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Online Appendix 1: Studies using mechanistic knowledge to test the impacts of genetic variation found in wild
populations
This table includes a few of the notable studies in eukaryotes that have identified candidate genes underlying ecologically important traits and tested
the impacts of these genetic variants on phenotype and fitness. In many cases the gene of interest has not yet been isolated from other putative
genetic differences; in cases where it has been the methods used to control for background genetic variation are noted. For further discussion of
these examples, and other studies using mechanistic knowledge to study the impacts of ecologically relevant genetic variation in natural
populations, see Dean & Thornton (2007), Eanes (1999), Ehrenreich & Purugganan (2006), and Watt & Dean (2000).
Selection
pressure
Temperature
Temperature
Resistance to
tetrodotoxin
(TTX)
Low oxygen
(hyperbaric
hypoxia)
Species
Northern and
southern
populations of
the common
killifish
(Fundulus
heteroclitus)
Populations of
Colias butterflies
from varying
altitudes
Garter snake
(Thamnophis
sirtalis)populatio
ns that occur in
ares with, and
without, toxic
newts (Taricha
granulose)
Populations of
Deer mice
(Peromyscus
maniculatus)
from high
Gene(s) and causal
mutation(s)
Lactate dehydrogenase
(LDH-B), a glycolytic
enzyme.
Genetic variation in coding
region (SNP) and cisregulatory region
(unknown)*
Phosphoglucose Isomerase
(PGI), a glycolytic enzyme
Genetic variation in coding
region (SNPs)*
Voltage gated sodium
channel (Nav1.4), an ion
transporter
Genetic variation in coding
region (SNPs)
Two tightly linked paralogs
of hemoglobin (Hb), oxygen
binding enzyme
Genetic variation in coding
Impacts of genetic variation
Notes
References
B: LDH enzyme kinetics and differences in
gene expression
C: Concentration of ATP; glucose and
lactate metabolism; hemoglobin oxygen
affinity
M: Metabolic rate in embryos
P: Swimming performance; growth rate
F: Genetic evidence for selection in cisregulatory region (deviations from neutral
expectations; Tajima’s D; Fu & Li’s D; HKA)
-Effects of LDH-B are highly
dependent upon genetic background
(i.e. if tested in individuals from the
hybrid zone vs. the northern or
southern extremes)
B: PGI thermal stability and enzyme
kinetics
C: -M:-P: Flight performance, male mating
success, female fecundity
F: Fitness components (see performance
traits); changes in gene frequency across
life history stages; genetic evidence for
selection (McDonald-Krieitman tests;
Tajima’s D)
B: TTX binding to Nav1.4
C: Ion transport and action potential
propagation in presence of TTX
M: Behavioral modification based upon
resistance
P: Locomotion after TTX ingestion
F:--
-Controls for background genetic
variation: identical by descent lines
used to study enzyme kinetics
Crawford et al. 1989; Crawford &
Powers 1992; Dimichele et al. 1991;
Dimichele & Powers 1982a, b, 1984a,
b, 1991; Dimichele et al. 1986;
Dimichele & Westerman 1997; Fangue
et al. 2008, 2009; Paynter et al. 1991;
Place & Powers 1979; Powers &
Dimichele 1981; Powers et al. 1979;
Powers & Place 1978; Powers &
Schulte 1998; Schulte et al. 2000;
Schulte et al. 1997; Schultz et al. 1996
Carter & Watt 1988; Dahlhoff & Rank
2000; Klemme & Hanski 2009; Niitepõld
et al. 2009; Saastamoinen & Hanski
2008; Wang et al. 2009; Watt 1977,
1983, 1992; Watt et al. 1985; Watt et al.
1983; Watt et al. 1996; Watt et al. 2003
Wheat et al. 2006; Zamer & Hoffmann
1989
B: Hemoglobin-oxygen affinity (P50)
C:-M: Maximal metabolic rate (VȮ2 max)
P: Ability to maintain body temperature
(thermogenesis) and run in hypoxia
- Controls for background genetic
variation: Identical by descent lines to
study maximal metabolic rate and
hemoglobin oxygen affinity
-Controls for background genetic
variation: collection of hybrids and in
vivo injections of LDH-B enzymes into
embryos
-PGI is associated with temperature
adaptation in other insects (e.g. willow
beetle (Chrysomela aeneicollis) and
Glanville fritillary butterfly (Melitaea
cinxia) and invertebrates (e.g. the Sea
anemone, Metridium senile).
-Genetic variation in the voltage gated
sodium channel mutation also
underlies TTX resistance in
otherThamnophis spp. and pufferfish
Bricelj et al. 2005; Brodie 2002; Brodie
& Brodie 1990, 1991, 1999; Brodie et
al. 2005; Brodie et al. 2002; Feldman et
al. 2009; Geffeney et al. 2002; Geffeney
et al. 2005; Motychak et al. 1999;
Ridenhour et al. 1999; Ridenhour et al.
2004; Williams & Brodie 2002, 2003;
Venkatesh et al. 2005
Chappell & Snyder 1984; Chappell et
al. 1988; Hayes & O’Connor 1999;
Jessen et al. 1991; Kleinschmidt et al.
1986; McCraken et al. 2009a,b; Perutz
1983; Piccinini et al. 1990; Storz et al.
altitude
Predation
Adaptation to
fresh water
Adaptation to
fresh water
Adaptation to
fresh water
Pollinator
preference†
region (multiple SNPs)*
Oldfield mice
(Peromyscus
polionotus)
populations from
white sand
beaches and
fields
Melanocortin receptor
(Mc1r), protein receptor
Three-spine
stickleback
(Gasterosteus
aculeatus) from
fresh-water and
marine
populations
Ectodysplasin
(Eda), a signaling protein
belonging to the tumor
necrosis factor family
Three-spine
stickleback
(Gasterosteus
aculeatus) from
fresh-water and
marine
populations
Three-spine
stickleback
(Gasterosteus
aculeatus) from
fresh-water and
marine
populations
Morning glory
(Ipomoea
purpurea) with
blue-purple or
red-pink
flowers
Pitx1, a transcription factor
Genetic variation in coding
region (SNP)
Genetic variation in cisregulatory region*
Genetic variation in cisregulatory region*
Kit ligand (Kitlg), ligand of
the tyrosine-kinase receptor
Genetic variation in cisregulatory region*
Flavonoid 3’-hydroxylase
(F3’H), enzyme in the
anthocyanin synthesis
pathway
Genetic variation in coding
region (insertion in exon 3
results in mRNA missing
first 537bp of exon 3 and
produces a non-functional
enzyme)
F: Survival differences in mice with different
capacities for oxygen consumption (markrecapture); Genetic evidence for selection
[McDonald-Kreitman; patterns of Hb
nucleotide polymorphism and divergence
(FST) among altitudes and compared to
other genes]
B: decreased receptor activity (Mc1r)
C: Reduces signals to produce melanin
M: lighter fur color
P: decreased predation
F: Fitness component (predation) & a
hybrid zone study suggest strong selection
on coloration.
B: Expression of Eda
C: -M: Lateral plate formation (over-expression
of mouse Eda-A1 in transgenic fish
increases plate number)
P: growth rate; burst swimming ; movement
behavior
F: Increased fitness in fresh water
B: PitX1 expression at site where pelvic
buds normally develop
C: -M: Presence of pelvic spines
P: -F: --
-Hb variation is also associated with
hypoxia tolerance in high altitude
populations of other mammals, frogs
and birds. Genetic signatures of
selection and phylogentic comparative
methods suggest that Hb variation has
evolved adaptively in highland geese.
-Might be more than the two linked
genes
-Mc1r is also associated with color
polymorphisms in other species of
mice, and other mammals, lizards,
birds and fish
-Mechanistic understanding of the
biochemical pathways regulating
pigment production has aided the
search for other genes contributing to
variation in coat color in P.polionotus
and P.maniculatus [e.g. cis-regulatory
mutations in Agouti signaling protein
(Agouti)]
- Controls for background genetic
variation: insertion of mouse Eda gene
to increase expression, collecting rare
Eda heterozygotes to test fitness in
the wild
2007;Weber et al. 2002
Belk & Smith 1996; Gross et al. 2009;
Hoekstra et al. 2006; Kingsley et al.
2009; Linnen et al. 2009; Mullen &
Hoekstra 2008; Mullen et al. 2009;
Nachman et al. 2003; Rosenblum et al.
2004; Steiner et al. 2009; Steiner et al.
2007; Theron et al. 2001; Vage et al.
2005
Barrett et al. 2008, 2009a; Barrett et al.
2009b; Bergstrom 2002; Colosimo et al.
2005; Colosimo et al. 2004; Knecht et
al. 2007; Marchinko 2009; Marchinko &
Schluter 2008
-Variation in PitX1 contributes to pelvic
reduction in other stickleback species
and mammals (mice & manatees)
Cresko et al. 2004; Shapiro et al. 2006;
Shapiro et al. 2004
B: Allele specific differences in Kitlg
expression in gills, ventral skin , and brain
C: Melanotcyte distribution and abundance
M: Coloration of gills and ventral skin
P: unknown
F: --
-Variation in kitlg expression
influences skin color in humans and
the genetic region shows signatures of
selection
Miller et al. 2007
B: Change in function of F3’H
C: F3’H is a branch point enzyme in the
anthocyanin synthesis pathway; Loss of
F3’H function means that the substrate,
dihydrokaempferol, is all redirected down
the red pigment precursor path
(pelargonidin), so there is no formation of
blue pigment precursors (cyanidin)
M: flower color changes from blue to red.
Insertion of red I.purpurea allele failed to
complement Arabidopsis null mutants, but
blue I.purpurea allele did
-Controls for background genetic
variation: heterologous transgenic
complementation assays in A.thaliana.
Chang et al. 2005; Clegg & Durbin
2003; Coberly & Rausher 2008; Des
Marais 2008; Fehr & Rausher 2004;
Habu et al. 1998;Lu et al. 2009;
Rausher 2008; Streisfeld & Rausher
2009; Zufall & Rausher 2003, 2004
-Variation in F3’H expression also
influences flower color variation
between blue-purple I.purpurea and
red-pink I. quamoclit and I. horsfalliae
(Note that other anthocyanin enzymes
also vary in expression and/or function
among these species)
P: pollinator attraction (bees vs.
hummingbirds)
F:--
Appropriate
life history
timing
Populations of
Arabidopsis
thaliana from
different latitudes
Flowering locus C (FLC), a
MADS box transcription
factor that represses
downstream genes inducing
flowering
Genetic variants differ
among early flowering
populations. In the
Landsberg erecta strain a
1.2 Kb transposable
element insertion in intron 1
is responsible for decreased
expression. Other wild
accessions have different
causal mutations, but these
are often also in Intron 1*
Food
acquisition
Darwins’ finches
(G. magnirostris
and other
Geospiza spp.)
Variation in unknown gene
that regulates bone
morphogenetic protein 4
(BMP4), a signaling protein
that is a member of the
transforming growth factorbeta superfamily
Note that the gene is still
unknown in this example.
B: FLC expression is reduced due to
repressive chromatin modifications
mediated by silencing short interfering
RNAs (siRNAs) generated from related
transposable elements elsewhere in the
genome
C: Changes in the expression of floral
repressor genes
M: -P: Flowering time & germination
temperature sensitivity
F: Field experiments find evidence that the
FRI/FLC multi-locus genotype influences
fitness. Population genetic screens find
evidence for selection on FRI, but do not
find evidence for recent selection on FLC.
B: Differential expression of BMP4 in beak
mesenchyme during development
C: Differential cell proliferation in regions
with increased BMP4 expression
M: Beak width and depth correlate with
BMP4 expression. Also, BMP4 expression
in transgenic chicken embryos results in
expected beak width and depth differences
P: Seed cracking ability is dependent on
beak size and shape
F: Beak size and shape influence fitness
(measured directly)
-Variations in Ipmyb1, a transcription
factor, and chalcone synthase D, an
anthocyanin pathway enzyme also
influence flower color in I. purpata
from blue-purple to white
-The expression of genes in the
anthocyananin synthesis pathway
respond to variations in temperature
and UV light.
-FLC acts pleiotropicaly to influence
seed germination and flowering time
-Controls for background genetic
variation: heterologous transgenic
complementation assays in A.thaliana.
-Other genes impacting flowering time
in natural populations of Arabidopsis
include FRIGIDA (FRI) (for which
impacts on fitness have been
measured in the field), cryptochrome 2
(CRY2), Flowering locus M (FLM), and
phytochrome c (PHYC)
Caicedo et al. 2004; Chiang et al. 2009;
El Assal et al. 2003; Ehrenreich et al.
2009; Flowers et al. 2009; Johanson et
al. 2000; Koornneef et al. 1994; Korves
et al. 2007; Lee et al. 1994; Le Corre
2005; Lempe et al. 2005; Liu et al.
2004; Michaels et al. 2003; Samis et al.
2004; Shindo et al. 2005; Shindo et al.
2006; Stinchcombe et al. 2005;
Stinchcombe et al. 2004; Toomajian et
al. 2006; Werner et al. 2005a, b
-Effects of FLC are dependent on FRI
genotype
- The fitness effects of flowering time
variation, underlain by interactions
between FLC and FRI alleles have
been shown. However, population
genetic data suggests that mutations
in FLC were not initially selected for.
-Unclear if causal mutation is in BMP4
cis regulatory region or a trans-acting
factor
- Controls for background genetic
variation: BMP4 over-expression
vector tested in chicken embryos
- Increased expression of Calmodulin
(CaM), a signal transduction enzyme,
is linked to the evolution of longer
beaks in the cactus finches (G.
scandens and G. conirostris)
Abbott et al. 1977; Abzhanov et al.
2006; Abzhanov et al. 2004; Boag &
Grant 1978, 1981, 1984; Gibbs & Grant
1987; Grant 1985; Grant & Grant 1982,
1989, 1996; Grant 1981; Grant et al.
1985; Grant & Grant 1980a, b, 2000,
2002, 2006, 2008; Keller et al. 2001;
Millington & Grant 1983; Price et al.
1984; Schluter & Grant 1984; Schluter
et al. 1985; Smith et al. 1978
B= Biochemical phenotype (includes variation of protein function or amount, interactions among proteins, and variation in the output of biochemical pathways and
networks)
C=Cellular phenotype
M=Morphological, behavioral or physiological traits
P=Performance traits
F=Fitness (may be measured through fitness components, from genetic evidence, or directly through genotype frequency changes).
*Gene identified but exact genetic variant is not
†
Note that the selective forces driving floral color changes are still debated, but thought to include pollinator preference or pleiotropic effects of pathway changes
(see Rausher 2008).
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