Current Genomics (v.14, #4)

Most traits of biological importance, including traits for human complex diseases (e.g., obesity and diabetes),are continuously distributed. These complex or quantitative traits are controlled by multiple genetic loci called QTLs(quantitative trait loci), environments and their interactions. The laboratory mouse has long been used as a pilot animalmodel for understanding the genetic architecture of quantitative traits. Next-generation sequencing analyses and genomewideSNP (single nucleotide polymorphism) analyses of mouse genomes have revealed that classical inbred strains commonlyused throughout the world are derived from a few fancy mice with limited and non-randomly distributed geneticdiversity that occurs in nature and also indicated that their genomes are predominantly Mus musculus domesticus in origin.Many QTLs for a huge variety of traits have so far been discovered from a very limited gene pool of classical inbredstrains. However, wild M. musculus mice consisting of five subspecies widely inhabit areas all over the world, and hencea number of novel QTLs may still lie undiscovered in gene pools of the wild mice. Some of the QTLs are expected to improveour understanding of human complex diseases. Using wild M. musculus subspecies in Asia as examples, this reviewillustrates that wild mice are untapped natural resources for valuable QTL discovery.

Regulation of Cellulase and Hemicellulase Gene Expression in Fungi by Antonella Amore, Simona Giacobbe, Vincenza Faraco (230-249).
Research on regulation of cellulases and hemicellulases gene expression may be very useful for increasing theproduction of these enzymes in their native producers. Mechanisms of gene regulation of cellulase and hemicellulase expressionin filamentous fungi have been studied, mainly in Aspergillus and Trichoderma. The production of these extracellularenzymes is an energy-consuming process, so the enzymes are produced only under conditions in which thefungus needs to use plant polymers as an energy and carbon source. Moreover, production of many of these enzymes iscoordinately regulated, and induced in the presence of the substrate polymers. In addition to induction by mono- andoligo-saccharides, genes encoding hydrolytic enzymes involved in plant cell wall deconstruction in filamentous fungi canbe repressed during growth in the presence of easily metabolizable carbon sources, such as glucose. Carbon catabolite repressionis an important mechanism to repress the production of plant cell wall degrading enzymes during growth on preferredcarbon sources. This manuscript reviews the recent advancements in elucidation of molecular mechanisms responsiblefor regulation of expression of cellulase and hemicellulase genes in fungi.

Gene-based Genomewide Association Analysis: A Comparison Study by Guolian Kang, Bo Jiang, Yuehua Cui (250-255).
The study of gene-based genetic associations has gained conceptual popularity recently. Biologic insight intothe etiology of a complex disease can be gained by focusing on genes as testing units. Several gene-based methods (e.g.,minimum p-value (or maximum test statistic) or entropy-based method) have been developed and have more power than asingle nucleotide polymorphism (SNP)-based analysis. The objective of this study is to compare the performance of theentropy-based method with the minimum p-value and single SNP-based analysis and to explore their strengths and weaknesses.Simulation studies show that: 1) all three methods can reasonably control the false-positive rate; 2) the minimump-value method outperforms the entropy-based and the single SNP-based method when only one disease-related SNP occurswithin the gene; 3) the entropy-based method outperforms the other methods when there are more than two diseaserelatedSNPs in the gene; and 4) the entropy-based method is computationally more efficient than the minimum p-valuemethod. Application to a real data set shows that more significant genes were identified by the entropy-based method thanby the other two methods.

by Amarjit Saini, Sarabjit Mastana, Fiona Myers, Mark Lewis (256-267).
Skeletal muscle is a post-mitotic tissue maintained by repair and regeneration through a population of stemcell-like satellite cells. Following muscle injury, satellite cell proliferation is mediated by local signals ensuring sufficientprogeny for tissue repair. Age-related changes in satellite cells as well as to the local and systemic environment potentiallyimpact on the capacity of satellite cells to generate sufficient progeny in an ageing organism resulting in diminishedregeneration. 'Rejuvenation' of satellite cell progeny and regenerative capacity by environmental stimuli effectors suggestthat a subset of age-dependent satellite cell changes may be reversible. Epigenetic regulation of satellite stem cells that includeDNA methylation and histone modifications which regulate gene expression are potential mechanisms for such reversiblechanges and have been shown to control organismal longevity. The area of health and ageing that is likely tobenefit soonest from advances in the biology of adult stem cells is the emerging field of regenerative medicine. Furtherstudies are needed to elucidate the mechanisms by which epigenetic modifications regulate satellite stem cell function andwill require an increased understanding of stem-cell biology, the environment of the aged tissue and the interaction betweenthe two.

KRAB-Zinc Finger Proteins: A Repressor Family Displaying Multiple Biological Functions by Angelo Lupo, Elena Cesaro, Giorgia Montano, Diana Zurlo, Paola Izzo, Paola Costanzo (268-278).
Zinc finger proteins containing the Kruppel associated box (KRAB-ZFPs) constitute the largest individual familyof transcriptional repressors encoded by the genomes of higher organisms. KRAB domain, positioned at the NH2 terminusof the KRAB-ZFPs, interacts with a scaffold protein, KAP-1, which is able to recruit various transcriptional factorscausing repression of genes to which KRAB ZFPs bind. The relevance of such repression is reflected in the large numberof the KRAB zinc finger protein genes in the human genome. However, in spite of their numerical abundance little is currentlyknown about the gene targets and the physiological functions of KRAB- ZFPs. However, emerging evidence linksthe transcriptional repression mediated by the KRAB-ZFPs to cell proliferation, differentiation, apoptosis and cancer.Moreover, the fact that KRAB containing proteins are vertebrate-specific suggests that they have evolved recently, andthat their key roles lie in some aspects of vertebrate development. In this review, we will briefly discuss some regulatoryfunctions of the KRAB-ZFPs in different physiological and pathological states, thus contributing to better understand theirbiological roles.

Evolutionary Constraints Favor a Biophysical Model Explaining Hox Gene Collinearity by Yannis Almirantis, Astero Provata, Spyros Papageorgiou (279-288).
The Hox gene collinearity enigma has often been approached using models based on biomolecular mechanisms.The biophysical model is an alternative approach based on the hypothesis that collinearity is caused by physicalforces pulling the Hox genes from a territory where they are inactive to a distinct spatial domain where they are activatedin a step by step manner. Such Hox gene translocations have recently been observed in support of the biophysical model.Genetic engineering experiments, performed on embryonic mice, gave rise to several unexpected mutant expressions thatthe biomolecular models cannot predict. On the contrary, the biophysical model offers convincing explanation. Evolutionaryconstraints consolidate the Hox clusters and as a result, denser and well organized clusters may create more efficientphysical forces and a more emphatic manifestation of gene collinearity. This is demonstrated by stochastic modeling withwhite noise perturbing the expression of Hox genes. As study cases the genomes of mouse and amphioxus are used. Theresults support the working hypothesis that vertebrates have adopted their comparably more compact Hox clustering as atool needed to develop more complex body structures. Several experiments are proposed in order to test further the physicalforces hypothesis.