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Title: Bitter Taste Genetics: PTC and Other Stories


1
Bitter Taste Genetics PTC and Other Stories
  • Lynn Jorde and Steve Wooding
  • Department of Human Genetics
  • University of Utah School of Medicine

2
Overview
  • PTC evidence for balancing selection
  • PTC in chimps and humans
  • The other bitter taste receptor genes

3
Michael Bamshad, MD
Stephen Wooding, PhD
4
Molecules involved in taste perception
Sour Ion channels
Salty Ion channels
Sweet TAS1R family of G-protein coupled receptors
Umami TAS1R family of G-protein coupled receptors
Bitter TAS2R family (25 functional members)
5
Sweet and Umami (T1R)
6
The Bitter Draught Adriaen Brouwer, 1635
7
Many plants contain toxins
Digitoxin
Ricin
Abrin
Strychnine
8
Many plant toxins taste bitter
Quinine
Nicotine
Salicin
Papaverine
9
Biomedical relevance of bitter taste
Bitter-taste sensitivity
Smoking
Diet Choice
Body Mass Index
Cancer
10
Bitter-taste (TAS2R) Receptors
11
Bitter-taste (TAS2R) Receptors
TAS2R
12
Bitter-taste receptors bind plant toxins
TAS2R10 strychnine TAS2R14 a-thujones TAS2R16
salicin, cyanogenic compounds
Bufe et al., Nat. Gen., 2002 Behrens et al.,
BBRC, 2004
13
Phenylthiocarbamide (PTC)
  • Synthetic
  • Bitter or tasteless
  • Fox 1932
  • Variable sensitivity
  • Similar in structure to plant compounds
  • Blakeslee 1932
  • Taste blindness is Mendelian recessive
  • Fisher et al., 1939
  • Variable sensitivity in chimp
  • Thousands of individuals have been typed for PTC
    taster status

14
PTC Gene
  • Drayna et al., 2003
  • Genome-wide linkage analysis
  • Utah CEPH families
  • PTC gene localized to chromosome 7 and
    subsequently cloned
  • PTC Gene (TAS2R38)
  • Haplotypes strongly associated with phenotype
  • Accounted for 50-85 of phenotypic variance

How have natural selection and population
history affected the PTC gene?
15
PTC resequencing in humans
  • Sequenced entire coding region (1,002 bp)
  • 174 individuals (348 chromosomes)
  • 40 African
  • 69 Asian
  • 55 European
  • 10 Native American
  • Not selected for PTC sensitivity
  • Anthropological sampling

Wooding et al., 2004, Am. J. Hum. Genet. 74
637-46
16
Diversity in PTC
  • 6 nucleotide substitutions in humans

17
Diversity in PTC
  • 6 nucleotide substitutions
  • 7 haplotypes

PAV
AVI
18
Diversity in PTC
  • 6 nucleotide substitutions
  • 7 haplotypes

PAV
AVI
Taster Allele
Nontaster Allele
19
Allele frequencies
T
t
Native American
African
Asian
European
FST 0.05
20
Has selection been acting?
Neutrality Not Rejected, p gt 0.06
21
Has selection been acting?
Neutrality rejected
Exceeds 99.5 of D values reported for gt1,600
genes
Wooding et al., Am. J. Hum. Genet., 2004
22
How has selection acted?
Nontaster alleles are not premature stop codons
or frameshifts
HYPOTHESIS Nontaster allele is a functional
receptor that binds ligands other than PTC.
23
What happened in chimps?
24
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25
TAS2R38 Resequencing in 37 Wild-born Chimpanzees
AGG Start
ATG Start
Wooding et al., 2006, Nature 440 930-4
26
Hypothesized PTC Tasting in Chimpanzees
Non-taster
Taster
Wooding et al., 2006, Nature 440 930-4
27
How does AGG make a nontaster allele?
ATG
AGG
Full-length Protein PTC response
Truncated Protein no PTC response
28
Phenotyping Chimpanzees
29
Is AGG the nontaster allele in chimps?
  • Genotype-phenotype association analysis
  • 40 chimpanzee subjects
  • Genotyped
  • Phenotyped
  • Apples soaked in H2O or 4.0 mM PTC
  • Response on a 1-5 scale (1 Readily Accepted 5
    Strongly Rejected)
  • Fishers Exact Test (2x2)

Expected
Taster
Nontaster
23
1
Taster
Observed
7
8
Nontaster
Rejected no association (p lt 10-3) AGG/AGG
broken start chimps eat PTC apples
30
Humans versus Chimps
Humans
Chimps
T, t alleles
T, t alleles
5050 frequencies
5050 frequencies
3 amino acid changes
One start codon change
Same gene, same phenotype, same
allele frequencies different mechanism.
31
Fishers Hypothesis
Taster
Human
Non-Taster
Chimpanzee
Ch
Hu
Ch
t
T
t
Hu
T
Chimp-Human Divergence
Ancestral Gene
Ancestral Gene
32
Resequencing all 25 TAS2R genes in 55 humans
  • Do all TAS2Rs have two clusters (i.e., T and t)?
  • No some have very low levels of variation.
  • Are all TAS2R alleles found at similar
    frequencies across populations?
  • No Some have dramatically different frequencies
  • On average populations differ more at TAS2Rs than
    at other genes

TAS2R49
FST 0.33
Kim et al., 2005, Hum. Mutation 26 199-204
33
Population Differentiation Implies Local
Adaptation
PTC
Observed Simulated
FST
TAS2Rs (p lt 0.01)
Kim et al., 2005, Hum. Mutation 26 199-204
34
TAS2R genes are involved in the perception of
many substances
  • Alcohol
  • Subjects with PTC taster haplotype experience
    more bitterness and have lower alcohol intake
  • (Duffy et al., 2004, Alcohol Clin. Exp. Res. 28
    1629-37)
  • Variant in TAS2R16 is strongly associated with
    risk of alcohol dependence (Hinrichs et al.,
    2006, Am. J. Hum. Genet. 78 103-11)
  • Cigarette smoke
  • Some evidence that PTC tasters are aversive to
    cigarette smoke and less likely to become smokers
  • (Enoch et al., 2001, Addict. Behav. 26 399-404)
  • Saccharin and acesulfame K
  • Activate TAS2R43 and TAS2R44 bitter taste
    receptors
  • (Kuhn et al., 2004, J. Neurosci. 10 10260-5)

35
Summary
  • Polymorphism in the human PTC gene is maintained
    by balancing natural selection
  • Humans and chimps both have taster and non-taster
    alleles, but these alleles arose independently
  • Substantial inter-population differentiation of
    TAS2R genes exists, consistent with local
    adaptation to environmental toxins

36
Acknowledgments
University of Utah Mike Bamshad, Steve Wooding,
Diane Dunn, Bob Weiss, Mike Howard NIH Dennis
Drayna, U. Kim Potsdam Bernd Bufe, Wolfgang
Meyerhof University of Arizona Anne Stone
37
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38
How has selection acted?
39
How does AGG make a nontaster allele?
ATG
AGG
DNA
TCC
TAC
Transcription
AUG
AGG
RNA
Translation
Met
Met
Met
Protein
40
Has selection been acting?
  • Tajimas D statistic
  • Compares S

S Number of nucleotide substitutions
41
Has selection been acting?
  • Tajimas D statistic
  • Compares S and P

P Mean pairwise nucleotide difference
42
Has selection been acting?
  • Tajimas D statistic
  • Compares S and P
  • Affected by shape of haplotype network

43
Has selection been acting?
  • Tajimas D statistic
  • Compares S and P
  • Affected by shape of haplotype network

S 6
S 6
44
Has selection been acting?
  • Tajimas D statistic
  • Compares S and P
  • Affected by shape of haplotype network

S 6
S 6
P 0.1
P 3.0
45
Has selection been acting?
  • Tajimas D statistic
  • Compares S and P
  • Affected by shape of haplotype network

S 6
S 6
P 0.1
P 3.0
D -2.0
D 3.6
46
Has selection been acting?
  • Tajimas D statistic
  • Compares S and P
  • Affected by shape of haplotype network

Balancing selection or Local adaptation
Positive selection
47
Human Variation
48
Habitats
49
Genes and diet
Gene Phenotype
Hemochromatosis Iron absorption

Angiotensinogen Sodium retention
Lactase Lactose tolerance

Alcohol dehydrogenase Ethanol metabolism

50
Environmentally Responsive Genes
Genes controlling the active interface
between the human body and its environment
Genes involved in Sensory perception Immune
system Toxin metabolism
Bitter-taste sensitivity
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