Download AGCTTGCTATCGGTAAGCTTAGCTTAGCT

The evolution of lactose tolerance
09 December 2005
Volvox
meeting
Sean Myles
Max Planck Institute for Evolutionary Anthropology
Leipzig, Germany
Lactose = complex sugar
Lactase = digestive enzyme
Lactose
Lactase
Glucose + Galactose
Some humans are strange!
• All mammals and most humans stop producing
lactase after weaning
• Lactose tolerance = lactase persistence
• Simple dominant mode of inheritance
• Human genetic polymorphism
• Where is the mutation?
Genetic association study
Step 1: Identify a candidate gene
Step 2: Find a mutation in the candidate gene
that associates with the trait of interest
Lactose intolerant people
AGCTTGCTATCGGTAAGCTTAGCTTAGCT
AGCTTGCTATCGGTAAGCTTAGCTTAGCT
AGCTTGCTATCGGTAAGCTTAGCTTAGCT
AGCTTGCTATCGGTAAGCTTAGCTTAGCT
Lactose tolerant people
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
The Lactase Gene
MCM6
LCT
= exon
C-13910T
• 100% association with lactose tolerance
• lies in a transcription factor binding site
Lactose tolerance frequencies in the Old World
Sweden
99%
Germany
80%
Greece
47%
Bedouin
85%
Beja
87%
Tuareg
87%
Fulani
78%
Tussi
93%
South Africa
5%
Japan
15%
China
~10%
Frequency of lactose
tolerance
30%
30-60%
 60%
Natural Selection
“Variations, however slight and from whatever cause proceeding, if they be in any
degree profitable to the individuals of a species […] will tend to the preservation of
such individuals, and will generally be inherited by the offspring.
The offspring, also, will thus have a better chance of surviving, for, of the many
individuals of any species which are periodically born, but a small number can
survive. I have called this principle, by which each slight variation, if useful, is
preserved, by the term natural selection.”
(Charles Darwin in The Origin, 1859)
Traits that have been driven up in frequency
by natural selection are called adaptations.
The culture-historical hypothesis
Simoons (1965)
• Cultures that relied on milk as a nutritional
source experienced natural selection for
lactose tolerance
Gene-culture coevolution
• Humans co-directed their own biological
evolution by creating the selection pressure
for lactose tolerance
Gene-Culture Coevolution
Cultural mediation of selection pressures
Natural
Selection
Time
t+1
Et+1
Natural
Selection
Gene
pool
Culture
Development
Cultural inheritance
Et
Gene
pool
Genetic inheritance
t
Development
Cultural mediation of selection pressures
Culture
Detecting the signature of
selection from genetic data
AGCTTGCTATCGGTAAGCTTAGCTTAGCT
AGCTTGCTATCGGTAAGCTTAGGTTAGCT
AGCTTGCTATCGGTAAGCTTAGCTTAGCT
AGCTTGCTATCGGTATGCTTAGCTTAGCT
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
AGCTTGCTATTGGTATGCTTAGCTTAGCT
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
SNP = single nucleotide polymorphisms
• Occurrence 1 in 1000 nucleotides
• Main source of human genetic variation
Genome-wide SNP data
• HapMap project
• approx. 3 million SNPs in 4 human populations
• project will be extended
• Perlegen data
• approx. 1.5 million SNPs in 3 human populations
• Populations include:
African-Americans
European-Americans
Chinese-Americans
Fst – genetic differentiation
• Fst:
– a measure of frequency difference between populations
Population A
Population B
= T allele
= C allele
Little population
differentiation
Low Fst
Pop A = 20%
Lots of
population
differentiation
High Fst
Pop A = 20%
Pop B = 30%
Pop B = 80%
African-Americans vs. European Americans
Fst distribution for 1.5 million SNPs
# of SNPs within and around the lactase gene = 100
# of top 1% Fst SNPs within lactase gene = 15
top 1% Fst = 0.5
Evidence for selection?
How unusual does the lactase gene look?
How often are 15 out of 100 SNPs within the top 1%
of the Fst distribution in the whole data set?
Sample 10,000 times from data
at random blocks of 100 SNPs
and count # of top 1% SNPs in
each iteration
Observed = 15, p = 0.016
What about African dairying populations?
.
Ga’ali (.53) (0)
Wolof (.51) (0)
Shaigi (.38) (0)
Nuer (.22) (0)
Dinka (.26) (0)
Evidence for convergent evolution??
Red
Frequency of lactose tolerance
Blue
Expected frequency of lactose tolerance
from frequency of -13910T
Lessons from Lactase
• Lactose tolerance is rare worldwide and is found at
high frequencies only in dairying populations
• Genetic signature of selection: the lactase gene in
Europeans possesses one of the strongest
signatures of selection to be detected in the
human genome
• Gene-culture coevolution: culture can drive
biological evolution in humans
• Convergent evolution: lactose tolerance may be an
example of recent convergent evolution in humans