Bitter taste genetics ptc and other stories
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Bitter Taste Genetics: PTC and Other Stories. Lynn Jorde and Steve Wooding Department of Human Genetics University of Utah School of Medicine. Overview. PTC: evidence for balancing selection PTC in chimps and humans The other bitter taste receptor genes. Michael Bamshad, MD.

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Bitter taste genetics ptc and other stories

Bitter Taste Genetics: PTC and Other Stories

Lynn Jorde and Steve Wooding

Department of Human Genetics

University of Utah School of Medicine


Overview

Overview

  • PTC: evidence for balancing selection

  • PTC in chimps and humans

  • The other bitter taste receptor genes


Bitter taste genetics ptc and other stories

Michael Bamshad, MD

Stephen Wooding, PhD


Molecules involved in taste perception

Molecules involved in taste perception


Bitter taste genetics ptc and other stories

Sweet and Umami (T1R)

T1R1

T1R2

T1R3

1

3

High-affinity umami receptor

Cell types observed in vivo

3

2

High-affinity sugar receptor

3

Low-affinity umami receptor


Bitter taste genetics ptc and other stories

The Bitter Draught

Adriaen Brouwer, 1635


Many plants contain toxins

Many plants contain toxins

Digitoxin

Ricin

Abrin

Strychnine


Many plant toxins taste bitter

Many plant toxins taste bitter

Quinine

Nicotine

Salicin

Papaverine


Biomedical relevance of bitter taste

Biomedical relevance of bitter taste

Bitter-taste sensitivity

Smoking

Diet Choice

Cancer

Body Mass Index


Bitter taste tas2r receptors

Bitter-taste (TAS2R) Receptors


Bitter taste genetics ptc and other stories

x

Ca+

Ca+

Ca+

Ca+

Ga

Bitter-taste (TAS2R) Receptors

TAS2R


Bitter taste receptors bind plant toxins

L’absinthe

Edgar Degas, 1876

Bitter-taste receptors bind plant toxins

TAS2R10strychnine

TAS2R14a-thujones

TAS2R16salicin, cyanogenic compounds

Bufe et al., Nat. Gen., 2002; Behrens et al., BBRC, 2004


Phenylthiocarbamide ptc

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


Ptc gene

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?


Ptc resequencing in humans

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


Bitter taste genetics ptc and other stories

Diversity in PTC

  • 6 nucleotide substitutions in humans


Bitter taste genetics ptc and other stories

Diversity in PTC

  • 6 nucleotide substitutions

    • 7 haplotypes

PAV

AVI


Bitter taste genetics ptc and other stories

Diversity in PTC

  • 6 nucleotide substitutions

    • 7 haplotypes

PAV:

AVI:

Taster

Allele

Nontaster

Allele


Bitter taste genetics ptc and other stories

Allele frequencies

T

t

Native

American

African

Asian

European

FST = 0.05


Bitter taste genetics ptc and other stories

Has selection been acting?

Neutrality Not Rejected, p > 0.06


Bitter taste genetics ptc and other stories

Has selection been acting?

Neutrality rejected

Exceeds 99.5% of D values reported for >1,600 genes

Wooding et al., Am. J. Hum. Genet., 2004


Bitter taste genetics ptc and other stories

Tt

+

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.


Bitter taste genetics ptc and other stories

What happened in chimps?


Bitter taste genetics ptc and other stories

TAS2R38 Resequencingin

37 Wild-born Chimpanzees

AGG Start

ATG Start

Wooding et al., 2006, Nature 440: 930-4


Bitter taste genetics ptc and other stories

Hypothesized PTC Tasting in Chimpanzees

“Non-taster”

“Taster”

Wooding et al., 2006, Nature 440: 930-4


How does agg make a nontaster allele

How does AGG make a nontaster allele?

ATG

AGG

Full-length Protein: PTC response

Truncated Protein: no PTC response


Phenotyping chimpanzees

Phenotyping Chimpanzees


Is agg the nontaster allele in chimps

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)

    • Fisher’s Exact Test (2x2)

Expected

Taster

Nontaster

1

23

Taster

Observed

7

8

Nontaster

  • Rejected no association (p < 10-3)

  • AGG/AGG “broken start” chimps eat PTC apples


Bitter taste genetics ptc and other stories

Humans versus Chimps

Humans

Chimps

T, t alleles

T, t alleles

50:50 frequencies

50:50 frequencies

3 amino acid changes

One start codon change

Same gene, same phenotype, same allele

frequencies… different mechanism.


Fisher s hypothesis

Fisher’s Hypothesis

“Taster”

Human

“Non-Taster”

Chimpanzee

Ch

t

Ch

Hu

t

T

Hu

T

Chimp-Human

Divergence

Ancestral Gene

Ancestral Gene


Bitter taste genetics ptc and other stories

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


Bitter taste genetics ptc and other stories

Population Differentiation Implies Local Adaptation

PTC

Observed

Simulated

FST

TAS2Rs (p < 0.01)

Kim et al., 2005, Hum. Mutation 26: 199-204


Tas2r genes are involved in the perception of many substances

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)


Summary

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


Bitter taste genetics ptc and other stories

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


Bitter taste genetics ptc and other stories

How has selection acted?


How does agg make a nontaster allele1

How does AGG make a nontaster allele?

ATG

AGG

DNA

TCC

TAC

Transcription

AUG

AGG

RNA

Translation

Met

Met

Met

Protein


Has selection been acting

Has selection been acting?

  • Tajima’s D statistic

    • Compares S

S = Number of nucleotide substitutions


Has selection been acting1

Has selection been acting?

  • Tajima’s D statistic

    • Compares S and P

P = Mean pairwise nucleotide difference


Has selection been acting2

Has selection been acting?

  • Tajima’s D statistic

    • Compares S and P

    • Affected by “shape” of haplotype network


Has selection been acting3

Has selection been acting?

  • Tajima’s D statistic

    • Compares S and P

    • Affected by “shape” of haplotype network

S = 6

S = 6


Has selection been acting4

Has selection been acting?

  • Tajima’s D statistic

    • Compares S and P

    • Affected by “shape” of haplotype network

S = 6

S = 6

P = 0.1

P = 3.0


Has selection been acting5

Has selection been acting?

  • Tajima’s D statistic

    • Compares S and P

    • Affected by “shape” of haplotype network

S = 6

S = 6

P = 0.1

P = 3.0

D = 3.6

D = -2.0


Has selection been acting6

Has selection been acting?

  • Tajima’s D statistic

    • Compares S and P

    • Affected by “shape” of haplotype network

Balancing selection

or

Local adaptation

Positive selection


Bitter taste genetics ptc and other stories

Human Variation


Bitter taste genetics ptc and other stories

Habitats


Genes and diet

Genes and diet


Environmentally responsive genes

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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