|
Current Genomics
ISSN: 1389-2029
Upcoming Articles
Molecular Genetics of Alcohol Dependence and Related
Endophenotypes
Yann Le Strat, Nicolas Ramoz, Gunter Schuman, Philip Gorwoo
[Abstract]
Pan-Vertebrate Toll-Like Receptors During Evolution
Hiroyuki Oshiumi, Aya Matsuo, Misako Matsumoto and Tsukasa
Seya
[Abstract]
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
[Abstract]
Gene Expression Profiling as a Tool for Positional
Cloning of Genes-Shortcut or the Longest Way Round
Lena Wester Rosenlöf
[Abstract]
Systems Behavior: Of Male Courtship, the Nervous System
and Beyond in Drosophila
B. Dauwalder
[Abstract]
Molecular Effects of the CTG Repeats in Mutant Dystrophia
Myotonica Protein Kinase Gene
Beatriz Llamusí and Ruben Artero
[Abstract]
Meta Analysis of Gene Expression Data within and Across
Species
Ana Carolina Fierro, Filip Vandenbussche, Kristof Engelen,
Yves Van de Peer and Kathleen Marchal
[Abstract]
Genetics in Osteoarthritis
Mercedes Fernández-Moreno, Ignacio Rego, Vanessa Carreira-Garcia
and Francisco J. Blanco
[Abstract]
Genomic Instability and Carcinogenesis: An Update
Wael M. Abdel-Rahman
[Abstract]
Alternative Splicing and Tumor Progression
Claudia Ghigna, Cristina Valacca and Giuseppe Biamonti
[Abstract]
Periostin as a Heterofunctional Regulator of Cardiac
Development and Disease
Simon J. Conway and Jeffery D. Molkentin
[Abstract]
Toxicogenomics to Improve Comprehension of the Mechanisms
Underlying Responses of In Vitro and In Vivo
Systems to Nanomaterials: A Review
Anna Poma and Maria Laura Di Giorgio
[Abstract]
Abstracts
[Back to top]
Molecular Genetics of Alcohol Dependence
and Related Endophenotypes
Yann Le Strat, Nicolas Ramoz, Gunter Schumann, Philip
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]
Pan-Vertebrate Toll-Like Receptors During Evolution
Hiroyuki Oshiumi, Aya Matsuo, Misako Matsumoto and
Tsukasa 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]
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]
Gene Expression Profiling as a Tool for
Positional Cloning of Genes-Shortcut or the Longest Way Round
Lena Wester 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]
Systems Behavior: Of Male Courtship, the Nervous System
and Beyond in Drosophila
B. Dauwalder
Male courtship in fruit flies is regulated by the same major
regulatory genes that also determine general sexual differentiation
of the animal. Elaborate genetics has given us insight into
the roles of these master genes. These findings have suggested
two separate and independent pathways for the regulation of
sexual behavior and other aspects of sexual differentiation.
Only recently have molecular studies started to look at the
downstream effector genes and how they might control sex-specific
behavior. These studies have confirmed the essential role
of the previously identified male specific products of the
fruitless gene in the neuronal circuits in which
it is expressed. But there is increasing evidence that a number
of non-neuronal tissues and pathways play a pivotal role in
modulating this circuit and assuring efficient courtship.
[Back to top]
Molecular Effects of the CTG Repeats in Mutant Dystrophia
Myotonica Protein Kinase Gene
Beatriz Llamusí and Ruben Artero
Myotonic Dystrophy type 1 (DM1) is a multi-system disorder
characterized by muscle wasting, myotonia, cardiac conduction
defects, cataracts, and neuropsychological dysfunction. DM1
is caused by expansion of a CTG repeat in the 3´untranslated
region (UTR) of the Dystrophia Myotonica Protein Kinase
(DMPK) gene. A body of work demonstrates that DMPK
mRNAs containing abnormally expanded CUG repeats are toxic
to several cell types. A core mechanism underlying symptoms
of DM1 is that mutant DMPK RNA interferes with the
developmentally regulated alternative splicing of defined
pre-mRNAs. Expanded CUG repeats fold into ds(CUG) hairpins
that sequester nuclear proteins including human Muscleblind-like
(MBNL) and hnRNP H alternative splicing factors. DM1 cells
activate CELF family member CUG-BP1 protein through hyperphosphorylation
and stabilization in the cell nucleus. CUG-BP1 and MBNL1 proteins
act antagonistically in exon selection in several pre-mRNA
transcripts, thus MBNL1 sequestration and increase in nuclear
activity of CUG-BP1 both act synergistically to missplice
defined transcripts. Mutant DMPK-mediated effect
on subcellular localization, and defective phosphorylation
of cytoplasmic CUG-BP1, have additionally been linked to defective
translation of p21 and MEF2A in DM1, possibly explaining delayed
differentiation of DM1 muscle cells. Mutant DMPK
transcripts bind and sequester transcription factors such
as Specificity protein 1 leading to reduced transcription
of selected genes. Recently, transcripts containing long hairpin
structures of CUG repeats have been shown to be a Dicer ribonuclease
target and Dicer-induced downregulation of the mutant DMPK
transcripts triggers silencing effects on RNAs containing
long complementary repeats. In summary, mutant DMPK
transcripts alter gene transcription, alternative splicing,
and translation of specific gene transcripts, and have the
ability to trigger gene-specific silencing effects in DM1
cells. Therapies aimed at reversing these gene expression
alterations should prove effective ways to treat DM1.
[Back to top]
Meta Analysis of Gene Expression Data within and Across
Species
Ana Carolina Fierro, Filip Vandenbussche, Kristof Engelen,
Yves Van de Peer and Kathleen Marchal
Since the second half of the 1990s, a large number of genome-wide
analyses have been described that study gene expression at
the transcript level. To this end, two major strategies have
been adopted, a first one relying on hybridization techniques
such as microarrays, and a second one based on sequencing
techniques such as serial analysis of gene expression (SAGE),
cDNA-AFLP, and analysis based on expressed sequence tags (ESTs).
Despite both types of profiling experiments becoming routine
techniques in many research groups, their application remains
costly and laborious. As a result, the number of conditions
profiled in individual studies is still relatively small and
usually varies from only two to few hundreds of samples for
the largest experiments. More and more, scientific journals
require the deposit of these high throughput experiments in
public databases upon publication. Mining the information
present in these databases offers molecular biologists the
possibility to view their own small-scale analysis in the
light of what is already available. However, so far, the richness
of the public information remains largely unexploited. Several
obstacles such as the correct association between ESTs and
microarray probes with the corresponding gene transcript,
the incompleteness and inconsistency in the annotation of
experimental conditions, and the lack of standardized experimental
protocols to generate gene expression data, all impede the
successful mining of these data. Here, we review the potential
and difficulties of combining publicly available expression
data from respectively EST analyses and microarray experiments.
With examples from literature, we show how meta-analysis of
expression profiling experiments can be used to study expression
behavior in a single organism or between organisms, across
a wide range of experimental conditions. We also provide an
overview of the methods and tools that can aid molecular biologists
in exploiting these public data.
[Back to top]
Genetics in Osteoarthritis
Mercedes Fernández-Moreno, Ignacio Rego,
Vanessa Carreira-Garcia and Francisco J. Blanco
Osteoarthritis is a degenerative articular disease with complex
pathogeny because diverse factors interact causing a process
of deterioration of the cartilage. Despite the multifactorial
nature of this pathology, from the 50’s it´s known
that certain forms of osteoarthritis are related to a strong
genetic component. The genetic bases of this disease do not
follow the typical patterns of mendelian inheritance and probably
they are related to alterations in multiple genes. The identification
of a high number of candidate genes to confer susceptibility
to the development of the osteoarthritis shows the complex
nature of this disease. At the moment, the genetic mechanisms
of this disease are not known, however, which seems clear
is that expression levels of several genes are altered, and
that the inheritance will become a substantial factor in future
considerations of diagnosis and treatment of the osteoarthritis.
[Back to top]
Genomic Instability and Carcinogenesis: An
Update
Wael M. Abdel-Rahman
Cancers arise as a result of stepwise accumulation of mutations
which may occur at the nucleotide level and/or the gross chromosomal
level. Many cancers particularly those of the colon display
a form of genomic instability which may facilitate and speed
up tumor initiation and development. In few instances, a “mutator
mutation” has been clearly implicated in driving the
accumulation of other carcinogenic mutations. For example,
the post-replicative DNA mismatch repair deficiency results
in dramatic increase in insertion/deletion mutations giving
rise to the microsatellite instability (MSI) phenotype and
may predispose to a spectrum of tumours when it occurs in
the germline. Although many sporadic cancers show multiple
mutations suggesting unstable genome, the role of this instability
in carcinogenesis, as opposed to the power of natural selection,
has been a matter of controversy. This review gives an update
of the latest data on these issues particularly recent data
from genome-wide, high throughput techniques as well as mathematical
modelling. Throughout this review, reference will be made
to the relevance of genomic instability to the pathogenesis
of colorectal carcinoma particularly its hereditary and familial
subsets.
[Back to top]
Alternative Splicing and Tumor Progression
Claudia Ghigna, Cristina Valacca and Giuseppe Biamonti
Alternative splicing is a key molecular mechanism
for increasing the functional diversity of the eukaryotic
proteomes. A large body of experimental data implicates aberrant
splicing in various human diseases, including cancer. Both
mutations in cis-acting splicing elements and alterations
in the expression and/or activity of splicing regulatory factors
drastically affect the splicing profile of many cancer-associated
genes. In addition, the splicing profile of several cancer-associated
genes is altered in particular types of cancer arguing for
a direct role of specific splicing isoforms in tumor progression.
Deciphering the mechanisms underlying aberrant splicing in
cancer may prove crucial to understand how splicing machinery
is controlled and integrated with other cellular processes,
in particular transcription and signaling pathways. Moreover,
the characterization of splicing deregulation in cancer will
lead to a better comprehension of malignant transformation.
Cancer-associated alternative splicing variants may be new
tools for the diagnosis and classification of cancers and
could be the targets for innovative therapeutical interventions
based on highly selective splicing correction approaches.
[Back to top]
Periostin as a Heterofunctional Regulator of Cardiac Development
and Disease
Simon J. Conway and Jeffery D. Molkentin
Periostin (Postn) is a heterofunctional secreted
extracellular matrix (ECM) protein comprised of four fasciclin
domains that promotes cellular adhesion and movement, as well
as collagen fibrillogenesis. Postn is expressed in unique
growth centers during embryonic development where it facilitates
epithelial-mesenchymal transition (EMT) of select cell populations
undergoing reorganization. In the heart, Postn is expressed
in the developing valves, cardiac fibroblasts and in regions
of the outflow track. In the adult, Postn expression is specifically
induced in areas of tissue injury or areas with ongoing cellular
re-organization. In the adult heart Postn is induced in the
ventricles following myocardial infarction, pressure overload
stimulation, or generalized cardiomyopathy. Here we will review
the functional consequences associated with Postn induction
in both the developing and adult heart. The majority of data
collected to date suggest a common function for Postn in both
development and disease as a potent inducible regulator of
cellular reorganization and extracellular matrix homeostasis,
although some alternate and controversial functions have also
been ascribed to Postn, the validity of which will
be discussed here.
[Back to top]
Toxicogenomics to Improve Comprehension of the Mechanisms
Underlying Responses of In Vitro and In Vivo
Systems to Nanomaterials: A Review
Anna Poma and Maria Laura Di Giorgio
Engineered nanomaterials are commonly defined as materials
with at least one dimension of 100 nanometers or less. Such
materials typically possess nanostructure-dependent properties
(e.g., chemical, mechanical, electrical, optical, magnetic,
biological), which make them desiderable for commercial or
medical application. However, these same properties may potentially
lead to nanostructure-dependent biological activity that differs
from and is not directly predicted by the bulk properties
of the constitutive chemicals and compounds. Nanoparticles
and nanomaterials can be on the same scale of living cells
components, including proteins, nucleic acids, lipids and
cellular organelles. When considering nanoparticles it must
be asked how man-made nanostructures can interact with or
influence biological systems. Carbon nanotubes (CNTs) are
an example of carbon-based nanomaterial, which has won a huge
spreading in nanotechnology. The incorporation of CNTs in
living systems has raised many concerns because of their hydrophobicity
and tendency to aggregate and accumulate into cells, organs,
and tissues with dangerous effects.
Applications of toxicogenomics to both investigative and predictive
toxicology will contribute to the in-depth investigation of
molecular mechanisms or the mode of nanomaterials action that
is achieved by using conventional toxicological approaches.
Parallel toxicogenomic technologies will promote a valuable
platform for the development of biomarkers, in order to predict
possible nanomaterial’s toxicity. The potential of characteristic
gene expression profiles (“fingerprint”) of exposure
or toxicological response to nanoparticles will be discussed
in the review to enhance comprehension of the molecular mechanism
of in vivo and in vitro system exposed to
nanomaterials.
|
