Genes for High Altitudes Jay F Storz 329 Science DOI 10 1126 science 1192481 40 2010 This copy is for your personal non commercial use only If you wish to distribute this article to others colleagues clients or customers by clicking here you can order high quality copies for your can be obtained by here Permission to republish or repurpose articles or portions of articles following the guidelines The following resources related to this article are available online at www sciencemag org this information is current as of Updated information and services version of this article at http www sciencemag org content 329 5987 40 full html February 7 2014 This article http www sciencemag org content 329 5987 40 full html ref list 1 9 of which can be accessed free cites 12 articles This article has been http www sciencemag org content 329 5987 40 full html related urls 6 articles hosted by HighWire Press see cited by This article appears in the following Evolution http www sciencemag org cgi collection evolution subject collections including high resolution figures can be found in the online 4 4 4 1 1 1 0 0 0 2 2 2 7 7 7 y y y r r r a a a u u u r r r b b b e e e F F F n n n o o o g g g r r r o o o g g g a a a m m m e e e c c c n n n e e e c c c s s s w w w w w w w w w m m m o o o r r r f f f i i i d d d e e e d d d a a a o o o n n n w w w o o o D D D l l l print ISSN 0036 8075 online ISSN 1095 9203 is published weekly except the last week in December by the Copyright Science American Association for the Advancement of Science 1200 New York Avenue NW Washington DC 20005 2010 by the American Association for the Advancement of Science all rights reserved The title is a registered trademark of AAAS Science PERSPECTIVES E VO LU T ION Genes for High Altitudes Jay F Storz During the past 100 000 to 200 000 years anatomically modern humans successfully colonized a diverse range of environments across the planet Some of the most extreme of these environ ments are found on the high altitude plateaus of Central Asia and the Andes The Tibetan Plateau appears to have been inhabited for 25 000 years and permanent settlements have been established at elevations of 3500 to 4500 m 1 2 Residents of these lofty alti tudes descend from a long line of highland ancestors who lived long enough to repro duce in spite of the physiological challenges associated with chronic oxygen deprivation Thus studies of indigenous high altitude residents provide the opportunity to identify genes that may have played a role in hypoxia adaptation On pages 72 and 75 of this issue Simonson et al 3 and Yi et al 4 respec tively combine genomic and candidate gene analyses to identify the genetic basis of high altitude adaptation in Tibetans Together with another recent analysis 5 the studies reveal that genes in the hypoxia inducible factor HIF oxygen signaling pathway have been subject to strong and recent positive selection in Tibetan highlanders Hypoxic stress impinges on well char acterized physiological pathways related to oxidative energy metabolism which has facilitated the identi cation of high altitude adaptation mechanisms in nonhuman ani mals 6 7 An alternative to this candidate gene approach is to screen DNA sequence variations polymorphisms across the entire genome to identify chromosomal regions that have contributed to high altitude adap tation This population genomics approach holds the promise of identifying genes whose function and adaptive importance were pre viously unanticipated The HIF family of transcription factors regulates oxygen homeostasis by coordinat ing the transcriptional response to hypoxia The human gene endothelial PAS domain pro tein 1 EPAS1 also called HIF2 encodes the oxygen sensitive subunit of the HIF 2 tran scription factor and plays an important role in regulating erythropoiesis After conduct ing genome scans to identify candidate genes for high altitude adaptation association stud School of Biological Sciences University of Nebraska Lincoln NE 68588 USA E mail jstorz2 unl edu Analyses of genomes from Tibetan populations reveal a signaling pathway that may account for high altitude adaptation considering the effects on pregnancy outcomes at high altitude 10 12 because elevated hemoglobin con centration in the maternal circulation is associated with restricted fetal growth and increased fetal mortal ity in utero Given these adverse effects why is an increased hemoglobin concentration such an integral part of the acclimatization response to hypoxia in humans One possible explanation is that the HIF mediated increase in hemoglobin concentra tion is a misdirected response to hypobaric hypoxia that originally evolved as a response to anemia Hypobaric hypoxia and anemia both result in reduced tissue oxygenation but their root causes differ In anemia reduced tis sue oxygenation is caused by a curtailed oxy gen transport capacity of the blood and can therefore be recti ed by increasing hemoglo bin concentration By contrast in hypobaric hypoxia the reduced tissue oxygenation has an external cause The reduced oxygen ten sion of inspired air leads to a reduced oxygen saturation of arterial blood Under these cir cumstances a dramatically increased hemo globin concentration may further impede oxygen delivery to metabolizing tissues If our hominid ancestors were never forced to contend with the physiological challenges of low oxygen environments it might be unrea sonable to expect that we would have evolved an appropriate physiological response to chronic hypoxia If certain features of the acclimatiza tion response to hypoxia are maladaptive then many adaptive changes in high altitude populations may result from selection on genetically based trait variation that counter acts the effects of environmentally induced changes In the case of hemoglobin concen tration in Tibetans for example selection has not favored a trait value outside the ancestral range of variation Instead selection appears to have favored a blunted erythropoietic response such that hemoglobin concentration at high altitude is maintained at the sea level status quo Although the mechanism has yet to be elucidated it appears that regulatory M O C O T O H P K C O T S I I T D E R C The high life Tibetans who have lived at high altitudes for nearly 25 000 years survive the low oxygen environment through a low blood hemoglobin concentration ies demonstrated that noncoding variants in and around the genes EPAS1 EGLN1 a reg ulator of HIF and