalian
vertebrates. Recent extensive genome projects revealed that
teleosts contain almost all subsets of TLRs that correspond
to human TLRs (TLR1, 2, 3, 4, 5, 7, 8, and 9), whereas the
urochordate Ciona intestinalis contains only a few
TLR genes. Therefore, mammals likely obtained almost all TLR
family members at the beginning of vertebrate evolution. This
premise is further supported by several functional analyses
of non-mammalian TLRs. We have summarized several teleost
TLRs with unique properties distinct from mammalian TLRs to
outline their specific roles. According to Takifugu rubripes
genome project, the puffer fish possesses fish-specific
TLR21 and 22. Surprisingly, phylogenetic analyses indicate
that TLR21 and 22 emerged during an early period of vertebrate
evolution in parallel with other TLRs and that the mammalian
ancestor lost TLR21 and 22 during evolution. Our laboratory
recently revealed that TLR22 recognizes double-strand RNA
and induces interferon production through the TICAM-1 adaptor,
as in TLR3, but unlike TLR3, TLR22 localizes to the cell surface.
Therefore, differential expression of TLR3 and TLR22, rather
than simple redundancy of RNA sensors, may explain the effective
protection of fish from RNA virus infection in the water.
In this review, we summarize the similarities and differences
of the TLR family in various vertebrates and introduce these
unique TLRs for a possible application to the field of clinical
practices for cancer or virus infection.
[Back to top]
Gene Expression Profiling as a Tool for Positional Cloning
of Genes-Shortcut or the Longest Way Round
L.W. Rosenlöf
The identification of quantitative trait loci, QTL, in
arthritis animal models is a straight forward process. However,
to identify the underlying genes is a great challenge. One
strategy frequently used, is to combine QTL analysis with
genomic/proteomic screens. This has resulted in a number of
publications where carefully performed genomic analyses present
likely candidate genes for their respective QTL´s. However,
seldom the findings are reconnected to the QTL controlled
phenotypes. In this review, we use our own data as an illustrative
example that “very likely candidate genes” identified
by genomic/proteomics is not necessarily the same as true
QTL underlying genes.
[Back to top]
Hsp90 Affecting Chromatin Remodeling Might Explain Transgenerational
Epigenetic Inheritance in Drosophila
D.M. Ruden and X. Lu
Transgenerational epigenetic inheritance, while poorly
understood, is of great interest because it might help explain
the increase in the incidence of diseases with an environmental
contribution in humans, such as cancer, diabetes, and heart
disease. Here, we review five Drosophila examples
of transgenerational epigenetic inheritance and propose a
unified mechanism that involves Polycomb Response Element/Trithorax
Response Element (PRE/TRE) occupancy by either Polycomb Group
(PcG) protein complexes or Trithorax group (TrxG) complexes.
Among their other activities, PcG complexes cause histone
3 lysine 27 tri-methylation associated with repressed chromatin,
whereas Trithorax group (TrxG) complexes induce histone 3
lysine 4 tri-methylation associated with actively transcribed
chromatin. In this model, Hsp90 is an environmentally sensitive
chromatin remodeling regulator that causes a switch in the
chromatin from a permissive state to a non-permissive state
for transcription. Consistent with this model, Hsp90 has recently
been shown to be a chaperone for Tah1p (TPR-containing protein
associated with Hsp90) and Pih1p (protein interacting with
Hsp90), which connect to the chromatin remodelling factor
Rvb1p (RuvB-like protein 1)/Rvb2p in yeast [1]. Also, Hsp90
is required for optimal activity of the histone H3 lysine-4
methyltransferase SMYD3 in mammals [2, 3]. Since PcG and TrxG
complexes are involved in the post-translational modifications
of histones, and since such modifications have been shown
to be required to maintain imprinted marks, this unified mechanism
might also help to explain transgenerational epigenetic inheritance
in humans.
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