Advances in Genome Science

Prader-Willi syndrome (PWS) is a complex genetic disorder that affects multiple systems due to genomic imprinting errors in which loss of paternally expressed genes from the chromosome 15q11-q13 region causes this rare obesity related disorder. About 70% of individuals with PWS will have a paternal de novo deletion of the 15q11- q13 region consisting of two subtypes (i.e., larger Type I or smaller Type II). A second genetic cause is maternal disomy 15 in which both 15s are from the mother and seen in about 25% of cases. The remaining subjects have either defects in the imprinting center that controls the activity of genes under it’s control. This syndrome is characterized by a typical facial appearance, hypotonia with a poor suck and feeding difficulties during infancy, hypogonadism and hypogenitalism, short stature and growth and other hormone deficiencies with short stature and small hands and feet. Learning and behavioral problems (e.g., skin picking, temper tantrums) are present in the majority of subjects. Food seeking and hyperphagia leads to obesity in early childhood. Obesity is a significant health problem and PWS is considered the most common known genetic cause of life-threatening obesity in children. Growth hormone therapy is often prescribed to improve stature, body composition (increased muscle mass and strength with lowered fat quanity). Syndrome specific standardized growth charts are now available to assist in monitoring growth patterns during growth hormone treatment from infancy to adulthood. The chromosome 15q11-q13 region contains multiple genes and transcripts in which a dozen are imprinted and paternally expressed and when disturbed leads to PWS. Angelman syndrome, an entirely different disorder is due to loss of a maternally expressed gene (i.e., UBE3A) located in the same chromosome region. Other genes in the area are either bialletically (normally) expressed or show paternal bias of expression. This review will summarize the clinical features, current understanding of genetic causes and natural history with clinical presentation of individuals with PWS.

Hearing loss is a very diffuse disease in the population and many cases are associated to genetic causes. Most of the identified mutations have been identified in the GJB2 gene encoding connexin 26, a transmembrane protein that is a constituent of fundamental structures (gap junctions channels) involved in molecules (ions and small metabolites) exchanges between cells. It has been demonstrated that GJB2 mutations are causative for different forms of hearing impairment, non-syndromic forms: recessive (DFNB1) and sometimes dominant (DFNA3) as well as syndromic dominant forms with hearing impairment associated to several types of epidermis problems. Connexin 26, in fact, has a relevant role in inner ear functioning but in the skin too, where connexins 26 has been demonstrated to participate in regulation of growth and differentiation of skin. As well as for many cases of hearing loss, skin phenotypes described for connexin 26 mutations are highly variable. Reasons for this high phenotypic variability are actually not clear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. Effects of some mutations on channels function and the relevant role of the hemichannel are discussed.

In spite of the good prognosis of thyroid carcinoma (TC), a metastatic disease is developed by approximately 5% of patients, not responsive to radioactive iodine (RAI), and with a more aggressive behaviour. The absence of specific and effective drugs for aggressive TC leads to the need of new efforts towards new drugs development.

Several genetic alterations in different molecular pathways in TC have been shown in the last decades, associated with TC development and progression. Rearranged during transfection (RET)/papillary thyroid carcinoma gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the studied pathways, determinant in TC development. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the above-mentioned molecular pathways involved in growth, angiogenesis, local and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), and they have been shown capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for MTC treatment; sorafenib and lenvatinib have been approved for DTC refractory to RAI. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds, and to personalize the therapy in each TC patient.

The human genome must be tightly packaged in order to fit inside the nucleus of a cell. Genome organization is functional rather than random, which allows for the proper execution of gene expression programs and other biological processes. Recently, three-dimensional chromatin organization has emerged as an important transcriptional control mechanism. For example, enhancers were shown to regulate target genes by physically interacting with them regardless of their linear distance and even if located on different chromosomes. These chromatin contacts can be measured with the “chromosome conformation capture” (3C) technology and other 3C-related techniques. Given the recent innovation of 3C-derived approaches, it is not surprising that we still know very little about the structure of our genome at high-resolution. Even less well understood is whether there exist distinct types of chromatin contacts and importantly, what regulates them. A new form of regulation involving the expression of long non-coding RNAs (lncRNAs) was recently identified. lncRNAs are a very abundant class of non-coding RNAs that are often expressed in a tissue-specific manner. Although their different subcellular localizations points to their involvement in numerous cellular processes, it is clear that lncRNAs play an important role in regulating gene expression. They have been shown to bind several ribonucleoprotein complexes including the polycomb repression complex, which modify chromatin epigenetically by transferring histone marks, but how they control transcription however is mostly unknown. In this review, we provide an overview of known lncRNA transcription regulation activities. We also discuss potential mechanisms by which ncRNAs might exert three-dimensional transcriptional control and what recent studies have revealed about their role in shaping our genome.

Fungal laccases are generalists biocatalysts with potential applications that range from bioremediation to novel green processes. Fuelled by molecular oxygen, these enzymes can act on dozens of molecules of different chemical nature, and with the help of redox mediators, their spectrum of oxidizable substrates is further pushed towards xenobiotic compounds (pesticides, industrial dyes, PAHs), biopolymers (lignin, starch, cellulose) and other complex molecules. In recent years, extraordinary efforts have been made to engineer fungal laccases by directed evolution and semi-rational approaches to improve their functional expression or stability. All these studies have taken advantage of Saccharomyces cerevisiae as a heterologous host, not only to secrete the enzyme but also, to emulate the introduction of genetic diversity through in vivo DNA recombination. Here, we discuss all these endeavours to convert fungal laccases into valuable biomolecular platforms on which new functions can be tailored by directed evolution.

Since the advent of Darwinian genetics, there has been much interest in the evolutionary origin of the Orchidaceae, one of the most species-rich angiosperm families. Orchids have highly diversified and specialized flowers, and some species exhibit an uncoupled rate of morphological and molecular evolution. Recently, these peculiar characteristics have enhanced the study of the orchid MADS-box genes involved in flower development. This large gene family encodes transcription factors that constitute the main regulatory network driving the formation of flower organs. Recent analyses have highlighted the role of the MADS-box genes in orchids and shown that different evolutionary forces act on the coding and non-coding regions of these genes. The most widely accepted theory proposed to explain the evolution of the orchid perianth is the “orchid code”, which posits that the orchid floral organs became diversified through a series of duplications and mutations of the MADS-box genes, followed by functional diversification.

Since the sequencing of the nuclear genome of Arabidopsis thaliana more than ten years ago, various large-scale analyses of gene function have been performed in this model species. In particular, the availability of collections of lines harbouring random T-DNA or transposon insertions, which include mutants for almost all of the ~28,000 A. thaliana genes, has been crucial for the success of forward and reverse genetic approaches. In the foreseeable future, genome-wide phenotypic data from mutant analyses will become available for Arabidopsis, and will stimulate a flood of novel in-depth gene-function analyses. In this review, we consider the present status of resources and concepts for systematic studies of gene function in A. thaliana. Current perspectives on the utility of loss-of-function and gain-of-function mutants will be discussed in light of the genetic and functional redundancy of many A. thaliana genes.

Plants respond to low temperatures with changes in their pattern of gene expression and protein products. Many species of tropical or subtropical origin are injured or killed by non-freezing low temperature, and exhibit various symptoms of chilling injury such as chlorosis, necrosis, or growth retardation. In contrast, chilling tolerant species are able to grow at such cold temperatures. Conventional breeding methods have met with limited success in improving the cold tolerance of important crop plants through inter-specific or inter-generic hybridization. Recent studies involving full genome profiling/sequencing, mutational and transgenic plant analyses have provided a deep insight of the complex transcriptional mechanism that operates under cold stress. The alterations in expression of genes in response to cold temperatures are followed by increases in the levels of hundreds of metabolites, some of which are known to have protective effects against the damaging effects of cold stress. Various low temperature inducible genes have been isolated from plants. Most appear to be involved in tolerance to cold stress and the expression of some of them is regulated by C-repeat binding factor/dehydration-responsive element binding (CBF/DREB1) transcription factors. Numerous physiological and molecular changes occur during cold acclimation reveals that the cold resistance is more complex than perceived and involves more than one pathway. The findings summarized in this review have shown potential practical applications for breeding cold tolerance in crop and horticultural plants suitable to temperate geographical locations.