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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 8, Number 7, November 2007
Contents
Myostatin in the Pathophysiology of Skeletal Muscle
Pp. 415-422
G. Carnac, B. Vernus and A. Bonnieu
[Abstract]
Role of Insulin and Growth Hormone/Insulin-Like Growth
Factor-I Signaling in Lifespan Extension: Rodent Longevity
Models for Studying Aging and Calorie Restriction
Pp. 423-428
T. Chiba, H. Yamaza and I. Shimokawa
[Abstract]
Genetic and Environmental Factors in Complex Neurodevelopmental
Disorders Pp. 429-444
K.M.J. van Loo and G.J.M. Martens
[Abstract]
Characteristics of Human and Mouse Orthologous Protein
Coding Nucleotide Sequences with Large G+C Content Variations
Pp. 445-452
H. Nakashima
[Abstract]
The HLA Region and Autoimmune Disease: Associations
and Mechanisms of Action Pp. 453-465
S.C.L. Gough and M.J. Simmonds
[Abstract]
HLA Genes in Mayos Population from Northeast Mexico
Pp. 466-475
A. Arnaiz-Villena, J. Moscoso, J. Granados, J.I. Serrano-Vela,
A. de la Peña, R. Reguera, A. Ferri, E. Seclen, R.
Izaguirre, N. Perez-Hernandez and G. Vargas-Alarcon
[Abstract]
Incomplete Coverage of Candidate Genes: A Poorly Considered
Bias Pp. 476-483
A. Drago, D. De Ronchi and A. Serretti
[Abstract]
Abstracts
[Back to top]
Myostatin in the Pathophysiology of Skeletal
Muscle
G. Carnac, B. Vernus and A. Bonnieu
Myostatin is an endogenous, negative regulator of muscle growth
determining both muscle fiber number and size. The myostatin
pathway is conserved across diverse species ranging from zebrafish
to humans. Experimental models of muscle growth and regeneration
have implicated myostatin as an important mediator of catabolic
pathways in muscle cells. Inhibition of this pathway has emerged
as a promising therapy for muscle wasting. Here we discuss
the recent developments and the controversies in myostatin
research, focusing on the molecular and cellular mechanisms
underlying the actions of myostatin on skeletal muscle and
the potential therapeutic role of myostatin on muscle related
disorders.
[Back to top]
Role of Insulin and Growth Hormone/Insulin-Like Growth
Factor-I Signaling in Lifespan Extension: Rodent Longevity
Models for Studying Aging and Calorie Restriction
T. Chiba, H. Yamaza and I. Shimokawa
Insulin/insulin-like growth factor-I (IGF-I) pathways are
recognized as critical signaling pathways involved in the
control of lifespans in lower organisms to mammals. Caloric
restriction (CR) reduces plasma concentration of insulin,
growth hormone (GH), and IGF-I. CR retards various age-dependent
disorders such as nuerodegenerative diseases and extends lifespan
in laboratory rodents. These beneficial effects of CR are
partly mimicked in spontaneous or genetically engineered rodent
models of reduced insulin and GH/IGF-I axis. Most of these
long-living rodents show increased insulin sensitivity; however,
recent study has revealed that some other rodents show normal
or reduced insulin sensitivity. Thus, increased insulin sensitivity
might be not prerequisite for lifespan extension in insulin/GH/IGF-I
altered longevity rodent models. These results highlighted
that, for lifespan extension, the intracellular signaling
molecules of insulin/GH/IGF-I pathways might be more important
than actual peripheral or systemic insulin action.
[Back to top]
Genetic and Environmental Factors in Complex Neurodevelopmental
Disorders
K.M.J. van Loo and G.J.M. Martens
Complex neurodevelopmental disorders, such as schizophrenia,
autism, attention deficit (hyperactivity) disorder, (manic)
depressive illness and addiction, are thought to result from
an interaction between genetic and environmental factors.
Association studies on candidate genes and genome-wide linkage
analyses have identified many susceptibility chromosomal regions
and genes, but considerable efforts to replicate association
have been surprisingly often disappointing. Here, we summarize
the current knowledge of the genetic contribution to complex
neurodevelopmental disorders, focusing on the findings from
association and linkage studies. Furthermore, the contribution
of the interaction of the genetic with environmental and epigenetic
factors to the aetiology of complex neurodevelopmental disorders
as well as suggestions for future research are discussed.
[Back to top]
Characteristics of Human and Mouse Orthologous Protein
Coding Nucleotide Sequences with Large G+C Content Variations
H. Nakashima
Characteristics of human and mouse orthologous gene sequences
which have large G+C content variations were investigated
in this study. The orthologous gene pairs were classified
into two groups according to the deviation between human and
mouse G+C content at the third codon position (GC3) and were
subsequently analyzed. In one group, mouse genes had higher
GC3 than the corresponding human genes and in another group,
human genes had higher GC3 than mouse. Furthermore, the orthologous
pairs were separated based on the deviation between human
or mouse GC3 and the G+C content at the third codon position
of identical codons (IC3), to examine the effect of increased
or decreased G+C content in human or mouse sequences. The
nucleotide substitution patterns between human and mouse sequences
in the two groups were remarkably distinct, and consistent
with the state of G+C-rich or G+C-poor sequences. The effect
of increase or decrease of G+C content in human or mouse sequences
was not clear in the nucleotide substitution patterns. The
chromosomal locations of human and mouse orthologous gene
pairs were different between the two groups. The genes located
on an identical syntenic segment showed the trend of having
similar G+C content. Moreover, the same gene order of some
genes on different chromosomes of both species demonstrated
the gene rearrangements between human and mouse. Our study
indicated that the chromosomal locations and rearrangements
are associated with the GC3 variation between human and mouse
sequences.
[Back to top]
The HLA Region and Autoimmune Disease: Associations
and Mechanisms of Action
S.C.L. Gough and M.J. Simmonds
The HLA region encodes several molecules that play key roles
in the immune system. Strong association between the HLA region
and autoimmune disease (AID) has been established for over
fifty years. Association of components of the HLA class II
encoded HLA-DRB1-DQA1-DQB1 haplotype has been detected
with several AIDs, including rheumatoid arthritis, type 1
diabetes and Graves’ disease. Molecules encoded by this
region play a key role in exogenous antigen presentation to
CD4+ Th cells, indicating the importance of this pathway in
AID initiation and progression. Although other components
of the HLA class I and III regions have also been investigated
for association with AID, apart from the association of HLA-B*27
with ankylosing spondylitis, it has been difficult to determine
additional susceptibility loci independent of the strong linkage
disequilibrium (LD) with the HLA class II genes. Recent advances
in the statistical analysis of LD and the recruitment of large
AID datasets have allowed investigation of the HLA class I
and III regions to be re-visited. Association of the HLA class
I region, independent of known HLA class II effects, has now
been detected for several AIDs, including strong association
of HLA-B with type 1 diabetes and HLA-C
with multiple sclerosis and Graves’ disease. These results
provide further evidence of a possible role for bacterial
or viral infection and CD8+ T cells in AID onset. The advances
being made in determining the primary associations within
the HLA region and AIDs will not only increase our understanding
of the mechanisms behind disease pathogenesis but may also
aid in the development of novel therapeutic targets in the
future.
[Back to top]
HLA Genes in Mayos Population from Northeast Mexico
A. Arnaiz-Villena, J. Moscoso, J. Granados, J.I. Serrano-Vela,
A. de la Peña, R. Reguera, A. Ferri, E. Seclen, R.
Izaguirre, N. Perez-Hernandez and G. Vargas-Alarcon
HLA class I and class II alleles have been studied in 60 unrelated
people belonging to Mayos ethnic group, which lives in the
Mexican Pacific Sinaloa State. Mayos HLA profile was compared
to other Amerindians and worldwide populations’ profile.
A total of 14,896 chromosomes were used for comparisons. Genetic
distances between populations, Neigbour-Joining dendrograms
and correspondence analyses were performed to determine the
genetic relationship among population. The new specific Mayo
HLA haplotypes found are: HLA-A*02-B*35-DRB1*1406-DQB1*0301;
HLA-A*02- B*48-DRB1*0404-DQB1*0302; HLA-A*24-B*51-DRB1*0407-DQB1*0302
and HLA-A*02-B*08-DRB1*0407- DQB1*0302. However, the typical
Meso American HLADRB1*0407 represents a 40% of all DRB1 alleles.
While common HLA characteristics are found in Amerindian distant
ethnic groups, still new group specific HLA haplotypes are
being found, suggesting that a common founder effect (i.e.
high DRB1*0407) is noticed. Moreover, new HLA haplotypes are
almost certainly appearing along time probably due to specific
pathogen (?) selection for diversity. Mayo language is close
to the Tarahumara one (another geographically close group);
notwithstanding both groups are not genetically close according
to our results, showing again the different evolution of genes
and languages, which do not correlate. Finally, Sinaloa is
one of the Mexican States in which more European genes are
found. However, the results presented in this paper, where
no European HLA genes are seen in Mayos, should have a bearing
in establishing transplant programs and in HLA and disease
studies.
[Back to top]
Incomplete Coverage of Candidate Genes: A Poorly Considered
Bias
A. Drago, D. De Ronchi and A. Serretti
Current genetic investigations are performed both on the basis
of a rational and biologically based choice of candidate genes
and through genome wide scans. Nonetheless, lack of replication
is a common problem in psychiatric genetics as well as in
other genetic fields. There are a number of reasons for this
inconsistency, among them a well known but poorly considered
issue is gene coverage. The aim of the present paper is to
focus on this well known and defectively deemed bias, especially
when a candidate gene approach is chosen. The rational and
the technical feasibility of this proposal are discussed as
well as a survey of current investigations. The known consistent
methodology to fix this bias is also discussed.
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