Polymorphic pseudogenes in the human genome - a comprehensive assessment.

Background: Over the past decade, variations of the coding portion of the human genome have become increasingly evident. In this study, we focus on polymorphic pseudogenes, a unique and relatively unexplored type of pseudogene whose inactivating mutations have not yet been fixed in the human genome at the global population level. Thus, polymorphic pseudogenes are characterized by the presence in the population of both coding alleles and non-coding alleles originating from Loss-of-Function (LoF) mutations.

Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease.

Background: De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes involving errors of DNA repair/replication. These spontaneous errors play a significant role in the causation of genetic disorders, and their importance in the context of molecular diagnostic medicine has become steadily more apparent as more DNMs have been reported in the literature.

Naturally occurring genetic diseases caused by de novo variants in domestic animals.

With the advent of next-generation sequencing, an increasing number of cases of de novo variants in domestic animals have been reported in scientific literature primarily associated with clinically severe phenotypes. The emergence of new variants at each generation is a crucial aspect in understanding the pathology of early-onset diseases in animals and can provide valuable insights into similar diseases in humans. With the aim of collecting deleterious de novo variants in domestic animals, we searched the scientific literature and compiled reports on 42 de novo variants in 31 genes in domestic animals.

A partial duplication of an X-linked gene exclusive of a primate lineage (Macaca).

Gene duplication plays a significant role in evolution. Paralogous gene copies may be lost due to the successive accumulation of deleterious mutations or remain active in the genome. In this work, a partial duplication of an X-linked region in the Macaca genus is identified and explored.

Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (Na 1.5).

Common genetic polymorphisms may modify the phenotypic outcome when co-occurring with a disease-causing variant, and therefore understanding their modulating role in health and disease is of great importance. The polymorphic p.His558Arg variant of the sodium voltage-gated channel alpha subunit 5 (Na 1.

A Robust Assay to Monitor Ataxin-3 Amyloid Fibril Assembly.

Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine repeat in the protein ataxin-3, which is deposited as intracellular aggregates in affected brain regions. Despite the controversial role of ataxin-3 amyloid structures in SCA3 pathology, the identification of molecules with the capacity to prevent aberrant self-assembly and stabilize functional conformation(s) of ataxin-3 is a key to the development of therapeutic solutions. Amyloid-specific kinetic assays are routinely used to measure rates of protein self-assembly in vitro and are employed during screening for fibrillation inhibitors.

The repertoire of the elongation of very long-chain fatty acids (Elovl) protein family is conserved in tambaqui (Colossoma macropomum): Gene expression profiles offer insights into the sexual differentiation process.

Elongation of very long-chain fatty acids (Elovl) proteins are critical players in the regulation of the length of a fatty acid. At present, eight members of the Elovl family (Elovl1-8), displaying a characteristic fatty acid substrate specificity, have been identified in vertebrates, including teleost fish. In general, Elovl1, Elovl3, Elovl6 and Elovl7 exhibit a substrate preference for saturated and monounsaturated fatty acids, while Elovl2, Elovl4, Elovl5 and Elovl8 use polyunsaturated fatty acids (PUFA) as substrates.

Assessing the effects of PMM2 variants on protein stability.

Phosphomannomutase 2 deficiency, PMM2-CDG, is the most frequent disorder of protein N-glycosylation. It is an autosomal recessive disease with a broad clinical and biochemical phenotype. Trying to predict the impact of novel variants is often a challenge due to the high number of variants and the difficulty to establish solid genotype-phenotype correlations.

Genetic Variability of the Functional Domains of Chromodomains Helicase DNA-Binding (CHD) Proteins.

In the past few years, there has been an increasing neuroscientific interest in understanding the function of mammalian chromodomains helicase DNA-binding (CHD) proteins due to their association with severe developmental syndromes. Mammalian CHDs include nine members (CHD1 to CHD9), grouped into subfamilies according to the presence of specific functional domains, generally highly conserved in evolutionary terms. Mutations affecting these domains hold great potential to disrupt protein function, leading to meaningful pathogenic scenarios, such as embryonic defects incompatible with life.

Evolution and Functional Characteristics of the Novel That Play Pivotal Roles in Fatty Acid Biosynthesis.

Elongation of very long-chain fatty acid (Elovl) proteins are key enzymes that catalyze the rate-limiting step in the fatty acid elongation pathway. The most recently discovered member of the Elovl family, Elovl8, has been proposed to be a fish-specific elongase with two gene paralogs described in teleosts. However, the biological functions of Elovl8 are still to be elucidated.

An ancestral nuclear receptor couple, PPAR-RXR, is exploited by organotins.

Environmental chemicals have been reported to greatly disturb the endocrine and metabolic systems of multiple animal species. A recent example involves the exploitation of the nuclear receptor (NR) heterodimeric pair composed by PPAR/RXR (peroxisome proliferator-activated receptor/retinoid X receptor), which shows lipid perturbation in mammalian species. While gene orthologues of both of these receptors have been described outside vertebrates, no functional characterization of PPAR has been carried in protostome lineages.

Compensatory epistasis explored by molecular dynamics simulations.

A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms of compensatory epistasis can alleviate the mutations' otherwise pathogenic effects. Examples of compensated variants have been described in the literature but the interacting residue(s) postulated to play a compensatory role have rarely been ascertained.

Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity.

Understanding the role of common polymorphisms in modulating the clinical phenotype when they co-occur with a disease-causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.

SLC35A2-CDG: Novel variant and review.

encodes the X-linked transporter that carries uridine diphosphate (UDP)-galactose from the cytosol to the lumen of the Golgi apparatus and the endoplasmic reticulum. Pathogenic variants have been associated to a congenital disorder of glycosylation (CDG) with epileptic encephalopathy as a predominant feature. Among the sixty five patients described so far, a strong gender bias is observed as only seven patients are males.

GBA3: a polymorphic pseudogene in humans that experienced repeated gene loss during mammalian evolution.

The gene encoding the cytosolic β-glucosidase GBA3 shows pseudogenization due to a truncated allele (rs358231) that is polymorphic in humans. Since this enzyme is involved in the transformation of many plant β-glycosides, this particular case of gene loss may have been influenced by dietary adaptations during evolution. In humans, apart from the inactivating allele, we found that GBA3 accumulated additional damaging mutations, implying an extensive GBA3 loss.

PseudoChecker: an integrated online platform for gene inactivation inference.

The rapid expansion of high-quality genome assemblies, exemplified by ongoing initiatives such as the Genome-10K and i5k, demands novel automated methods to approach comparative genomics. Of these, the study of inactivating mutations in the coding region of genes, or pseudogenization, as a source of evolutionary novelty is mostly overlooked. Thus, to address such evolutionary/genomic events, a systematic, accurate and computationally automated approach is required.

The Echinodermata PPAR: Functional characterization and exploitation by the model lipid homeostasis regulator tributyltin.

The wide ecological relevance of lipid homeostasis modulators in the environment has been increasingly acknowledged. Tributyltin (TBT), for instance, was shown to cause lipid modulation, not only in mammals, but also in fish, molluscs, arthropods and rotifers. In vertebrates, TBT is known to interact with a nuclear receptor heterodimer module, formed by the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR).

Essential genetic findings in neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) represent a growing medical challenge in modern societies. Ever-increasing sophisticated diagnostic tools have been continuously revealing a remarkably complex architecture that embraces genetic mutations of distinct types (chromosomal rearrangements, copy number variants, small indels, and nucleotide substitutions) with distinct frequencies in the population (common, rare, de novo). Such a network of interacting players creates difficulties in establishing rigorous genotype-phenotype correlations.

Convergent inactivation of the skin-specific C-C motif chemokine ligand 27 in mammalian evolution.

The appearance of mammalian-specific skin features was a key evolutionary event contributing for the elaboration of physiological processes such as thermoregulation, adequate hydration, locomotion, and inflammation. Skin inflammatory and autoimmune processes engage a population of skin-infiltrating T cells expressing a specific C-C chemokine receptor (CCR10) which interacts with an epidermal CC chemokine, the skin-specific C-C motif chemokine ligand 27 (CCL27). CCL27 is selectively produced in the skin by keratinocytes, particularly upon inflammation, mediating the adhesion and homing of skin-infiltrating T cells.

Complete Inactivation of Sebum-Producing Genes Parallels the Loss of Sebaceous Glands in Cetacea.

Genomes are dynamic biological units, with processes of gene duplication and loss triggering evolutionary novelty. The mammalian skin provides a remarkable case study on the occurrence of adaptive morphological innovations. Skin sebaceous glands (SGs), for instance, emerged in the ancestor of mammals serving pivotal roles, such as lubrication, waterproofing, immunity, and thermoregulation, through the secretion of sebum, a complex mixture of various neutral lipids such as triacylglycerol, free fatty acids, wax esters, cholesterol, and squalene.

The Singularity of Cetacea Behavior Parallels the Complete Inactivation of Melatonin Gene Modules.

Melatonin, the hormone of darkness, is a peculiar molecule found in most living organisms. Emerging as a potent broad-spectrum antioxidant, melatonin was repurposed into extra roles such as the modulation of circadian and seasonal rhythmicity, affecting numerous aspects of physiology and behaviour, including sleep entrainment and locomotor activity. Interestingly, the pineal gland-the melatonin synthesising organ in vertebrates-was suggested to be absent or rudimentary in some mammalian lineages, including Cetacea.

Evolutionary Exploitation of Vertebrate Peroxisome Proliferator-Activated Receptor γ by Organotins.

Globally persistent man-made chemicals display ever-growing ecosystemic consequences, a hallmark of the Anthropocene epoch. In this context, the assessment of how lineage-specific gene repertoires influence organism sensitivity toward endocrine disruptors is a central question in toxicology. A striking example highlights the role of a group of compounds known as obesogens.

Retention of fatty acyl desaturase 1 (fads1) in Elopomorpha and Cyclostomata provides novel insights into the evolution of long-chain polyunsaturated fatty acid biosynthesis in vertebrates.

Background: Provision of long-chain polyunsaturated fatty acids (LC-PUFA) in vertebrates occurs through the diet or via endogenous production from C precursors through consecutive elongations and desaturations. It has been postulated that the abundance of LC-PUFA in the marine environment has remarkably modulated the gene complement and function of Fads in marine teleosts. In vertebrates two fatty acyl desaturases, namely Fads1 and Fads2, encode ∆5 and ∆6 desaturases, respectively.

"": A Draft Genome Assembly, Liver Transcriptome, and Nutrigenomics of the European Sardine, .

Clupeiformes, such as sardines and herrings, represent an important share of worldwide fisheries. Among those, the European sardine (, Walbaum 1792) exhibits significant commercial relevance. While the last decade showed a steady and sharp decline in capture levels, recent advances in culture husbandry represent promising research avenues.

A complete enzymatic capacity for long-chain polyunsaturated fatty acid biosynthesis is present in the Amazonian teleost tambaqui, Colossoma macropomum.

In vertebrates, the essential fatty acids (FA) that satisfy the dietary requirements for a given species depend upon its desaturation and elongation capabilities to convert the C polyunsaturated fatty acids (PUFA), namely linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3), into the biologically active long-chain (C) polyunsaturated fatty acids (LC-PUFA), including arachidonic acid (ARA, 20:4n-6), eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Recent studies have established that tambaqui (Colossoma macropomum), an important aquaculture-produced species in Brazil, is a herbivorous fish that can fulfil its essential FA requirements with dietary provision C PUFA LA and ALA, although the molecular mechanisms underpinning such ability remained unclear. The present study aimed at cloning and functionally characterizing genes encoding key desaturase and elongase enzymes, namely fads2, elovl5 and elovl2, involved in the LC-PUFA biosynthetic pathways in tambaqui.