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Fertility and child survivorship among Tibetan women at high altitude in Nepal
Cynthia M Beall, Ph.D.Case Western Reserve University
Geoff Childs, Ph.D.Washington University
Sienna Craig, Ph.D.Dartmouth College
April 10, 2014
The take home message
Measuring reproductive fitness is complicated.
Factors in addition to heritable variation contribute to variation in fitness indicators.
High altitude populations are the outcome of natural experiments.
Courtesy of Brooke Thomas
A severe, unavoidable and graded stress
Altitude, m
0 1000 2000 3000 4000 5000 6000 7000
% S
ea
Le
vel P
iO2
40
50
60
70
80
90
100
Time for natural selection
High Altitude
Low Altitude Ancestors
Two migrations
• 30,000+ ya
• ~10,000 ya
Genetic and molecular pathway
Low Altitude High Altitude12
13
14
15
16
17
18
19
25d, 5400m56d, 4200m28d, 3800m72d, 5260m11d, 4300m21d, 4300m18d, 4300m16d, 5050m16d, 5050m2
Hem
oglo
bin
conc
entr
ation
, gm
/dL
Sensor EGLN1
Transcription Factor Subunit
EPAS1
Target Gene
EPO
Different outcomes of the natural experiment
Altitude versus Hemoglobin Concentration
Altitude, meters
0 1000 2000 3000 4000 5000
Hem
oglo
bin
co
nce
ntra
tion,
gm
/dL
14
16
18
20
22
Andean (Cosio, 1972)
Tibetan (Beall, various)
Hypothesis: Tibetans have undergone selection for a dampened hemoglobin response.
Hb variance is heritable among Tibetans.
1. Heritability, h2=0.64
2. Hb associates with SNP sites in loci of oxygen homeostasis pathway.
3. Tibetan allele frequency is divergent at those SNP sites.
4. Tibetans exhibit an altitude gradient in allele frequency at those SNP sites.
http://genegeek.ca/2010/11/human-chromosomes-and-karyotype
Exome allele frequencies identified EPAS1.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711608/bin/nihms408300f1.jpg
“Tibetan” alleles increase with altitude
Xu S et al. Mol Biol Evol 2011;28:1003-1011
GENOTYPES
Tibetan homozygote Other homozygote
Hem
og
lob
in c
on
c., g
m/d
L
14
16
18
20
22 4200m, EPAS1
4300m, EPAS1
4300m, EPAS1 MF
4350m, EGLN1 & PPARA
3800m, EPAS1 Sh
100m, EPAS1
EPAS1 and EGLN1 associate with hemoglobin concentration
Do these ‘high-among-Tibetans’ alleles associate with Darwinian, reproductive, fitness?
Test the hypothesis among Tibetan women
Fitness indicators integrate many factors.
DIRECT INFLUENCES
• Genotype• Intercourse• Conceptional• Gestational factors
FITNESS
• Pregnancies• Live births• Surviving children
INDIRECT INFLUENCES
• Social, Economic, Migration, Environmental factors
K. Davis & J. Blake 1956 Social structure and Fertility: an analytic framework. Econ. Dev. & Cult. Change
Conceptional and social factors account for variance in pregnancies.
Number of Pregnancies
Indirect, direct variables
Age Last Preg
Age First P
reg
Infant Morta
lityTwins
Husband/Natal Villa
ge
Cu
mu
lati
ve R
2
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Not Continuously MarriedContinuously Married
4.4 + 2.6, n=410
6.5 + 2.8, n=600
Conceptional and social factors account for variance in surviving children.
3.0 + 2.0, n=239
4.1 + 2.2, n=350
Children surviving to reproductive age (15 yrs)
Indirect, direct variables
Age Last Preg
Age First P
reg
Contraceptio
n
Relative W
ealth
Infant Morta
lityTwins
Natal village
Cu
mu
lati
ve R
2
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
Not continuously married
Continuously married
The take home message
Appreciate the indirect and direct influences on reproductive success.
They are a challenge and an opportunity.
Questions?