1. 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

2. The take home message Measuring reproductive fitness is complicated. Factors in addition to heritable variation contribute to variation in fitness indicators. Measuring reproductive fitness is complicated. Factors in addition to heritable variation contribute to variation in fitness indicators.

3. High altitude populations are the outcome of natural experiments. Courtesy of Brooke Thomas

4. A severe, unavoidable and graded stress

5. Time for natural selection High Altitude Low Altitude Ancestors Two migrations 30,000+ ya ~10,000 ya

6. Genetic and molecular pathway Hemoglobin concentration, gm/dL Sensor EGLN1 Transcription Factor Subunit EPAS1 Target Gene EPO

7. Different outcomes of the natural experiment

8. Hypothesis: Tibetans have undergone selection for a dampened hemoglobin response.

9. Hb variance is heritable among Tibetans. 1.Heritability, h 2 =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

10. Exome allele frequencies identified EPAS1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711608/bin/nihms408300f1.jpg

11. “Tibetan” alleles increase with altitude Xu S et al. Mol Biol Evol 2011;28:1003-1011

12. EPAS1 and EGLN1 associate with hemoglobin concentration

13. Do these ‘high-among-Tibetans’ alleles associate with Darwinian, reproductive, fitness?

14. Test the hypothesis among Tibetan women

17. 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

18. Conceptional and social factors account for variance in pregnancies. 4.4 + 2.6, n=410 6.5 + 2.8, n=600

19. Conceptional and social factors account for variance in surviving children. 3.0 + 2.0, n=239 4.1 + 2.2, n=350

20. The take home message Appreciate the indirect and direct influences on reproductive success. They are a challenge and an opportunity. Appreciate the indirect and direct influences on reproductive success. They are a challenge and an opportunity.

21. Questions? cmb2@case.edu