Tatiana V. Morozova
North Carolina State University
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Featured researches published by Tatiana V. Morozova.
Genome Biology | 2006
Tatiana V. Morozova; Robert Rh Anholt; Trudy F. C. Mackay
BackgroundAlcoholism presents widespread social and human health problems. Alcohol sensitivity, the development of tolerance to alcohol and susceptibility to addiction vary in the population. Genetic factors that predispose to alcoholism remain largely unknown due to extensive genetic and environmental variation in human populations. Drosophila, however, allows studies on genetically identical individuals in controlled environments. Although addiction to alcohol has not been demonstrated in Drosophila, flies show responses to alcohol exposure that resemble human intoxication, including hyperactivity, loss of postural control, sedation, and exposure-dependent development of tolerance.ResultsWe assessed whole-genome transcriptional responses following alcohol exposure and demonstrate immediate down-regulation of genes affecting olfaction, rapid upregulation of biotransformation enzymes and, concomitant with development of tolerance, altered transcription of transcriptional regulators, proteases and metabolic enzymes, including biotransformation enzymes and enzymes associated with fatty acid biosynthesis. Functional tests of P-element disrupted alleles corresponding to genes with altered transcription implicated 75% of these in the response to alcohol, two-thirds of which have human orthologues.ConclusionExpression microarray analysis is an efficient method for identifying candidate genes affecting complex behavioral and physiological traits, including alcohol abuse. Drosophila provides a valuable genetic model for comparative genomic analysis, which can inform subsequent studies in human populations. Transcriptional analyses following alcohol exposure in Drosophila implicate biotransformation pathways, transcriptional regulators, proteolysis and enzymes that act as metabolic switches in the regulation of fatty acid metabolism as important targets for future studies of the physiological consequences of human alcohol abuse.
Genome Biology | 2007
Tatiana V. Morozova; Robert Rh Anholt; Trudy F. C. Mackay
BackgroundAlcoholism is a complex disorder determined by interactions between genetic and environmental risk factors. Drosophila represents a powerful model system to dissect the genetic architecture of alcohol sensitivity, as large numbers of flies can readily be reared in defined genetic backgrounds and under controlled environmental conditions. Furthermore, flies exposed to ethanol undergo physiological and behavioral changes that resemble human alcohol intoxication, including loss of postural control, sedation, and development of tolerance.ResultsWe performed artificial selection for alcohol sensitivity for 35 generations and created duplicate selection lines that are either highly sensitive or resistant to ethanol exposure along with unselected control lines. We used whole genome expression analysis to identify 1,678 probe sets with different expression levels between the divergent lines, pooled across replicates, at a false discovery rate of q < 0.001. We assessed to what extent genes with altered transcriptional regulation might be causally associated with ethanol sensitivity by measuring alcohol sensitivity of 37 co-isogenic P-element insertional mutations in 35 candidate genes, and found that 32 of these mutants differed in sensitivity to ethanol exposure from their co-isogenic controls. Furthermore, 23 of these novel genes have human orthologues.ConclusionCombining whole genome expression profiling with selection for genetically divergent lines is an effective approach for identifying candidate genes that affect complex traits, such as alcohol sensitivity. Because of evolutionary conservation of function, it is likely that human orthologues of genes affecting alcohol sensitivity in Drosophila may contribute to alcohol-associated phenotypes in humans.
PLOS Genetics | 2010
Michael M. Magwire; Akihiko Yamamoto; Mary Anna Carbone; Natalia V. Roshina; Alexander V. Symonenko; Elena G. Pasyukova; Tatiana V. Morozova; Trudy F. C. Mackay
Understanding the genetic and environmental factors that affect variation in life span and senescence is of major interest for human health and evolutionary biology. Multiple mechanisms affect longevity, many of which are conserved across species, but the genetic networks underlying each mechanism and cross-talk between networks are unknown. We report the results of a screen for mutations affecting Drosophila life span. One third of the 1,332 homozygous P–element insertion lines assessed had quantitative effects on life span; mutations reducing life span were twice as common as mutations increasing life span. We confirmed 58 mutations with increased longevity, only one of which is in a gene previously associated with life span. The effects of the mutations increasing life span were highly sex-specific, with a trend towards opposite effects in males and females. Mutations in the same gene were associated with both increased and decreased life span, depending on the location and orientation of the P–element insertion, and genetic background. We observed substantial—and sex-specific—epistasis among a sample of ten mutations with increased life span. All mutations increasing life span had at least one deleterious pleiotropic effect on stress resistance or general health, with different patterns of pleiotropy for males and females. Whole-genome transcript profiles of seven of the mutant lines and the wild type revealed 4,488 differentially expressed transcripts, 553 of which were common to four or more of the mutant lines, which include genes previously associated with life span and novel genes implicated by this study. Therefore longevity has a large mutational target size; genes affecting life span have variable allelic effects; alleles affecting life span exhibit antagonistic pleiotropy and form epistatic networks; and sex-specific mutational effects are ubiquitous. Comparison of transcript profiles of long-lived mutations and the control line reveals a transcriptional signature of increased life span.
Botanica Marina | 2004
Tatiana Yu. Orlova; Tatiana V. Morozova; Kristin E. Gribble; David M. Kulis; Donald M. Anderson
Abstract Forty-two different dinoflagellate cyst types were found in recent sediment samples collected between July 1999–September 2002 from 44 stations along the eastern coast of Russia. This represents the first survey of recent dinoflagellate cysts in Russian marine waters. Forty cysts were identified to the species level, representing 17 genera. The most common cysts were those of ellipsoidal Alexandrium spp., Protoceratium reticulatum, Gonyaulax spp., Polykrikos kofoidii, P. schwartzii, Protoperidinium americanum, P. minutum, P. conicoides, P. subinerme, P. conicum and Scrippsiella trochoidea. Fifteen of the dinoflagellate species have not previously been recorded as motile cells in Russian marine waters: Alexandrium cf. minutum, Cochlodinium cf. polykrikoides, Diplopsalis cf. lebourae, Fragilidium mexicanum, Gonyaulax elongata, G. membranaceae, Gymnodinium cf. catenatum, Pentapharsodinium dalei, P. tyrrhenicum, Protoperidinium americanum, P. cf. avellanum, Scrippsiella cf. lachrymosa, S. cf. precaria, S. cf. rotunda and Warnowia cf. rosea. Cysts of the potentially toxic species Alexandrium cf. minutum, A. tamarense and Gymnodinium cf. catenatum were also found in this survey. Ellipsoidal Alexandrium tamarense type cysts were widely distributed and dominated many localities in the study area. These data suggest that additional cyst surveys should be conducted in areas of the eastern Russian coastline not yet investigated, and that the potential for paralytic shellfish poisoning toxicity as a result of blooms of toxic species may be more widespread than previously documented.
Genetics | 2009
Tatiana V. Morozova; Julien F. Ayroles; Katherine W. Jordan; Laura H. Duncan; Mary Anna Carbone; Richard F. Lyman; Eric A. Stone; Diddahally R. Govindaraju; R. Curtis Ellison; Trudy F. C. Mackay; Robert R. H. Anholt
Identification of risk alleles for human behavioral disorders through genomewide association studies (GWAS) has been hampered by a daunting multiple testing problem. This problem can be circumvented for some phenotypes by combining genomewide studies in model organisms with subsequent candidate gene association analyses in human populations. Here, we characterized genetic networks that underlie the response to ethanol exposure in Drosophila melanogaster by measuring ethanol knockdown time in 40 wild-derived inbred Drosophila lines. We associated phenotypic variation in ethanol responses with genomewide variation in gene expression and identified modules of correlated transcripts associated with a first and second exposure to ethanol vapors as well as the induction of tolerance. We validated the computational networks and assessed their robustness by transposon-mediated disruption of focal genes within modules in a laboratory inbred strain, followed by measurements of transcript abundance of connected genes within the module. Many genes within the modules have human orthologs, which provides a stepping stone for the identification of candidate genes associated with alcohol drinking behavior in human populations. We demonstrated the potential of this translational approach by identifying seven intronic single nucleotide polymorphisms of the Malic Enzyme 1 (ME1) gene that are associated with cocktail drinking in 1687 individuals of the Framingham Offspring cohort, implicating that variation in levels of cytoplasmic malic enzyme may contribute to variation in alcohol consumption.
Genome Biology | 2012
Tatiana V. Morozova; David Goldman; Trudy F. C. Mackay; Robert Rh Anholt
Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms.
PLOS ONE | 2009
Mary Anna Carbone; Julien F. Ayroles; Akihiko Yamamoto; Tatiana V. Morozova; Steven A. West; Michael M. Magwire; Trudy F. C. Mackay; Robert R. H. Anholt
Background Glaucoma is the worlds second leading cause of bilateral blindness with progressive loss of vision due to retinal ganglion cell death. Myocilin has been associated with congenital glaucoma and 2–4% of primary open angle glaucoma (POAG) cases, but the pathogenic mechanisms remain largely unknown. Among several hypotheses, activation of the unfolded protein response (UPR) has emerged as a possible disease mechanism. Methodology / Principal Findings We used a transgenic Drosophila model to analyze whole-genome transcriptional profiles in flies that express human wild-type or mutant MYOC in their eyes. The transgenic flies display ocular fluid discharge, reflecting ocular hypertension, and a progressive decline in their behavioral responses to light. Transcriptional analysis shows that genes associated with the UPR, ubiquitination, and proteolysis, as well as metabolism of reactive oxygen species and photoreceptor activity undergo altered transcriptional regulation. Following up on the results from these transcriptional analyses, we used immunoblots to demonstrate the formation of MYOC aggregates and showed that the formation of such aggregates leads to induction of the UPR, as evident from activation of the fluorescent UPR marker, xbp1-EGFP. Conclusions / Significance Our results show that aggregation of MYOC in the endoplasmic reticulum activates the UPR, an evolutionarily conserved stress pathway that culminates in apoptosis. We infer from the Drosophila model that MYOC-associated ocular hypertension in the human eye may result from aggregation of MYOC and induction of the UPR in trabecular meshwork cells. This process could occur at a late age with wild-type MYOC, but might be accelerated by MYOC mutants to account for juvenile onset glaucoma.
Chemical Senses | 2014
Shilpa Swarup; Tatiana V. Morozova; Sruthipriya Sridhar; Michael Nokes; Robert R. H. Anholt
Nutrient intake and avoidance of toxins are essential for survival and controlled by attractive and aversive feeding responses. Drosophila melanogaster presents one of the best characterized systems for studies on chemosensation, which is mediated by multigene families of chemoreceptors, including olfactory receptors, gustatory receptors, and odorant-binding proteins (OBPs). Although the response profiles of gustatory receptors have been well studied, the contribution of OBPs to food intake is largely unknown. As most aversive (“bitter”) tastants are hydrophobic, we hypothesized that OBPs may fulfill an essential function in transporting bitter tastants to gustatory receptors to modulate feeding behavior. Here, we used 16 RNAi lines that inhibit expression of individual target Obp genes and show that OBPs modulate sucrose intake in response to a panel of nine bitter compounds. Similar to their function in olfaction, OBPs appear to interact with bitter compounds in a combinatorial and sex-dependent manner. RNAi-mediated reduction in expression of individual Obp genes resulted either in enhanced or reduced intake of sucrose in the presence of bitter compounds, consistent with roles for OBPs in transporting tastants to bitter taste receptors, sequestering them to limit their access to these receptors, or interacting directly with gustatory neurons that respond to sucrose.
Molecular Genetics and Genomics | 2014
Tatiana V. Morozova; Trudy F. C. Mackay; Robert R. H. Anholt
Alcohol abuse and alcoholism incur a heavy socioeconomic cost in many countries. Both genetic and environmental factors contribute to variation in the inebriating effects of alcohol and alcohol addiction among individuals within and across populations. From a genetics perspective, alcohol sensitivity is a quantitative trait determined by the cumulative effects of multiple segregating genes and their interactions with the environment. This review summarizes insights from model organisms as well as human populations that represent our current understanding of the genetic and genomic underpinnings that govern alcohol metabolism and the sedative and addictive effects of alcohol on the nervous system.
Genetics Research | 2012
Shilpa Swarup; Susan T. Harbison; Lauren E. Hahn; Tatiana V. Morozova; Akihiko Yamamoto; Trudy F. C. Mackay; Robert R. H. Anholt
Summary Epistasis is an important feature of the genetic architecture of quantitative traits, but the dynamics of epistatic interactions in natural populations and the relationship between epistasis and pleiotropy remain poorly understood. Here, we studied the effects of epistatic modifiers that segregate in a wild-derived Drosophila melanogaster population on the mutational effects of P-element insertions in Semaphorin-5C (Sema-5c) and Calreticulin (Crc), pleiotropic genes that affect olfactory behaviour and startle behaviour and, in the case of Crc, sleep phenotypes. We introduced Canton-S B (CSB) third chromosomes with or without a P-element insertion at the Crc or Sema-5c locus in multiple wild-derived inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and assessed the effects of epistasis on the olfactory response to benzaldehyde and, for Crc, also on sleep. In each case, we found substantial epistasis and significant variation in the magnitude of epistasis. The predominant direction of epistatic effects was to suppress the mutant phenotype. These observations support a previous study on startle behaviour using the same D. melanogaster chromosome substitution lines, which concluded that suppressing epistasis may buffer the effects of new mutations. However, epistatic effects are not correlated among the different phenotypes. Thus, suppressing epistasis appears to be a pervasive general feature of natural populations to protect against the effects of new mutations, but different epistatic interactions modulate different phenotypes affected by mutations at the same pleiotropic gene.