Current Genomics (v.13, #4)

Gastrulation, the process that puts the three major germlayers, the ectoderm, mesoderm and endoderm in their correct topological position in the developing embryo, is characterised by extensive highly organised collective cell migration of epithelial and mesenchymal cells. We discuss current knowledge and insights in the mechanisms controlling these cell behaviours during gastrulation in the chick embryo. We discuss several ideas that have been proposed to explain the observed large scale vortex movements of epithelial cells in the epiblast during formation of the primitive streak. We review current insights in the control and execution of the epithelial to mesenchymal transition (EMT) underlying the formation of the hypoblast and the ingression of the mesendoderm cells through the streak. We discuss the mechanisms by which the mesendoderm cells move, the nature and dynamics of the signals that guide these movements, as well as the interplay between signalling and movement that result in tissue patterning and morphogenesis. We argue that instructive cell-cell signaling and directed chemotactic movement responses to these signals are instrumental in the execution of all phases of gastrulation.

Building a Robust A-P Axis by Alysha Heimberg (278-288).
Since the last common ancestor of Metazoa, animals have evolved complex body plans with specialized cells and spatial organization of tissues and organs. Arguably, one of the most significant innovations during animal evolutionary history was the establishment of a bilateral plane of symmetry on which morphological features (e.g. tissues, organs, appendages, skeleton) could be given specific coordinates within the animal along the anterior-posterior (A-P) and dorsal-ventral (D-V) axes. Hox genes are a known group of eumetazoan transcription factors central to regulating A-P patterning, but less well known and under current investigation is the broader regulatory landscape incorporating these genes, including microRNA (miRNA) regulation. The degree to which evolutionarily conserved targeting of Hox genes by Hox-embedded miRNAs contributes directly to A-P patterning is under investigation, yielding contrasting information dependent on the organism and miRNA of interest. The widespread A-P patterning defects observed in recent miR-196 loss-of-function studies solidifies the importance of miRNA regulation in Hox genetic hierarchies, and elucidating the developmental and evolutionary importance of all Hox-embedded miRNAs remains a challenge for the future.

The elongated, snake-like skeleton, as it has convergently evolved in numerous reptilian and amphibian lineages, is from a developmental biologist’s point of view amongst the most fascinating anatomical peculiarities in the animal kingdom. This type of body plan is characterized by a greatly increased number of vertebrae, a reduction of skeletal regionalization along the primary body axis and loss of the limbs. Recent studies conducted on both mouse and snakes now hint at how changes inside the gene regulatory circuitries of the Hox genes and the somitogenesis clock likely underlie these striking departures from standard tetrapod morphology, suggesting scenarios by which snakes and other elongated species may have evolved from more ordinarily bodied ancestors.

The vertebrate A-P axis is a time axis. The head is made first and more and more posterior levels are made at later and later stages. This is different to the situation in most other animals, for example, in Drosophila. Central to this timing is Hox temporal collinearity (see below). This occurs rarely in the animal kingdom but is characteristic of vertebrates and is used to generate the primary axial Hox pattern using time space translation and to integrate successive derived patterns (see below). This is thus a different situation than in Drosophila, where the primary pattern guiding Hox spatial collinearity is generated externally, by the gap and segmentation genes.

After completion of the human genome, genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with cancer initiation and progression. Most of the studies identified SNPs that were located outside the coding region, and the odds ratios were too low to implement in clinical practice. Although the genome gives information about genome sequence and structure, the human epigenome provides functional aspects of the genome. Epigenome-wide association studies (EWAS) provide an opportunity to identify genome-wide epigenetic variants that are associated with cancer. However, there are problems and issues in implementing EWAS to establish an association between epigenetic profiles and cancer. Few challenges include selection and handling of samples, choice of population and sample size, accurate measurement of exposure, integrating data, and insufficient information about the role of repeat sequences. The current status of EWAS, challenges in the field, and their potential solutions are discussed in this article.

Many pharmacogenomic biomarkers (PGBM) were identified and translated into clinical practice, affecting the usage of drugs via label updates. In this context, abacavir is one of the most brilliant examples of pharmacogenetic studies translated into clinical practice. Pharmacogenetic studies have revealed that abacavir HSRs are highly associated with the major histocompatibility complex class I. Large studies established the effectiveness of prospective HLA-B*57:01 screening to prevent HSRs to abacavir. Accordingly to these results the abacavir label has been modified: the European Medicines Agency (EMA) and the FDA recommend/suggested that the administration of abacavir must be preceded by a specific genotyping test. The HLA locus is extremely polymorphic, exhibiting many closely related alleles, making it difficult to discriminate HLA-B*57:01 from other related alleles, and a number of different molecular techniques have been developed recently to detect the presence of HLA-B*57:01. In this review, we provide a summary of the available techniques used by laboratories to genotype HLA-B*57:01, outlining the scientific and pharmacoeconomics pros and cons.

Amyotrophic Lateral Sclerosis (ALS) is a progressive and disabling neurodegenerative disorder characterized by upper and lower motor neuron loss, leading to respiratory insufficiency and death after 3-5 years. Riluzole is currently the only FDA approved drug for ALS, but it has only modest effects on survival. The majority of ALS cases are sporadic and probably associated to a multifactorial etiology. With the completion of genome sequencing in humans and model organisms, together with the advent of DNA microarray technology, the transcriptional cascades and networks underlying neurodegeneration in ALS are being elucidated providing new potential pharmacological targets. The main challenge now is the effective screening of the myriad of targets to identify those with the most therapeutic utility. The present review will illustrate how the identification, prioritization and validation of preclinical therapeutics can be achieved through genomic analysis of critical pathways and networks deregulated in ALS pathology.

In the post-genome era, high throughput gene expression profiling has been successfully used to develop genomic biomarker panels (GBP) that can be integrated into clinical decision making. The development of GBPs in the context of personalized medicine is a scientifically challenging and resource-intense process. It needs to be accomplished in a systematic phased approach to address biological variation related to a clinical phenotype (e.g. disease etiology, gender, etc.) and minimize technical variation (noise). Here we present the methodological aspects of GBP development based on the experience of the Cardiac Allograft Rejection Gene Expression Observation (CARGO) study, a study that lead to the development of a molecular classifier for rejection screening in heart transplant patients.