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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 7, Number 3, May 2006
Contents
Current Concepts on the Genetics and Pharmacogenetics
of Inflammatory Bowel Disease: Do they Help in Clinical Management?
Pp. 149-162
P.L. Lakatos and L. Lakatos
[Abstract]
Operons Across Prokaryotes: Genomic Analyses and
Predictions 300+ Genomes Later Pp. 163-170
G. Moreno-Hagelsieb
[Abstract]
Molecular Detection of Bacteria Producing Newer
Types of β-Lactamases
Pp. 171-177
J.D.D. Pitout
[Abstract]
Therapeutic DNA Delivery to Skeletal Muscle
Pp. 179-190
A. Quigley, K. Lowes, A.J. Kornberg, M.J. Cook and R.
Kapsa
[Abstract]
Suggestive Associations Between Polymorphisms
in PAX9, MSX1 Genes and Third Molar Agenesis in Humans
Pp. 191-196
C.P.B. Saito, F.J. Bianchi, R.C.R. Peres and S.R.P. Line
[Abstract]
Clustering Periodic Patterns of Gene Expression
Based on Fourier Approximations Pp. 197-203
B.-R. Kim, R.C. Littell and R. Wu
[Abstract]
Abstracts
[Back to top]
Current Concepts on the Genetics and Pharmacogenetics
of Inflammatory Bowel Disease: Do they Help in Clinical Management?
P.L. Lakatos and L. Lakatos
The pathogenesis of inflammatory bowel disease is only
partially understood; various environmental and host (e.g.
genetic-, epithelial-, immune and non-immune) factors are
involved. It is a multifactorial polygenic disease with probable
genetic heterogeneity. Much of the recent emphasis in inflammatory
bowel disease genetics research has been directed at the evaluation
of candidate disease susceptibility genes within inflammatory
bowel disease linkage intervals. Such studies have elucidated
associations of numerous gene variants (e.g. NOD2/CARD15,
SLC22A4/A5 and DLG5) with inflammatory bowel disease, but
most of these require further replication and functional validation.
Some genes are associated with inflammatory bowel disease
itself, while others increase the risk of ulcerative colitis
or Crohn’s disease or are associated with disease location
and/or behaviour. Recently, some new data also indicated at
a possible role for genetics in predicting therapeutic success
(e.g. response to infliximab or steroids). Genetic information
acquired in recent years helps in understanding the pathogenesis
of inflammatory bowel disease and identifying a number of
potential targets for therapeutic intervention. In the future,
genetics may also help in more accurate diagnosis and prediction
of disease course and response to therapy in inflammatory
bowel disease.
[Back to top]
Operons Across Prokaryotes: Genomic Analyses
and Predictions 300+ Genomes Later
G. Moreno-Hagelsieb
With operon predictions based on conservation of gene
order and 330 Prokaryotic genomes available, I am able to
show that in most of the genomes analyzed about 70% of the
genes in operons are separated by distances of -20 to 30 base
pairs. Most of the differences in this tendency might be related
to the appearance of signals inside the operons. However,
a closer look at the extreme exceptions confirms that annotation
problems are partly responsible for inter-genic distance distributions
that deviate from that of operons in Escherichia coli
K12. I also argue that the inter-genic distances of adjacent
genes in different transcription units (transcription unit
boundaries or TUBs) should be expected to be more variable
than those for genes in the same operon. Using phylogenetic
profiles I show that predictions adjusted on a per genome
basis might help increase the accuracy of operon predictions.
Improvements in automated annotation might be necessary to
fully evaluate the overall tendencies of genes in operons
towards short intergenic distances, and to better understand
differences in regulatory complexity across Prokaryotes.
[Back to top]
Molecular Detection of Bacteria Producing
Newer Types of β-Lactamases
J.D.D. Pitout
In Gram-negative pathogens, β-lactamase
production remains the most important contributing factor
to β-lactam
resistance. β-lactamases
are bacterial enzymes that inactivate β-lactam
antibiotics by hydrolysis, which results in ineffective compounds.
The three major groups usually referred to as the “newer
β-lactamases”
are plasmid-mediated AmpC enzymes, extended-spectrum β-lactamases
(ESBLs) and carbapenem-hydrolyzing enzymes (including metallo-β-lactamases
[MBLs]). Molecular methods that include simple and multiplex
PCR, real-time PCR, DNA sequencing and various hybridization-based
techniques are used widely in research and reference laboratories
for the detection of organisms producing newer β-lactamases.
The routine screening in clinical diagnostic laboratories
of organisms producing TEM, SHV and OXA types of ESBLs using
genotypic methods remains problematic, while the detection
of CTX-Ms, plasmid-mediated AmpCs and MBLs shows clinical
usefulness. Molecular methods have advantages over phenotypic
tests by accurately detecting resistant genes in a rapid fashion
and by defining the precise genetic basis of the resistance
mechanism providing important information valuable to the
early introduction of infection control practices. Molecular
assays have the potential to complement conventional phenotypic
susceptibility techniques and impact directly on patient care.
[Back to top]
Therapeutic DNA Delivery to Skeletal Muscle
A. Quigley, K. Lowes, A.J. Kornberg, M.J. Cook and R.
Kapsa
Gene therapy has advanced rapidly over the last
few decades due to the development of viral and plasmid vectors
for gene delivery and strategies for the direct alteration
of DNA/RNA species. Gene replacement using modified viral
vectors and plasmids has yielded the greatest levels of therapeutic
protein expression in muscle to date, however there are issues
with immune mediated response to transgene and viral proteins,
hindering sustained expression. New efforts have been made
to make viral delivery of genes safer and sustainable, these
include the development of hybrid vectors and “gutted”
helper dependant vectors.
Non-viral methods of gene delivery and repair provide an alternative
to viral based methods. Major concerns with non-viral approaches
include the effective distribution and integration of therapeutic
molecules throughout the muscle. However, a number of methods
have been developed to overcome these obstacles. These include
electroporation, vascular injection and occlusion, myotoxins
promoting muscle regeneration, muscle specific promoters and
the use of pharmacological agents to enhance DNA delivery
for gene delivery or gene repair. A number of non-viral plasmid
based protocols for gene delivery to muscle have reached the
clinical trial stage and show great promise. This review discusses
recent advances in viral and non-viral based therapies for
muscle diseases, the issues faced by these technologies and
current efforts to overcome these obstacles.
[Back to top]
Suggestive Associations Between Polymorphisms
in PAX9, MSX1 Genes and Third Molar Agenesis in Humans
C.P.B. Saito, F.J. Bianchi, R.C.R. Peres and S.R.P.
Line
Hypodontia, the congenital agenesis of one or few permanent
teeth is among the most common alterations in human dentition.
Pax9 and Msx1 genes have critical roles in craniofacial development.
Mutations in these genes cause severe tooth agenesis in humans
and mice. The aim of the present work was to study the association
of the CA repeat in the first intron of MSX1 gene
and the C-160T polymorphism in the promoter region of PAX9
gene and hypodontia in humans, with emphasis on third molar
agenesis. DNA extracted from buccal epithelial cells was amplified
by the Polymerase Chain Reaction. Denaturing Gel Electrophoresis,
DNA sequencing and PCR-RLFP were employed on the investigation
of the polymorphisms. The 169 bp allele of MSX1-CA
repeat was the most prevalent in both groups. Borderline associations
were found for MSX1 gene. The 169-bp allele was more
frequent in individuals with hypodontia (OR=1.9; 95% CI= 1.0
– 3.6; p=0.05) and 169/175 genotype was less prevalent
in individuals with hypodontia (OR=0.4; 95% CI=0.2 –
0.9; p=0.05). The CC genotype of the PAX9 C-160T
polymorphism was found at a significant higher frequency in
individuals with hypodontia (p=0.0009). A separated analysis
of individuals with third molar agenesis also revealed a positive
association with the CC genotype (p=0.0007).
[Back to top]
Clustering Periodic Patterns of Gene Expression
Based on Fourier Approximations
B.-R. Kim, R.C. Littell and R. Wu
DNA microarray analysis has emerged as a leading technology
to enhance our understanding of gene regulation and function
in cellular mechanism controls on a genomic scale. This technology
has advanced to unravel the genetic machinery of biological
rhythms by collecting massive gene expression data during
a time course. In this article, we have proposed a two-step
procedure for clustering periodic patterns of gene expression
in terms of different transcriptional profiles. In step 1,
a least squares approach was used to estimate the coefficients
that determine periodic gene expression profiles based on
Fourier series approximation. In step 2, the estimated Fourier
coefficients were employed to cluster genes into different
expression patterns with a traditional clustering analysis
and mixture model-based maximum likelihood method implemented
with the EM algorithm. Applying our procedure to a case study
published in Spellman et al. (1998), 632 cell-cycle
regulated genes measured at a multitude of different time
points were sorted into five distinct groups. The advantages
of this procedure lie in the biological relevance of results
obtained and the construction of a general frame-work within
which the interplay between gene expression and development
can be tested.
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