Current Genomics - Volume 8, Issue 7, 2007

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.

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.

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.

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.

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&apos 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&apos 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.

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.

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.