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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 8, Number 2, April 2007
Contents
Longevity Genomics Across Species Pp. 73-78
M. Kaeberlein
[Abstract]
Recent Computational Approaches to Understand
Gene Regulation: Mining Gene Regulation In Silico
Pp. 79-91
I. Abnizova, T. Subhankulova and W.R. Gilks
[Abstract]
Consensus Higher Order Repeats and Frequency of String
Distributions in Human Genome Pp. 93-111
V. Paar, I. Basar, M. Rosandic and M. Gluncic
[Abstract] [Supplementary
Data]
Functional Properties and Genomics of Glucose Transporters
Pp. 113-128
F.-Q. Zhao and A.F. Keating
[Abstract]
The Human Pseudoautosomal Region (PAR): Origin, Function
and Future Pp. 129-136
A.H. Mangs and B.J. Morris
[Abstract]
Maps of cis-Regulatory Nodes in Megabase
Long Genome Segments are an Inevitable Intermediate Step Toward
Whole Genome Functional Mapping Pp. 137-149
L.G. Nikolaev, S.B. Akopov, I.P. Chernov and E.D. Sverdlov
[Abstract]
Abstracts
[Back to top]
Longevity Genomics Across Species
M. Kaeberlein
Unbiased genome-wide studies of longevity in S. cerevisiae
and C. elegans have led to the identification of
more than one hundred genes that determine life span in one
or both organisms. Key pathways have been uncovered linking
nutrient and growth factor cues to longevity. Quantitative
measures of the degree to which aging is evolutionary conserved
are now possible. A major challenge for the future is determining
which of these genes play a similar role in human aging and
using that information to develop therapies toward age-associated
diseases.
[Back to top]
Recent Computational Approaches to Understand
Gene Regulation: Mining Gene Regulation In Silico
I. Abnizova, T. Subhankulova and W.R. Gilks
This paper reviews recent computational approaches to the
understanding of gene regulation in eukaryotes. Cis-regulation
of gene expression by the binding of transcription factors
is a critical component of cellular physiology. In eukaryotes,
a number of transcription factors often work together in a
combinatorial fashion to enable cells to respond to a wide
spectrum of environmental and developmental signals. Integration
of genome sequences and/or Chromatin Immuno-precipitation
on chip data with gene-expression data has facilitated in
silico discovery of how the combinatorics and positioning
of transcription factors binding sites underlie gene activation
in a variety of cellular processes.
The process of gene regulation is extremely complex and intriguing,
therefore all possible points of view and related links should
be carefully considered. Here we attempt to collect an inventory,
not claiming it to be comprehensive and complete, of related
computational biological topics covering gene regulation,
which may enlighten the process, and briefly review what is
currently occurring in these areas.
We will consider the following computational areas:
o gene regulatory network construction;
o evolution of regulatory DNA;
o studies of its structural and statistical informational
properties;
o and finally, regulatory RNA.
[Back to top]
Consensus Higher Order Repeats and Frequency of String
Distributions in Human Genome
V. Paar, I. Basar, M. Rosandic and M. Gluncic
Key string algorithm (KSA) could be viewed as robust computational
generalization of restriction enzyme method. KSA enables robust
and effective identification and structural analyzes of any
given genomic sequences, like in the case of NCBI assembly
for human genome. We have developed a method, using total
frequency distribution of all r-bp key strings in dependence
on the fragment length l, to determine the exact
size of all repeats within the given genomic sequence, both
of monomeric and HOR type. Subsequently, for particular fragment
lengths equal to each of these repeat sizes we compute the
partial frequency distribution of r-bp key strings; the key
string with highest frequency is a dominant key string, optimal
for segmentation of a given genomic sequence into repeat units.
We illustrate how a wide class of 3-bp key strings leads to
a key-string-dependent periodic cell which enables a simple
identification and consensus length determinations of HORs,
or any other highly convergent repeat of monomeric or HOR
type, both tandem or dispersed. We illustrated KSA application
for HORs in human genome and determined consensus HORs in
the Build 35.1 assembly. In the next step we compute suprachromosomal
family classification and CENP-B box / pJα
distributions for HORs. In the case of less convergent repeats,
like for example monomeric alpha satellite (20-40% divergence),
we searched for optimal compact key string using frequency
method and developed a concept of composite key string (GAAAC--CTTTG)
or flexible relaxation (28 bp key string) which provides both
monomeric alpha satellites as well as alpha monomer segmentation
of internal HOR structure. This method is convenient also
for study of R-strand (direct) / S-strand (reverse complement)
alpha monomer alternations. Using KSA we identified 16 alternating
regions of R-strand and S-strand monomers in one contig in
choromosome 7. Use of CENP-B box and/or pJα
motif as key string is suitable both for identification of
HORs and monomeric pattern as well as for studies of CENP-B
box / pJα
distribution. As an example of application of KSA to sequences
outside of HOR regions we present our finding of a tandem
with highly convergent 3434-bp long monomer in chromosome
5 (divergence less then 0.3%).
[Back to top]
Functional Properties and Genomics of Glucose Transporters
F.-Q. Zhao and A.F. Keating
Glucose is the major energy source for mammalian cells as
well as an important substrate for protein and lipid synthesis.
Mammalian cells take up glucose from extracellular fluid into
the cell through two families of structurally-related glucose
transporters. The facilitative glucose transporter family
(solute carriers SLC2A, protein symbol GLUT) mediates a bidirectional
and energy-independent process of glucose transport in most
tissues and cells, while the Na+/glucose cotransporter
family (solute carriers SLC5A, protein symbol SGLT) mediates
an active, Na+-linked transport process against
an electrochemical gradient. The GLUT family consists of thirteen
members (GLUT1-12 and HMIT). Phylogenetically, the members
of the GLUT family are split into three classes based on protein
similarities. Up to now, at least six members of the SGLT
family have been cloned (SGLT1-6). In this review, we report
both the genomic structure and function of each transporter
as well as intra-species comparative genomic analysis of some
of these transporters. The affinity for glucose and transport
kinetics of each transporter differs and ranges from 0.2 to
17mM. The ability of each protein to transport alternative
substrates also differs and includes substrates such as fructose
and galactose. In addition, the tissue distribution pattern
varies between species. There are different regulation mechanisms
of these transporters. Characterization of transcriptional
control of some of the gene promoters has been investigated
and alternative promoter usage to generate different protein
isoforms has been demonstrated. We also introduce some pathophysiological
roles of these transporters in human.
[Back to top]
The Human Pseudoautosomal Region (PAR): Origin, Function
and Future
A.H. Mangs and B.J. Morris
The pseudoautosomal regions (PAR1 and PAR2) of the human X
and Y chromosomes pair and recombine during meiosis. Thus
genes in this region are not inherited in a strictly sex-linked
fashion. PAR1 is located at the terminal region of the short
arms and PAR2 at the tips of the long arms of these chromosomes.
To date, 24 genes have been assigned to the PAR1 region. Half
of these have a known function. In contrast, so far only 4
genes have been discovered in the PAR2 region. Deletion of
the PAR1 region results in failure of pairing and male sterility.
The gene SHOX (short stature homeobox-containing)
resides in PAR1. SHOX haploinsufficiency contributes to certain
features in Turner syndrome as well as the characteristics
of Leri-Weill dyschondrosteosis. Only two of the human PAR1
genes have mouse homologues. These do not, however, reside
in the mouse PAR1 region but are autosomal. The PAR regions
seem to be relics of differential additions, losses, rearrangements
and degradation of the X and Y chromosome in different mammalian
lineages. Marsupials have three homologues of human PAR1 genes
in their autosomes, although, in contrast to mouse, do not
have a PAR region at all. The disappearance of PAR from other
species seems likely and this region will only be rescued
by the addition of genes to both X and Y, as has occurred
already in lemmings. The present review summarizes the current
understanding of the evolution of PAR and provides up-to-date
information about individual genes residing in this region.
[Back to top]
Maps of cis-Regulatory Nodes in Megabase
Long Genome Segments are an Inevitable Intermediate Step Toward
Whole Genome Functional Mapping
L.G. Nikolaev, S.B. Akopov, I.P. Chernov and E.D. Sverdlov
The availability of complete human and other metazoan
genome sequences has greatly facilitated positioning and analysis
of various genomic functional elements, with initial emphasis
on coding sequences. However, complete functional maps of
sequenced eukaryotic genomes should include also positions
of all non-coding regulatory elements. Unfortunately, experimental
data on genomic positions of a multitude of regulatory sequences,
such as enhancers, silencers, insulators, transcription terminators,
and replication origins are very limited, especially at the
whole genome level. Since most genomic regulatory elements
(e.g. enhancers) are generally gene-, tissue-, or cell-specific,
the prediction of these elements by computational methods
is difficult and often ambiguous. Therefore, the development
of high-throughput experimental approaches for identifying
and mapping genomic functional elements is highly desirable.
At the same time, the creation of whole-genome map of hundreds
of thousands of regulatory elements in several hundreds of
tissue/cell types is presently far beyond our capabilities.
A possible alternative for the whole genome approach is to
concentrate efforts on individual genomic segments and then
to integrate the data obtained into a whole genome functional
map. Moreover, the maps of polygenic fragments with functional
cis-regulatory elements would provide valuable data
on complex regulatory systems, including their variability
and evolution. Here, we reviewed experimental approaches to
the realization of these ideas, including our own developments
of experimental techniques for selection of cis-acting
functionally active DNA fragments from large (megabase-sized)
segments of mammalian genomes.
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