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?

cmb2@case.edu