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At the crossroads of genomics and ecology: The potential for a canary on a chip. Genomics and Environmental Protection. The new age of genomics. Genomics and Environmental Protection. The new age of genomics Applications of genomics data to human health.

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slide1

At the crossroads of genomics and ecology:

The potential for a canary on a chip

genomics and environmental protection1
Genomics and Environmental Protection
  • The new age of genomics
  • Applications of genomics data to human health
genomics and environmental protection2
Genomics and Environmental Protection
  • What is genomics?
  • Applications of genomics data to human health
  • Applications of genomics data to environmental health
the new age of genomics
The new age of genomics
  • A genome is the sum total of all an individual organism’s genes.
  • Thus, genomics analysis is the study of all the genes of a cell or tissue, at the DNA (genotype), mRNA (transcriptome), or protein (proteome) levels and can aid in understanding normal, adaptive, and abnormal cellular functions.

EPA definition 2002

slide7

A

B

slide9

cDNAMechanism Enzyme

YJR159W sorbitol metabolism sorbitol dehydrogenase YGL017W protein synthesis tRNA transferase

YEL008W unknown unknown YFL013C unknown unknown; similar Ifh1p,Nab3p YOL014W unknown unknown YGR144W thiamine biosyn unknown enzyme

YGL177W unknown unknown YDR372C unknown unknown YMR019W transcription Sin3-bind. protein YNR071C unknown UDPglucose 4-epimerase

YLR054C unknown unknown YAR002C-A membrane traffic secretious enzyme-unknown YMR273C cell cycle plasma membrane protein

other promising field proteomics
Other promising field:Proteomics
  • Proteomics- identifies and quantifies proteins, determines the localization, modifications, interactions, activities, and, ultimately, the function of proteins.
  • Limited use due to need for sequence information and expense
toxicogenomics
Toxicogenomics
  • Gene expression may be altered during toxicity or as a result of a disease
  • Measure associated changes in gene expression
  • More sensitive, characteristic and measureable endpoint than toxicity itself
  • Compliments existing methods
toxicogenomics1
Toxicogenomics
  • Determine mechanism of action
    • Genes associated with particular pathways
  • Create toxic signature
    • Don’t necessarily need to know genes
expression is not enough
Expression is not Enough
  • Changes in mRNA, protein or metabolic levels may also be nonspecific indicators of exposure to any stress without ties to a negative outcome.
  • To be meaningful toxicogenomics indicators, gene or protein expression must be linked to pathways as well as the overall phenotypic effects
  • Expression can be affected by diet, health, behavior, environment
genomics and human health
Genomics and Human Health
  • Drug discovery and drug safety
  • Genetics and disease
  • Genetics x Environment link
  • Environmental monitoring for exposure
  • Sensitive populations
ecology and genomics
Ecology and Genomics
  • Human health and model species focus of field
  • Ecological data-what can we learn about non-model organisms?
genomics and ecology
Genomics and Ecology
  • More precise measurement than traditional biochemical descriptions of behavior, physiology, population genetics
  • Large quantity of data
  • Comparable among species
  • Method to detail changes in response to environment
genomics and risk assessment

Ecological Risk Assessment

Genomics and Risk Assessment

Problem Formulation

Planning

Characterization of

Analysis

As Needed: Get Data, Iterate, Monitor

Exposure

Ecological

Effects

Risk Characterization

Communicate Results

Risk Management

genomics and ecological risk assessments
Genomics and Ecological Risk Assessments
  • Separate exposure and effects of multiple stressors
  • Describe effects of toxins-mechanism of action
  • Group compounds by mechanism of action
  • Measure exposure to and effects of stressors before damage occurs
traditional assessment of environmental exposure
Traditional Assessment of Environmental Exposure
  • Biomarkers of exposure
    • Peripheral blood levels of hepatic NZ’s or DNA adducts
    • Measure tissue toxin level or surrogate markers
  • Ecological risk assessments
    • Changes in community
    • Link to stressors after change
assessment endpoint
Assessment Endpoint
  • An explicit expression of the environmental value to be protected
  • Measurable entity
  • Based on:
    • Ecological relevance
    • Susceptibility to a stressor
    • Relevance to a management goal
example assessment endpoints
Example Assessment Endpoints
  • Bird survival
  • Eelgrass habitat distribution
  • Forest community structure
  • Fish survival, growth, reproduction
types of measures
Types of measures
  • Exposure
  • Effects
  • Ecosystem Receptor Characteristics
exposure analysis
Exposure Analysis
  • Describe stressor sources
  • Describe stressor distribution
  • Describe contact or co-occurance
  • Prepare exposure profile
ecological response analysis
Ecological Response Analysis
  • Stressor-response analysis
  • Establish causality
  • Link measures to assessment endpoints
  • Prepare stressor-response profile
slide29

Linking expression to exposure in vivo

Xenopus tadpoles

Jelaso et al. 2002

slide31

Linking exposure to changes in development

and changes in expression

Fathead minnow

Pimephales promelas

Cincinnati – NERL

Duluth-NHEERL

slide32

Male fathead minnow

Normal female

Female with male characters

(treated with trembolone)

slide33

Pimephales oocytes from fish exposed to Fadrozole

Normal oocyte

Fadrozole

treated oocyte

Gary Ankley

slide34

Currently only 12 protein- coding

  • DNA sequences availablein GenBank

-12S ribosomal RNA

-androgen receptor

-vitellogenin

-P450 aromatase (CYP19)

-peroxisome proliferator activated receptor isoform b

-P4501A (CYP1A)

-P450 17alpha-hydroxylase,17,20-lyase (cyp17 gene)

-aromatase

-natural resistance associated macrophage protein

-G6P1D

-glutathione S-transferase

-zona pellucida glycoprotein 3

fathead minnow gene homologs
fathead minnow gene homologs

Metabolic

delta-6 fatty acyl desaturase

glucose transporter 1

lactate dehydrongenase I

mt ATP synthase gamma unit

mt cytochrome c oxidase subunit II

mt cytochrome c oxidase subunit III

mt cytochrome b

mt NADH ubiquinone oxidoreductase subunit 4

taurine transporter

apolipoprotein

ITIH2

diamine oxidase

Na, K ATPase

adh 3

ada

UDP-glucose dehydrogenase

GAD 65

GAD 67

GTPase activating protein

Signal Transduction/Cell Cycle Regulation/Transcription

MAP kinase

G protein-coupled receptor kinase 7

janus kinase 3

MAP kinase kinase 6

jnk b

creatine kinase 1

creatine kinase 2

creatine kinase 3

mef 2c

mef2a

myo D

heat shock protein 90 beta

K-ras

Rap1b

Cyclin A2

Cyclin B

EF1 alpha

EF1 gamma

heat shock 90 alpha

cmos

Traf2

heat shock factor 2

smad 2

hexokinase

Structural

18S

60S

28S

alpha-globin

matrix metalloproteinase 9

myosin regulatory light chain

beta-actin

beta-globin

Desmoglein

keratin

lamin B1

lamin B2

dynein heavy chain

Endocrine

inhibin/activin

Pit-1

estrogen receptor beta

insulin receptor 2

Neural

pentraxin

presenilin

Immunological

integrin beta-2 chain

myeloid protein

C3-Q2

C3-H1

C3-H2

Developmental

retinol binding protein

fatty acid binding protein

retinoic acid receptor alpha

retinoic acid receptor gamma

Apoptotic

Tradd

Ann Miracle

sheepshead minnow cyprinodon variegatus

Linking in vivo expression data to in situ exposure

Sheepshead MinnowCyprinodon variegatus

Michael Hemmer

Gulf Breeze-NHEERL

  • Well documented life history
  • Sexually dimorphic
  • Eurythermal / Euryhaline
  • Fractional spawners
  • Primary consumer
ongoing epa research field studies
Ongoing EPA ResearchField Studies
  • Adult SHM collected over two years from six sites in Pensacola Bay system
  • Bayou sites: Texar (urban runoff), Chico (urban, industrial), Grande (Superfund sites)
  • Male SHM from several locations contained moderate to high levels of plasma Vtg

Courtesy of Michael Hemmer

NHEERL-Gulf Breeze

challenges
Challenges
  • Linking gene expression change to toxic endpoint or reproductive endpoint
  • Linking changes in gene expression to population or community level effect (ecological risk assessments)
  • Lack of genomic information on useful ecological species
toxicogenomics and ecology the potential for a canary on a chip
Toxicogenomics and ecology: the potential for a canary on a chip
  • What is toxicogenomics?
  • Applications of genomic data to human health
  • Applications to ecological health
    • EPA research and others
  • Applications for toxicology and beyond
applications for toxicology and beyond
Applications for toxicology and beyond
  • Predict community wide effects toxins and other stressors – ecological monitoring
  • Interspecies comparisions- sensitive species, competition among species
  • Elucidate mechanisms of complex traits
  • Identify importance of biological diversity
slide43

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Phenotype similarity

x

x

x

Genetic similarity

Heritability of secondary chemical production in plants

questions for the great lakes
Questions for the Great Lakes
  • What types of factors are affecting reproduction of sturgeon in the Great Lakes region?
  • How similar are sturgeon to model fish species (zebrafish, fathead minnow)?
  • Develop a comparable invertebrate model species (Daphnia, Chironomids, Dragonfly)
ecological genomics
Ecological Genomics
  • Use genomics as a tool answer ecological questions
  • Genomics data as a major part of ecological risk assessment