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Nuzhdin, S.

Publications and source records attributed to Nuzhdin, S..

4 recordsLinked to original sources

Evolution of phenotypic plasticity in response to ethanol between sister species with different ecological histories (Drosophila melanogaster and D. simulans)

The contribution of phenotypic plasticity to adaptation is contentious, with contradictory empirical support for its role in evolution. Here I investigate the possibility that phenotype plasticity has contributed to adaptation to a novel resource. If phenotype plasticity contributes to adaptation, it is thought to evolve in a process termed genetic accommodation. Under this model, the initial response to the environment is widely variable due to cryptic genetic variation, which is then refined by selection to a single adaptive response. I examine the role of phenotypic plasticity in adaptation here by comparing two species of Drosophila that differ in their adaptation to ethanol (Drosophila melanogaster and D. simulans). Both species are human commensals with a recent cosmopolitan expansion, but only D. melanogaster is adapted to ethanol exposure. I measure phenotype plasticity in response to ethanol with gene expression and an approach that combines information about expression and alternative splicing. I find evidence for adaptation to ethanol through genetic accommodation, suggesting that the evolution of phenotype plasticity contributed to the ability of D. melanogaster to exploit a novel resource. I also find evidence that alternative splicing may be more important for the adaptive response to ethanol than overall changes in exon expression.

evolutionary biology

Quantitative variation and evolution of spatially explicit morphogen expression in Drosophila

Robustness in development allows for the accumulation of neutral genetically based variation in expression, and here will be termed genetic stochasticity . This largely neutral variation is potentially important for both evolution and complex disease phenotypes. However, it has generally only been investigated as variation exhibited in the response to large genetic perturbations. In addition, work on variation in gene expression has similarly generally been limited to being spatial, or quantitative, but because of technical restrictions not both. Here we bridge these gaps by investigating replicated quantitative spatial gene expression using rigorous statistical models, in different genotypes, sexes, and species (Drosophila melanogaster and D. simulans). Using this type of quantitative approach with developmental data allows for effective comparison among conditions, including health versus disease. We apply this approach to the morphogenetic furrow, a wave of differentiation that sweeps across the developing eye disc. Within the morphogenetic furrow, we focus on four conserved morphogens, hairy, atonal, hedgehog, and Delta. Hybridization chain reaction quantitatively measures spatial gene expression, co-staining for all four genes simultaneously and with minimal effort. We find considerable variation in the spatial expression pattern of these genes in the eye between species, genotypes, and sexes. We also find that there has been evolution of the regulatory relationship between these genes. Lastly, we show that the spatial interrelationships of these genes evolved between species in the morphogenetic furrow. This is essentially the first population genetics of development as we are able to evaluate wild type differences in spatial and quantitative gene expression at the level of genotype, species and sex.

developmental biology

Suppression of Transposable Elements in Leukemic Stem Cells

Genomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing viral mimicry, causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.

cancer biology

Mapping Quantitative Trait Loci Underlying Circadian Light Sensitivity In Drosophila

Despite the significant advance in our understanding of the molecular basis of light entrainment of the circadian clock in Drosophila, the underlying genetic architecture is still largely unknown. The aim of this study was to identify loci associated with variation in circadian photosensitivity, which are important for the evolution of this trait. We have used complementary approaches that combined quantitative trait loci (QTL) mapping, complementation testing and transcriptome profiling to dissect this variation.\n\nWe identified a major QTL on chromosome 2, which was subsequently fine-mapped using deficiency complementation mapping into two smaller regions spanning 139 genes, some of which are known to be involved in functions which have been previously implicated in light entrainment. Two genes implicated with the clock and located within that interval, timeless and cycle, failed to complement the QTL, indicating that alleles of these genes contribute to the variation in light response. Specifically, we find that the timeless s/ls polymorphism that has been previously shown to constitute a latitudinal cline in Europe, is also segregating in our recombinant inbred lines, and is contributing to the phenotypic variation in light sensitivity.\n\nWe have also profiled gene expression in two recombinant inbred strains that differ significantly in their photosensitivity, and identified a total of 368 transcripts that showed differential expression (FDR < 0.1). Out of 131 transcripts that showed a significant RIL by treatment interaction (i.e. putative expression QTL), four are located within QTL2

genetics