A single nucleotide variant in the PPARγ-homolog Eip75B affects fecundity in Drosophila

ABSTRACTStill little is understood about the nucleotide changes that underlie variation in complex phenotypes. Variation in the PPARγ-homolog Eip75B has previously been suggested to be associated with longevity and life-history differences in the fruit fly Drosophila melanogaster. Using RNAi knockdown, we first demonstrate that reduced expression of Eip75B in adults affects lifespan, egg laying rate and egg volume. To then test the effect of a naturally occurring SNP variant within a cis-regulatory domain of Eip75B, we screened wildtype lines with alternative alleles and conducted precise genome editing using CRISPR/Cas9. These experiments revealed that this natural polymorphism has a significant effect on fecundity and egg-to-adult viability, but not on longevity or other life-history traits. These results provide a rare functional validation for the role of a natural allelic variant in adaptation of life-history traits directly linked to fitness at the single nucleotide level.

The evolution of natural systems - from the point of view of a philosopher.

According to the author, observed now natural polymorphism does not come down to the simplest neo-Darwinist constructions, but one way or another involves, as a provoking factor, the so-called "outside interference". Nevertheless, the indisputable fundamental role of the evolutionary principle is all the same visible literally at every step. This is both rather intricate genesis of prions, and microevolutionary shifts which, by the way, are taking place before our eyes (detection of new strains of bacteria and fungi resistant to various poisons or rare outlandish representatives of anaerobic and chemotrophic biota); just like the racial differences of people that, apparently, have been the best explained by J.-P. Lamarck who, alas, was then outcasted with almost the entire scientific world. Therefore, the natural progress is first of all, while creationism can, in general, be considered only as one of its tactical moves.

Natural polymorphism of Ym1 regulates pneumonitis through alternative activation of macrophages

We have positionally cloned the Ym1 gene, with a duplication and a promoter polymorphism, as a major regulator of inflammation. Mice with the RIIIS/J haplotype, with the absence of Ym1 expression, showed reduced susceptibility to mannan-enhanced collagen antibody–induced arthritis and to chronic arthritis induced by intranasal exposure of mannan. Depletion of lung macrophages alleviated arthritis, whereas intranasal supplement of Ym1 protein to Ym1-deficient mice reversed the disease, suggesting a key role of Ym1 for inflammatory activity by lung macrophages. Ym1-deficient mice with pneumonitis had less eosinophil infiltration, reduced production of type II cytokines and IgG1, and skewing of macrophages toward alternative activation due to enhanced STAT6 activation. Proteomics analysis connected Ym1 polymorphism with changed lipid metabolism. Induced PPAR-γ and lipid metabolism in Ym1-deficient macrophages contributed to cellular polarization. In conclusion, the natural polymorphism of Ym1 regulates alternative activation of macrophages associated with pulmonary inflammation.

Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients

ABSTRACT Mutations in the genes of the F420 signaling pathway of Mycobacterium tuberculosis complex, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, can lead to delamanid resistance. We searched for such mutations among 129 M. tuberculosis strains from Asia, South America, and Africa using whole-genome sequencing; 70 (54%) strains had at least one mutation in one of the genes. For 10 strains with mutations, we determined the MIC of delamanid. We found one strain from a delamanid-naive patient carrying the natural polymorphism Tyr29del (ddn) that was associated with a critical delamanid MIC.

Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-naïve Patients

Mutations in the genes of the F420 signaling pathway, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, of Mycobacterium tuberculosis (Mtb) complex can lead to delamanid resistance. We searched for such mutations among 129 Mtb strains from Asia, South-America, and Africa using whole-genome sequencing; 70 (54%) strains had at least one mutation in one of the genes. For ten strains with mutations, we determined the minimum inhibitory concentration (MIC) of delamanid. We found one strain from a delamanid-naïve patient carrying the natural polymorphism Tyr29del (ddn) that was associated with a critical MIC to delamanid.

A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice

Zika virus (ZIKV) infection is currently one of the major concerns in human public health due to its association with neurological disorders. Intensive effort has been implemented for the treatment of ZIKV, however there are not currently approved vaccines or antivirals available to combat ZIKV infection. In this sense, the identification of virulence factors associated with changes in ZIKV virulence could help to develop safe and effective countermeasures to treat ZIKV or to prevent future outbreaks. Here, we have compared the virulence of two related ZIKV strains from the recent outbreak in Brazil (2015), Rio Grande do Norte Natal (RGN) and Paraiba. In spite of both viruses being identified in the same period of time and region, significant differences in virulence and replication were observed using a validated mouse model of ZIKV infection. While ZIKV-RGN has a 50% mouse lethal dose (MLD50) of ~105 focus forming units (FFUs), ZIKV-Paraiba infection resulted in 100% of lethality with less than 10 FFUs. Combining deep-sequencing analysis and our previously described infectious ZIKV-RGN cDNA clone, we identified a natural polymorphism in the non-structural protein 2 A (NS2A) that increase the virulence of ZIKV. Moreover, results demonstrate that the single amino acid alanine to valine substitution at position 117 (A117V) in the NS2A was sufficient to convert the attenuated rZIKV-RGN in a virulent Paraiba-like virus (MLD50 < 10 FFU). The mechanism of action was also evaluated and data indicate that substitution A117V in ZIKV NS2A protein reduces host innate immune responses and viral-induced apoptosis in vitro. Therefore, amino acid substitution A117V in ZIKV NS2A could be used as a genetic risk-assessment marker for future ZIKV outbreaks.