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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 11, Number 2, April 2010
Contents
Myotonic Dystrophies 1 and 2: Complex Diseases with
Complex Mechanisms Pp. 77-90
B. Schoser and L. Timchenko
[Abstract] [Full
Text Article]
Genetic Interference: Don’t Stand So Close to Me
Pp. 91-102
L.E. Berchowitz and G.P. Copenhaver
[Abstract] [Full
Text Article]
The Origin of Amerindians and the Peopling of the
Americas According to HLA Genes: Admixture with Asian and
Pacific People Pp. 103-114
A. Arnaiz-Villena, C. Parga-Lozano, E. Moreno, C. Areces,
D. Rey and P. Gomez-Prieto
[Abstract] [Purchase
Article]
DNA Transposons: Nature and Applications in Genomics Pp.
115-128
M. Muñoz-López and J.L.
García-Pérez
[Abstract] [Purchase
Article]
Feud or Friend? The Role of the miR-17-92
Cluster in Tumorigenesis Pp. 129-135
J. Xiang and J. Wu
[Abstract]
[Purchase
Article]
Functional Annotation of Genes Overlapping Copy Number
Variants in Autistic Patients: Focus on Axon Pathfinding
Pp. 136-145
S. Sbacchi, F. Acquadro, I. Calò, F. Calì
and V. Romano
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Article]
Abstracts
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Myotonic Dystrophies 1 and 2: Complex Diseases with
Complex Mechanisms
B. Schoser and L. Timchenko
Two multi-system disorders, Myotonic Dystrophies type 1 and
type 2 (DM1 and DM2), are complex neuromuscular diseases caused
by an accumulation of expanded, non-coding RNAs, containing
repetitive CUG and CCUG elements. Similarities of these mutations
suggest similar mechanisms for both diseases. The expanded
CUGn and CCUGn RNAs mainly target two RNA binding proteins,
MBNL1 and CUGBP1, elevating levels of CUGBP1 and reducing
levels of MBNL1. These alterations change processing of RNAs
that are regulated by these proteins. Whereas overall toxicity
of CUGn/CCUGn RNAs on RNA homeostasis in DM cells has been
proven, the mechanisms which make these RNAs toxic remain
illusive. A current view is that the toxicity of RNA CUGn
and CCUGn is associated exclusively with global mis-splicing
in DM patients. However, a growing number of new findings
show that the expansion of CUGn and CCUGn RNAs mis-regulates
several additional pathways in nuclei and cytoplasm of cells
from patients with DM1 and DM2. The purpose of this review
is to discuss the similarities and differences in the clinical
presentation and molecular genetics of both diseases. We will
also discuss the complexity of the molecular abnormalities
in DM1 and DM2 caused by CUG and CCUG repeats and will summarize
the outcomes of the toxicity of CUG and CCUG repeats.
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Text Article]
Genetic Interference: Don’t Stand So Close to Me
L.E. Berchowitz and G.P. Copenhaver
Meiosis is a dynamic process during which chromosomes
undergo condensation, pairing, crossing-over and disjunction.
Stringent regulation of the distribution and quantity of meiotic
crossovers is critical for proper chromosome segregation in
many organisms. In humans, aberrant crossover placement and
the failure to faithfully segregate meiotic chromosomes often
results in severe genetic disorders such as Down syndrome
and Edwards syndrome. In most sexually reproducing organisms,
crossovers are more evenly spaced than would be expected from
a random distribution. This phenomenon, termed interference,
was first reported in the early 20th
century by Drosophila geneticists and has been subsequently
observed in a vast range of organisms from yeasts to humans.
Yet, many questions regarding the behavior and mechanism of
interference remain poorly understood. In this review, we
examine results new and old, from a wide range of organisms,
to begin to understand the progress and remaining challenges
to understanding the fundamental unanswered questions regarding
genetic interference.
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The Origin of Amerindians and the Peopling of the
Americas According to HLA Genes: Admixture with Asian and
Pacific People
A. Arnaiz-Villena, C. Parga-Lozano, E. Moreno, C. Areces,
D. Rey and P. Gomez-Prieto
The classical three-waves theory of American peopling through
Beringia was based on a mixed anthropological and linguistic
methodology. The use of mtDNA, Y chromosome and other DNA
markers offers different results according to the different
markers and methodologies chosen by different authors. At
present, the peopling of Americas remains uncertain, regarding:
time of population, number of peopling waves and place of
peopling entrance among other related issues. In the present
review, we have gathered most available HLA data already obtained
about First Native American populations, which raise some
doubts about the classical three waves of American peopling
hypothesis. In summary, our conclusions are: 1) North West
Canadian Athabaskans have had gene flow with: a) close neighboring
populations, b) Amerindians, c) Pacific Islanders including
East Australians and d) Siberians; 2) Beringia was probably
not the only entrance of people to America: Pacific Ocean
boat trips may have contributed to the HLA genetic American
profile (or the opposite could also be true); 3) Amerindians
entrance to America may have been different to that of Athabaskans
and Eskimos and Amerindians may have been in their lands long
before Athabaskans and Eskimos because they present and al-together
different set of HLA-DRB1 allele frequencies; 4) Amerindians
show very few “particular alleles”, almost all
are shared with other Amerindians, Athabaskans and Pacific
Islanders, including East Australians and Siberians; 5) Our
results do not support the three waves model of American peopling,
but another model where the people entrance is not only Beringia,
but also Pacific Coast. Reverse migration (America to Asia)
is not discarded and different movements of people in either
direction in different times are supported by the Athabaskan
population admixture with Asian-Pacific population and with
Amerindians, 6) HLA variability is more common than allele
veriability in Amerindians. Finally, it is shown that gene
genealogy analises should be completed with allele frequency
analyses in population relatednes and migrations studies.
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DNA Transposons: Nature and Applications in Genomics
M. Muñoz-López and J.L.
García-Pérez
Repeated DNA makes up a large fraction of a typical mammalian
genome, and some repetitive elements are able to move within
the genome (transposons and retrotransposons). DNA transposons
move from one genomic location to another by a cut-and-paste
mechanism. They are powerful forces of genetic change and
have played a significant role in the evolution of many genomes.
As genetic tools, DNA transposons can be used to introduce
a piece of foreign DNA into a genome. Indeed, they have been
used for transgenesis and insertional mutagenesis in different
organisms, since these elements are not generally dependent
on host factors to mediate their mobility. Thus, DNA transposons
are useful tools to analyze the regulatory genome, study embryonic
development, identify genes and pathways implicated in disease
or pathogenesis of pathogens, and even contribute to gene
therapy. In this review, we will describe the nature of these
elements and discuss recent advances in this field of research,
as well as our evolving knowledge of the DNA transposons most
widely used in these studies.
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Feud or Friend? The Role of the miR-17-92
Cluster in Tumorigenesis
J. Xiang and J. Wu
MicroRNAs (miRNAs) are short, noncoding, and single-stranded
RNA molecules that negatively regulate gene expression. They
are evolutionarily conserved from plants to animals. During
the last decade, miRNAs have been demonstrated as regulators
in fundamental biological processes, including cell growth,
proliferation, differentiation and apoptosis. By base pairing
to the complementary sites in the mRNA of the target gene,
miRNA can lead to repression of pro-ein translation or cleavage
of mRNA. Among over 700 miRNAs identified in the human genome,
several of them were confirmed as ‘oncomirs’,
which denote miRNAs associated with initiation and progression
of cancers. Generally, depending on their target genes, these
miRNAs function as tumor suppressors or oncogenes. However,
the miR-17-92 cluster in the human genome, which
encodes 7 mature microRNAs, has been validated as regulator
showing both oncogenic and tumor suppressive properties. The
miR-17-92 cluster targets mRNAs involved in distinct
pathways so that it may exert opposing effects. The transcription
factors E2Fs and c-Myc, which play critical roles in tumorigenesis,
could interact with the cluster. The feedback loops, which
are comprised of the transcription factors and the miR-17-92
cluster, weave a complex regulation net work of cancers.
The duality of this cluster reflects the complexities of cancer
progressions as well as the intricacies of the regulation
network of miRNAs and their targets. With the help of the
development of new experi-mental methods and bioinformatics,
further researches on the miR-17-92 cluster and other
oncomirs will give new insights into cancer diagnosis, therapy,
and prognosis.
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Functional Annotation of Genes Overlapping Copy Number
Variants in Autistic Patients: Focus on Axon Pathfinding
S. Sbacchi, F. Acquadro, I. Calò, F. Calì
and V. Romano
We have used Gene Ontology (GO) and pathway analyses to uncover
the common functions associated to the genes overlapping Copy
Number Variants (CNVs) in autistic patients. Our source of
data were four published studies [1-4]. We first applied a
two-step enrichment strategy for autism-specific genes. We
fished out from the four mentioned studies a list of 2928
genes overall overlapping 328 CNVs in patients and we first
selected a sub-group of 2044 genes after excluding those ones
that are also involved in CNVs reported in the Database of
Genomic Variants (enrichment step 1). We then selected from
the step 1-enriched list a sub-group of 514 genes each of
which was found to be deleted or duplicated in at least two
patients (enrichment step 2). The number of statistically
significant processes and pathways identified by the Database
for Annotation, Visualization and Integrated Discovery and
Ingenuity Pathways Analysis softwares with the step 2-enriched
list was significantly higher compared to the step 1-enriched
list. In addition, statistically significant GO terms, biofunctions
and pathways related to nervous system development and function
were exclusively identified by the step 2-enriched list of
genes. Interestingly, 21 genes were associated to axon growth
and pathfinding. The latter genes and other ones associated
to nervous system in this study represent a new set of autism
candidate genes deserving further investigation. In summary,
our results suggest that the autism’s “connectivity
genes” in some patients affect very early phases of
neurodevelopment, i.e., earlier than synaptogenesis.
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