Testes-specific hemoglobins in Drosophila evolved by a combination of sub- and neofunctionalization after gene duplication

<p>Abstract</p> <p>Background</p> <p>For a long time the presence of respiratory proteins in most insects has been considered unnecessary. However, in recent years it has become evident that globins belong to the standard repertoire of the insect genome. Like most other insect globins, the <it>glob1 </it>gene of <it>Drosophila melanogaster </it>displays a conserved expression pattern in the tracheae, the fat body and the Malpighian tubules.</p> <p>Results</p> <p>Here we show that the recently discovered <it>D. melanogaster </it>globin genes <it>glob2 </it>and <it>glob3 </it>both display an unusual male-specific expression in the reproductive tract during spermatogenesis. Both paralogs are transcribed at equivalent mRNA levels and largely overlap in their cellular expression patterns during spermatogenesis. Phylogenetic analyses showed that <it>glob2 </it>and <it>glob3 </it>reflect a gene duplication event that occurred in the ancestor of the <it>Sophophora </it>subgenus at least 40 million years ago. Therefore, flies of the <it>Drosophila </it>subgenus harbor only one <it>glob2/3</it>-like gene.</p> <p>Conclusions</p> <p>Phylogenetic and sequence analyses indicate an evolution of the <it>glob2 </it>and <it>glob3 </it>duplicates by a combination of sub- and neofunctionalization. Considering their restricted, testes-specific expression, an involvement of both globins in alleviating oxidative stress during spermatogenesis is conceivable.</p

Positive selection at codon 38 of the human KCNE1 (= minK) gene and sporadic absence of 38Ser-coding mRNAs in Gly38Ser heterozygotes

<p>Abstract</p> <p>Background</p> <p>KCNE1 represents the regulatory beta-subunit of the slowly activating delayed rectifier potassium channel (IKs). Variants of KCNE1 have repeatedly been linked to the long-QT syndrome (LQTS), a disorder which predisposes to deafness, ventricular tachyarrhythmia, syncope, and sudden cardiac death.</p> <p>Results</p> <p>We here analyze the evolution of the common Gly38Ser variant (rs1805127), using genomic DNAs, complementary DNAs, and HEK293-expressed variants of altogether 19 mammalian species. The between species comparison reveals that the human-specific Gly38Ser polymorphism evolved under strong positive Darwinian selection, probably in adaptation to specific challenges in the fine-tuning of IKs channels. The involved amino acid exchanges (Asp > Gly, Gly > Ser) are moderately radical and do not induce apparent changes in posttranslational modification. According to population genetic analyses (HapMap phase II) a heterozygote advantage accounts for the maintenance of the Gly38Ser polymorphism in humans. On the other hand, the expression of the 38Ser allele seems to be disadvantageous under certain conditions, as suggested by the sporadic deficiency of 38Ser-coding mRNAs in heterozygote Central Europeans and the depletion of homozygotes 38Ser in the Yoruban sample.</p> <p>Conclusion</p> <p>We speculate that individual differences in genomic imprinting or genomic recoding might have contributed to conflicting results of recent association studies between Gly38Ser polymorphism and QT phenotype. The findings thus highlight the relevance of mRNA data in future association studies of genotypes and clinical disorders. To the best of our knowledge, they moreover provide first time evidence for a unique pattern; i.e. coincidence of positive Darwinian selection and polymorphism with a sporadically suppressed expression of one allele.</p

Анализ пожарной безопасности магазина торговой сети ПАО "Магнит"

В статье проанализирована система пожарной безопасности магазина торговой сети "Магнит" с целью выявления уязвимых мест, профилактики пожаров и минимизации ущерба от потенциальных возгораний.The article analyzes the fire safety system of the Magnit retail chain store in order to identify vulnerabilities, prevent fires and minimize damage from potential fires

Identification of antiparasitic drug targets using a multi-omics workflow in the acanthocephalan model

Background: With the expansion of animal production, parasitic helminths are gaining increasing economic importance. However, application of several established deworming agents can harm treated hosts and environment due to their low specificity. Furthermore, the number of parasite strains showing resistance is growing, while hardly any new anthelminthics are being developed. Here, we present a bioinformatics workflow designed to reduce the time and cost in the development of new strategies against parasites. The workflow includes quantitative transcriptomics and proteomics, 3D structure modeling, binding site prediction, and virtual ligand screening. Its use is demonstrated for Acanthocephala (thorny-headed worms) which are an emerging pest in fish aquaculture. We included three acanthocephalans (Pomphorhynchus laevis, Neoechinorhynchus agilis, Neoechinorhynchus buttnerae) from four fish species (common barbel, European eel, thinlip mullet, tambaqui).Results: The workflow led to eleven highly specific candidate targets in acanthocephalans. The candidate targets showed constant and elevated transcript abundances across definitive and accidental hosts, suggestive of constitutive expression and functional importance. Hence, the impairment of the corresponding proteins should enable specific and effective killing of acanthocephalans. Candidate targets were also highly abundant in the acanthocephalan body wall, through which these gutless parasites take up nutrients. Thus, the candidate targets are likely to be accessible to compounds that are orally administered to fish. Virtual ligand screening led to ten compounds, of which five appeared to be especially promising according to ADMET, GHS, and RO5 criteria: tadalafil, pranazepide, piketoprofen, heliomycin, and the nematicide derquantel.Conclusions: The combination of genomics, transcriptomics, and proteomics led to a broadly applicable procedure for the cost- and time-saving identification of candidate target proteins in parasites. The ligands predicted to bind can now be further evaluated for their suitability in the control of acanthocephalans. The workflow has been deposited at the Galaxy workflow server under the URL tinyurl.com/yx72rda7

Correlates of evolutionary rates in the murine sperm proteome

Abstract Background Protein-coding genes expressed in sperm evolve at different rates. To gain deeper insight into the factors underlying this heterogeneity we examined the relative importance of a diverse set of previously described rate correlates in determining the evolution of murine sperm proteins. Results Using partial rank correlations we detected several major rate indicators: Phyletic gene age, numbers of protein-protein interactions, and survival essentiality emerged as particularly important rate correlates in murine sperm proteins. Tissue specificity, numbers of paralogs, and untranslated region lengths also correlate significantly with sperm genes’ evolutionary rates, albeit to a lesser extent. Multifunctionality, coding sequence or average intron lengths, and mean expression level have insignificant or virtually no independent effects on evolutionary rates in murine sperm genes. Gene ontology enrichment analyses of three equally sized murine sperm protein groups classified based on their evolutionary rates indicate strongest sperm-specific functional specialization in the most quickly evolving gene class. Conclusions We propose a model according to which slowly evolving murine sperm proteins tend to be constrained by factors such as survival essentiality, network connectivity, and/or broad expression. In contrast, evolutionary change may arise especially in less constrained sperm proteins, which might, moreover, be prone to specialize to reproduction-related functions. Our results should be taken into account in future studies on rate variations of reproductive genes

Cellular prion protein (PrPc) and hypoxia: true to each other in good times and in bad, in sickness and in health

The cellular prion protein (PrPc) and hypoxia appear to be tightly intertwined. Beneficial effects of PrPc on neuronal survival under hypoxic conditions such as focal cerebral ischemia are strongly supported. Conversely, increasing evidence indicates detrimental effects of increased PrPc expression on cancer progression, another condition accompanied by low oxygen tensions. A switch between anaerobic and aerobic metabolism characterizes both conditions. A cellular process that might unite both is glycolysis. Putative role of PrPc in stimulation of glycolysis in times of need is indeed thought provoking. A significance of astrocytic PrPc expression for neuronal survival under hypoxic conditions and possible association of PrPc with the astrocyte-neuron lactate shuttle (ANLS) is considered. We posit PrPc-induced lactate production via transactivation of lactate dehydrogenase A by hypoxia inducible factor 1α as an important factor for survival of both neurons and tumor cells in hypoxic microenvironment. Concomitantly, we discuss a cross-talk between Wnt/ß-catenin and PI-3K/Akt signaling pathways in executing PrPc-induced activation of glycolysis. Finally, we would like to emphasize that we see a great potential in joining expertise from both fields, neuroscience and cancer research in revealing the mechanisms underlying hypoxia-related pathologies. PrPc may prove focal point for future research

Additional File 2:

Table S5. Significantly enriched DAVID GO annotation clusters for three protein groups with different dN/dS estimates. (XLSX 17 kb

Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance

Deciphering the functional relationships of genes resulting from genome-wide screens for polymorphisms that are associated with phenotypic variations can be challenging. However, given the common association with certain phenotypes, a functional link should exist. We have tested this prediction in newly sequenced exomes of altogether 100 men representing different states of fertility. Fertile subjects presented with normal semen parameters and had naturally fathered offspring. In contrast, infertile probands were involuntarily childless and had reduced sperm quantity and quality. Genome-wide association study (GWAS) linked twelve non-synonymous single-nucleotide polymorphisms (SNPs) to fertility variation between both cohorts. The SNPs localized to nine genes for which previous evidence is in line with a role in male fertility maintenance: ANAPC1, CES1, FAM131C, HLA-DRB1, KMT2C, NOMO1, SAA1, SRGAP2, and SUSD2. Most of the SNPs residing in these genes imply amino acid exchanges that should only moderately affect protein functionality. In addition, proteins encoded by genes from present GWAS occupied peripheral positions in a protein–protein interaction network, the backbone of which consisted of genes listed in the Online Mendelian Inheritance in Man (OMIM) database for their implication in male infertility. Suggestive of an indirect impact on male fertility, the genes focused were indeed linked to each other, albeit mediated by other interactants. Thus, the chances of identifying a central player in male infertility by GWAS could be limited in general. Furthermore, the SNPs determined and the genes containing these might prove to have potential as biomarkers in the diagnosis of male fertility

Additional File 1:

Figure S1, Supplementary Methods, Tables S1-S4. Additional methods and results of additional analyses as specified in the main text. (PDF 429 kb