Current Genomics (v.14, #5)
Genetics in Diabetic Retinopathy: Current Concepts and New Insights by Olga Sim|-Servat, Cristina Hern|ndez, Rafael Sim| (289-299).
There is emerging evidence which indicates the essential role of genetic factors in the development of diabeticretinopathy (DR). In this regard it should be highlighted that genetic factors account for 25-50% of the risk of developingDR. Therefore, the use of genetic analysis to identify those diabetic patients most prone to developing DR might be usefulin designing a more individualized treatment. In this regard, there are three main research strategies: candidate gene studies,linkage studies and Genome-Wide Association Studies (GWAS). In the candidate gene approach, several genes encodingproteins closely related to DR development have been analyzed. The linkage studies analyze shared alleles amongfamily members with DR under the assumption that these predispose to a more aggressive development of DR. Finally,Genome-Wide Association Studies (GWAS) are a new tool involving a massive evaluation of single nucleotide polymorphisms(SNP) in large samples. In this review the available information using these three methodologies is critically analyzed.A genetic approach in order to identify new candidates in the pathogenesis of DR would permit us to design moretargeted therapeutic strategies in order to decrease this devastating complication of diabetes. Basic researchers, ophthalmologists,diabetologists and geneticists should work together in order to gain new insights into this issue.
Studies on the Pathophysiology and Genetic Basis of Migraine by Claudia F. Gasparini, Heidi G. Sutherland, Lyn R. Griffiths (300-315).
Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache.A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferesin many facets of people?s daily life including employment commitments and their ability to look after their families resultingin a reduced quality of life. Identification of the biological processes that underlie this relatively common afflictionhas been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by currentmedical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanismsinvolved in the various phases of headache and include the vascular and neurogenic theories. In relation to migrainepathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supportingevidence from imaging studies and animal models. The objective of current research is to better understand the pathwaysand mechanisms involved in causing pain and headache to be able to target interventions. The genetic component ofmigraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, infamily and case-control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological,vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis ofmigraine with the latest scientific evidence from genetic studies.
Molecular Population Genetics and Evolution of the Chagas? Disease Vector Triatoma infestans (Hemiptera: Reduviidae) by Beatriz A. Garc|a, Alicia R. P|rez de Rosas, Mar|a J. Blariza, Carla G. Grosso, Cintia J. Fern|ndez, Mar|a M. Stroppa (316-323).
Triatoma infestans (Klug) is the main vector of Chagas? disease in the Southern Cone of Latin America betweenthe latitudes 10? S and 46? S. The long-term effectiveness of the control campaigns is greatly dependent upon thevector population structure. Mitochondrial DNA (mtDNA) genes have been used in a number of T. infestans populationgenetic analyses. However, the maternally inherited markers as well as nuclear ribosomal DNA analyzed until the presentexhibited low or limited levels of variation. Analyses based on microsatellite markers strongly supported the existence ofsome type of stratification in T. infestans populations and supported the hypothesis of vector population recovery fromsurvivors of the insecticide-treated areas, highlighting the value of population genetic analyses in assessing theeffectiveness of Chagas? disease vector control programmes. Although phylogeographic studies have generally suggesteda Bolivian Andean origin of T. infestans, they recovered two reciprocal monophyletic groups of T. infestans and Bolivianpopulations who were not basal as expected for an ancestral group. In addition, a non-Andean origin could not be excludedby mtDNA genealogies that included sylvatic bugs from Gran Chaco. On the other side, mitochondrial and microsatellitemarkers supported the hypothesis of two independent migration events of colonization and secondary contacts insouthern South America. Since the phylogenetic analyses remain inconclusive, more sequences, not only from mitochondrialgenes but also from nuclear genes, need to be examined.
Genome-wide Membrane Protein Structure Prediction by Stefano Piccoli, Eda Suku, Marianna Garonzi, Alejandro Giorgetti (324-329).
Transmembrane proteins allow cells to extensively communicate with the external world in a very accurate andspecific way. They form principal nodes in several signaling pathways and attract large interest in therapeutic intervention,as the majority pharmaceutical compounds target membrane proteins. Thus, according to the current genome annotationmethods, a detailed structural/functional characterization at the protein level of each of the elements codified in thegenome is also required. The extreme difficulty in obtaining high-resolution three-dimensional structures, calls for computationalapproaches. Here we review to which extent the efforts made in the last few years, combining the structuralcharacterization of membrane proteins with protein bioinformatics techniques, could help describing membrane proteinsat a genome-wide scale. In particular we analyze the use of comparative modeling techniques as a way of overcoming thelack of high-resolution three-dimensional structures in the human membrane proteome.
Comparative Genomics of X-linked Muscular Dystrophies: The Golden Retriever Model by Candice Brinkmeyer-Langford, Joe N. Kornegay (330-342).
Duchenne muscular dystrophy (DMD) is a devastating disease that dramatically decreases the lifespan andabilities of affected young people. The primary molecular cause of the disease is the absence of functional dystrophin protein,which is critical to proper muscle function. Those with DMD vary in disease presentation and dystrophin mutation;the same causal mutation may be associated with drastically different levels of disease severity. Also contributing to thisvariation are the influences of additional modifying genes and/or changes in functional elements governing such modifiers.This genetic heterogeneity complicates the efficacy of treatment methods and to date medical interventions are limitedto treating symptoms. Animal models of DMD have been instrumental in teasing out the intricacies of DMD disease andhold great promise for advancing knowledge of its variable presentation and treatment. This review addresses the utility ofcomparative genomics in elucidating the complex background behind phenotypic variation in a canine model of DMD,Golden Retriever muscular dystrophy (GRMD). This knowledge can be exploited in the development of improved, morepersonalized treatments for DMD patients, such as therapies that can be tailor-matched to the disease course and genomicbackground of individual patients.