1. The evolution of lactose tolerance
09 December 2005
Volvox
meeting
Sean Myles
Max Planck Institute for Evolutionary Anthropology
Leipzig, Germany

2. Lactose Glucose + Galactose
Lactose = complex sugar
Lactase = digestive enzyme
Lactose Glucose + Galactose
Lactase

3. 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?

4. 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
AGCTTGCTATCGGTAAGCTTAGCTTAGCT
Lactose intolerant people
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
Lactose tolerant people

5. The Lactase Gene = exon C-13910T
LCT
MCM6
= exon
C-13910T
100% association with lactose tolerance
lies in a transcription factor binding site

6. Lactose tolerance frequencies in the Old World
Sweden
99%
Germany
80%
Greece
47%
Japan
15%
Bedouin
85%
China
~10%
Beja
87%
Frequency of lactose
tolerance
Tuareg
87%
30%
30-60%
 60%
Tussi
93%
Fulani
78%
South Africa 5%

7. Natural Selection Traits that have been driven up in frequency
“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.

8. 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

9. Gene-Culture Coevolution
Cultural mediation of selection pressures
Gene
pool t Et
Culture
Development
Natural
Selection
Cultural inheritance
Genetic inheritance
Time
Gene
pool
Et+1
t + 1
Culture
Natural
Selection
Development

10. Detecting the signature of selection from genetic data
AGCTTGCTATCGGTAAGCTTAGCTTAGCT
AGCTTGCTATCGGTAAGCTTAGGTTAGCT
AGCTTGCTATCGGTATGCTTAGCTTAGCT
AGCTTGCTATTGGTAAGCTTAGCTTAGCT
AGCTTGCTATTGGTATGCTTAGCTTAGCT
SNP = single nucleotide polymorphisms
Occurrence 1 in 1000 nucleotides
Main source of human genetic variation

11. 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

12. Fst – genetic differentiation
a measure of frequency difference between populations
Population A
Population B
Pop A = 20%
Pop B = 30%
= T allele
= C allele
Pop B = 80%
Little population differentiation
Low Fst
Lots of population differentiation
High Fst

13. 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

14. 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

15. Frequency of lactose tolerance Expected frequency of lactose tolerance
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 T

16. 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