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The Identification and Characterisation of Genetic Signals of Selection in High Altitude Populations

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posted on 22.11.2019, 17:36 authored by Amy Cole

Populations dwelling at high altitude (greater than 2500 meters above sea-level) are exposed to harsh environmental elements including, extreme cold, dietary acculturation, increased UV irradiance and hypobaric hypoxia. There is approximately 60% of the oxygen available to populations at high altitude compared to at sea-level. The ability to adapt to this reduction in oxygen availability is fundamental to the preservation of function, and of life. Identifying and characterising the genes involved in adaptation to hypoxia therefore offers an important and unique insight into hypoxia in general, and can in turn inform on a variety of human conditions and diseases of public health importance.

We established a geographically diverse cohort of high altitude populations, from the Himalaya, the Andes and the East African plateau, through fieldwork, collaborations and publically available datasets. Using both dense genotype data and whole genome sequencing we describe the population structure of these populations and apply a number of selection scans to identify regions of the genome that have undergone selection, enabling these populations to adapt to high altitude.

We show that genes mirror geography in the Himalayan region. We identified the Sherpa as a remarkably genetically isolated population relative to their neighbouring Nepali populations, characterised by varying proportions of Tibetan and ‘ancestral north Indian’ ancestry. The Andean Quechua were a relatively homogenous population, despite the complex demographic history of South America. We identified genetic signatures of selection that were both unique and common to geographically diverse high altitude populations, suggesting that these populations may be at different stages of convergent evolution. We identified a novel candidate hypoxic pathway containing the genes; ErBb4, GAB1 and ARHGEF7. To verify the robust application of our statistical tests of selection, and highlight the translational potential of this research we performed a preliminarily characterisation of these three candidate hypoxic genes. We measured the effects of each gene knockdown on HIF-1α (hypoxic inducible factor - 1α), a protein involved in the body’s most vital oxygen homeostasis pathway, in an in-vitro hypoxic environment.


Science Foundation Ireland


First Supervisor

Professor Gianpiero Cavalleri

Second Supervisor

Professor Cormac Taylor


A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2018.

Published Citation

Cole A. The Identification and Characterisation of Genetic Signals of Selection in High Altitude Populations [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2018.

Degree Name

Doctor of Philosophy (PhD)

Date of award


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