4125
The Journal of Experimental Biology 213, 4125-4136
© 2010. Published by The Company of Biologists Ltd
doi:10.1242/jeb.048181
Review
Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates
Jay F. Storz1,*, Graham R. Scott2 and Zachary A. Cheviron1
1
School of Biological Sciences, University of Nebraska, Lincoln, NE 68588, USA and 2School of Biology, University of St Andrews,
St Andrews, Fife KY16 8LB, UK
*Author for correspondence ([email protected])
Accepted 31 August 2010
Summary
High-altitude environments provide ideal testing grounds for investigations of mechanism and process in physiological
adaptation. In vertebrates, much of our understanding of the acclimatization response to high-altitude hypoxia derives from
studies of animal species that are native to lowland environments. Such studies can indicate whether phenotypic plasticity will
generally facilitate or impede adaptation to high altitude. Here, we review general mechanisms of physiological acclimatization
and genetic adaptation to high-altitude hypoxia in birds and mammals. We evaluate whether the acclimatization response to
environmental hypoxia can be regarded generally as a mechanism of adaptive phenotypic plasticity, or whether it might
sometimes represent a misdirected response that acts as a hindrance to genetic adaptation. In cases in which the acclimatization
response to hypoxia is maladaptive, selection will favor an attenuation of the induced phenotypic change. This can result in a
form of cryptic adaptive evolution in which phenotypic similarity between high- and low-altitude populations is attributable to
directional selection on genetically based trait variation that offsets environmentally induced changes. The blunted erythropoietic
and pulmonary vasoconstriction responses to hypoxia in Tibetan humans and numerous high-altitude birds and mammals
provide possible examples of this phenomenon. When lowland animals colonize high-altitude environments, adaptive phenotypic
plasticity can mitigate the costs of selection, thereby enhancing prospects for population establishment and persistence. By
contrast, maladaptive plasticity has the opposite effect. Thus, insights into the acclimatization response of lowland animals to
high-altitude hypoxia can provide a basis for predicting how altitudinal range limits might shift in response to climate change.
Key words: acclimatization, countergradient variation, hypoxia tolerance, oxygen transport, physiological genomics.
Introduction
!"#$%&'("()*+,+-."/0-1+-(2,3/0."*+,4+/("'+,#/0)-*,40/,"-.+2("#&("-#
1+5$&-"212, 04, 3$62"0'0#"5&', &*&3(&("0-7 80/, &"/%9/+&($"-#
.+/(+9/&(+2, ($&(, '".+, &(, $"#$, &'("()*+:, $6309&/"5, $630;"&, "2, &)-/+1"(("-#, +-."/0-1+-(&', 2(/+220/, ($&(, 5&--0(, 9+, 1"("#&(+*, 96
9+$&."0/&', &.0"*&-5+7, !"#$%&'("()*+, +-."/0-1+-(2, &/+, &'20
5$&/&5(+/"<+*, 96, '0=, &19"+-(, (+13+/&()/+2, /+'&(".+, (0, '0='&-*
+-."/0-1+-(2, &(, 2"1"'&/, '&("()*+2:, &-*, ($+/+40/+, 3/+2+-(
+-*0($+/1"5,&-"1&'2,="($,($+,&**"("0-&',3$62"0'0#"5&',5$&''+-#+,04
2)2(&"-"-#, 1+(&90'"5, $+&(, 3/0*)5("0-, "-, 23"(+, 04, ($+, /+*)5+*
&.&"'&9"'"(6,04,>? 40/,&+/09"5,30=+/,#+-+/&("0-7
@-,&-"1&',23+5"+2,($&(,"-$&9"(,&,9/0&*,/&-#+,04,+'+.&("0-&',<0-+2:
3$62"0'0#"5&', 5$&''+-#+2, &2205"&(+*, ="($, /+*)5+*, >? &.&"'&9"'"(6
&-*,/+*)5+*,&19"+-(,(+13+/&()/+,="'',(+-*,(0,"-5/+&2+,"-,2+.+/"(6
&2, &, 4)-5("0-, 04, &'("()*+7, A'("()*"-&', #/&*"+-(2, B, '"C+, '&("()*"-&'
#/&*"+-(2, B, &/+, &'20, 5$&/&5(+/"<+*, 96, /+'&(".+'6, )-"40/1, &-*
50-2"2(+-(,3&((+/-2,04,5$&-#+,"-,&,-)19+/,04,0($+/,+-."/0-1+-(&'
.&/"&9'+2,2)5$,&2,-+(,3/"1&/6,3/0*)5("."(67,>-+,C+6,*"44+/+-5+,"2
($&(, +50(0-&', (/&-2"("0-2, &5/022, &'("()*"-&', #/&*"+-(2, 055)/, 10/+
/&3"*'6,0.+/,&,#".+-,*"2(&-5+,($&-,($02+,&2205"&(+*,="($,'&("()*"-&'
#/&*"+-(27,D$+,23&("&''6,4"-+%#/&"-+*,+-."/0-1+-(&',.&/"&("0-,&5/022
&'("()*"-&',#/&*"+-(2,$&2,"130/(&-(,"13'"5&("0-2,40/,($+,/+'&(".+,/0'+2
04, #+-0(63"5, 23+5"&'"<&("0-, &-*, 3$+-0(63"5, 3'&2("5"(6, "3$62"0'0#"5&',&*&3(&("0-7
E$+-, +-."/0-1+-(&', $+(+/0#+-+"(6, "2, 4"-+, #/&"-+*:, "-*"."*)&'2
&/+, 40/5+*, (0, (0'+/&(+, &, 9/0&*, /&-#+, 04, +-."/0-1+-(&', 50-*"("0-2
0.+/,($+,50)/2+,04,($+"/,'"4+("1+27,F0-.+/2+'6:,=$+-,+-."/0-1+-(&'
$+(+/0#+-+"(6,"2,50&/2+,#/&"-+*:,"-*"."*)&'2,="'',+;3+/"+-5+,&,10/+
'"1"(+*, /&-#+, 04, 50-*"("0-27, A-, 0/#&-"21G2, 3+/5+".+*, #/&"-, 04
+-."/0-1+-(&', $+(+/0#+-+"(6, "2, *+(+/1"-+*, 96, "(2, '"4+, $"2(0/6, &-*
*"23+/2&',5&3&9"'"(67,80/,&,2+(,04,(&;&,($&(,&/+,50%*"2(/"9)(+*,&5/022
($+, 2&1+, &'("()*"-&', #/&*"+-(:, 23&("&', .&/"&("0-, "-, +-."/0-1+-(&'
50-*"("0-2, =0)'*, 9+, 3+/5+".+*, &2, 4"-+, #/&"-+*, 96, $"#$'6, 109"'+
0/#&-"212,2)5$,&2,9"/*2,0/,9&(2:,&-*,=0)'*,9+,3+/5+".+*,&2,50&/2+
#/&"-+*,96,/0*+-(2,&-*,0($+/,0/#&-"212,($&(,$&.+,10/+,/+2(/"5(+*
*"23+/2&', 5&3&9"'"("+2, HI+."-2:, JKLMN, .&-, D"+-*+/+-:, JKKJN, .&D"+-*+/+-:, JKKOP7, Q3&("&''6, 4"-+%#/&"-+*, +-."/0-1+-(&'
$+(+/0#+-+"(6, "2, +23+5"&''6, 50-*)5".+, (0, ($+, +.0')("0-, 04
3$+-0(63"5, 3'&2("5"(6:, &2, &-, "-5/+&2+*, &55'"1&("<&("0-, 5&3&5"(6
+-&9'+2,0/#&-"212,(0,(/&5C,5$&-#+2,"-,$&9"(&(%23+5"4"5,(/&"(,03("1&7
@4,-0,2"-#'+,3$+-0(63+,50-4+/2,$"#$+2(,4"(-+22,&5/022,($+,4)'',/&-#+
04, +-."/0-1+-(2:, ($+0/6, 3/+*"5(2, ($&(, *"23+/2&', &10-#, 23&("&''6
2+3&/&(+*, 2)9303)'&("0-2, ="'', #+-+/&''6, 3/010(+, ($+, +.0')("0-, 04
3$+-0(63"5, 3'&2("5"(6, 0.+/, #+-0(63"5, 23+5"&'"<&("0-, HQ5$+"-+/:
JKKRN, Q5$+"-+/:, JKKMN, *+, S0-#, &-*, T+$+/&:, ?UU?N, Q)'(&-, &-*
Q3+-5+/:, ?UU?P7, D$"2, ($+0/+("5&', 3/+*"5("0-, "2, /+'+.&-(, (0, &-"1&'
23+5"+2, ($&(, &/+, 50-("-)0)2'6, *"2(/"9)(+*, &5/022, 2(++3, &'("()*"-&' Carduelis!
#/&*"+-(27,E"($,/+#&/*,(0,($+,(+130/&',50130-+-(,04,+-."/0-1+-(&'
$+(+/0#+-+"(6:, ($+0/6, 3/+*"5(2, ($&(, 4')5()&("0-2, ($&(, 055)/, 0-, &
="($"-%#+-+/&("0-, ("1+25&'+, ="'', 9+, +23+5"&''6, 50-*)5".+, (0, ($+
+.0')("0-, 04, /+.+/2"9'+, 3'&2("5"(6, HV0/&-:, JKK?P7, D$"2, =0)'*, 9+
/+'+.&-(:, 40/, +;&13'+:, (0, 9"/*2, ($&(, 1"#/&(+, 0.+/, $"#$, 10)-(&"3&22+2,&-*,($+/+40/+,$&.+,(0,503+,="($,1&/C+*,5$&-#+2,"-,&19"+-(
(+13+/&()/+,&-*,>? &.&"'&9"'"(6,0-,&,*&"'6,0/,2+&20-&',9&2"27
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
4126 J. F. Storz, G. R. Scott and Z. A. Cheviron
W-."/0-1+-(%*+3+-*+-(, .&/"&("0-, "-, ($+, 3$+-0(63"5, +;3/+22"004, &, #".+-, #+-0(63+, 5&-, 9+, *+25/"9+*, &2, &, /+&5("0-, -0/1:, &-*
#+-0(63"5,.&/"&("0-,"-,/+&5("0-,-0/12,"2,/+4+//+*,(0,&2,&,#+-0(63+
! +-."/0-1+-(,"-(+/&5("0-,H8/6:,JKK?N,X"&,+(,&'7:,JKKYP7,A,#".+/+&5("0-, -0/1, 5&-, 9+, 50-2"*+/+*, &*&3(".+, "4, ($+, 3$+-0(63+
+;3/+22+*,"-,+&5$,+-."/0-1+-(&',2(&(+,"2,"-,($+,2&1+,*"/+5("0-,&2
($+,+-."/0-1+-(%23+5"4"5,03("1)1,4&.0/+*,96,2+'+5("0-,HF0-0.+/
&-*, Q5$)'(<:, JKKYN, .&-, D"+-*+/+-:, JKKJN, .&-, D"+-*+/+-:, JKKON
Z$&'&190/, +(, &'7:, ?UUOP7, [)/"-#, ($+, 50'0-"<&("0-, 04, &, -+=
+-."/0-1+-(:, &-, &*&3(".+, /+&5("0-, -0/1, =0)'*, 10.+, ($+, 1+&3$+-0(63+, 5'02+/, (0, ($+, -+=, (/&"(, 03("1)1, H\/"5+, +(, &'7:, ?UURN
Z$&'&190/,+(,&'7:,?UUOP7,T6,50-(/&2(:,&,1&'&*&3(".+,/+&5("0-,-0/1
=0)'*, 10.+, ($+, 1+&-, 3$+-0(63+, 4)/($+/, &=&6, 4/01, ($+, -+=
03("1)1:, &-*, =0)'*, ($+/+40/+, /+])"/+, 2+'+5("0-, 0-, #+-+("5&''6
9&2+*, (/&"(, .&/"&("0-, (0, 50)-(+/&5(, ($+, +-."/0-1+-(&''6, "-*)5+*
5$&-#+27,@-,5&2+2,"-,=$"5$,($+,(/&"(,03("1)1,"2,)-5$&-#+*,"-,($+
-+='6,50'0-"<+*,+-."/0-1+-(:,&,1&'&*&3(".+,/+&5("0-,-0/1,=0)'*
/+])"/+, 5013+-2&(0/6, #+-+("5, 5$&-#+2, (0, /+2(0/+, ($+, &-5+2(/&'
3$+-0(63+,HZ/+($+/:,?UUYP7,D$)2:,1&'&*&3(".+,3'&2("5"(6,5&-,/+2)'(
"-, &, 40/1, 04, 5/63("5, &*&3(".+, +.0')("0-, "-, =$"5$, 3$+-0(63"5
2"1"'&/"(6,9+(=++-,&-5+2(/&',&-*,*+/".+*,303)'&("0-2,"2,&((/"9)(&9'+
(0, ($+, +44+5(2, 04, *".+/#+-(, 2+'+5("0-, ($&(, 0442+(, +-."/0-1+-(&''6
"-*)5+*,(/&"(,*"44+/+-5+27
V)5$, 04, 0)/, )-*+/2(&-*"-#, 04, ($+, &55'"1&("<&("0-, /+230-2+, (0
$630;"&, *+/".+2, 4/01, 2()*"+2, 04, &-"1&', 23+5"+2, ($&(, &/+, -&(".+, (0
'0='&-*, +-."/0-1+-(27, D$+2+, 2()*"+2, 5&-, /+.+&', =$+($+/, ($+
$630;"&%"-*)5+*, 3$62"0'0#"5&', /+230-2+, (+-*2, (0, 10.+, ($+
303)'&("0-,1+&-,3$+-0(63+,5'02+/,(0,($+,4"(-+22,03("1)1,04,($+,-0-%
-&(".+, $"#$%&'("()*+, +-."/0-1+-(7, D$+, -&()/+, 04, ($+, &-5+2(/&'
&55'"1&("<&("0-,/+230-2+,5&-,($+/+40/+,"-*"5&(+,=$+($+/,3$+-0(63"5
3'&2("5"(6,5&-,9+,+;3+5(+*,(0,4&5"'"(&(+,0/,"13+*+,&*&3(&("0-,(0,$"#$
&'("()*+7, !+/+:, =+, /+."+=, #+-+/&', 1+5$&-"212, 04, 3$62"0'0#"5&'
&55'"1&("<&("0-, &-*, #+-+("5, &*&3(&("0-, (0, $"#$%&'("()*+, $630;"&, "9"/*2, &-*, 1&11&'27, ^&($+/, ($&-, /+."+="-#, ($+2+, 1+5$&-"212, "*+(&"':, =+, +.&')&(+, =$+($+/, ($+, &55'"1&("<&("0-, /+230-2+, (0
+-."/0-1+-(&',$630;"&,5&-,9+,/+#&/*+*,#+-+/&''6,&2,&,1+5$&-"21,04
&*&3(".+,3$+-0(63"5,3'&2("5"(6:,0/,=$+($+/,"(,/+3/+2+-(2,&,1"2*"/+5(+*
/+230-2+, ($&(, =0/C2, &(, 5/022, 3)/302+2, ="($, #+-+("5&''6, 9&2+*
3$62"0'0#"5&',&*&3(&("0-7
The nature of physiological adaptation to high-altitude
hypoxia
_-*+/,$630;"5,50-*"("0-2:,1&-6,&-"1&'2,&/+,&9'+,(0,5013+-2&(+
40/,&,/+*)5+*,>? 2)33'6,96,2)33/+22"-#,(0(&',1+(&90'"21:,($+/+96
/+*)5"-#,>? *+1&-*,H^&1"/+<,+(,&'7:,?UUOP7,@-,1&-6,+-*0($+/12
($&(, &/+, -&(".+, (0, $"#$%&'("()*+, +-."/0-1+-(2:, 1+(&90'"5
2)33/+22"0-, "2, -0(, &, ."&9'+, 03("0-, 40/, 503"-#, ="($, /+*)5+*, >?
&.&"'&9"'"(6, 0="-#, (0, ($+, +;"#+-5"+2, 04, &+/09"5, ($+/10#+-+2"2
&-*`0/, &+/09"5, +;+/5"2+7, @-, 9"/*2:, 40/, +;&13'+:, >? 50-2)13("0"-5/+&2+2,JY%,(0,?U%40'*,*)/"-#,4'"#$(,HE&/*,+(,&'7:,?UU?P7,@-,2)5$
5&2+2:,1&(5$"-#,>? 2)33'6,="($,&-,)-*"1"-"2$+*,0/,+.+-,"-5/+&2+*
>? *+1&-*,/+])"/+2,&-,+-$&-5+*,4');,5&3&5"(6,04,($+,>? (/&-230/(
3&($=&67
D$+/+, &/+, 2+.+/&', 50-.+5(".+, &-*, *"44)2".+, 2(+32, "-, ($+, >?
5&25&*+, 4/01, "-23"/+*, &"/, (0, ($+, ("22)+, 1"(05$0-*/"&, =$+/+
3$62"0'0#"5&',&*a)2(1+-(2,5&-,3/+2+/.+,($+,/&(+,04,>? 4');,"-,23"(+
04,$630;"&:,($+/+96,+-2)/"-#,&-,)-"-(+//)3(+*,2)33'6,04,>? (0,($+
+-+/#6%3/0*)5"-#, 1&5$"-+/6, 04, ($+, 5+''2, H8"#7JP7, D$+2+, 2(+32
"-5')*+, .+-("'&(0/6, 50-.+5("0-:, *"44)2"0-, &5/022, ($+, 9'00*B#&2
"-(+/4&5+:,5"/5)'&(0/6,50-.+5("0-:,*"44)2"0-,&5/022,($+,9'00*B("22)+
"-(+/4&5+, H"-5')*"-#, 4&5"'"(&(+*, *"44)2"0-, 96, 160#'09"-P:, &-*, >?
)("'"<&("0-,96,($+,("22)+,1"(05$0-*/"&7
Fig.1. O2 is transported from atmospheric air to the mitochondria of tissue
cells along a pathway with several diffusive and convective steps. The
steps in this O2 cascade are breathing, O2 diffusion across the blood–gas
interface, circulation of O2 throughout the body, O2 diffusion across the
blood–tissue interface to the mitochondria, and O2 utilization to generate
ATP by oxidative phosphorylation.
Mechanisms of phenotypic plasticity and genetic adaptation
in the O2 cascade
Pulmonary O2 transport
D$+, +44+5(".+-+22, 04, >? '0&*"-#, *)/"-#, $"#$%&'("()*+, $630;"&, "2
2(/0-#'6,"-4')+-5+*,96,3'&2("5"(6,"-,($+,3)'10-&/6,262(+1:,=$"5$
5013/"2+2,($+,4"/2(,(=0,2(+32,"-,($+,>? (/&-230/(,3&($=&6,H8"#7JP7
D$+, /&(+, 04, >? (/&-230/(, "-, ($+, &"/, 5013&/(1+-(, 04, ($+, ')-#2, 5&9+, *+25/"9+*, &2, ($+, 3/0*)5(, 04, .+-("'&("0-, HXP, &-*, ($+
"-23"/+*B&'.+0'&/, *"44+/+-5+, "-, >? 3&/("&', 3/+22)/+, H!>?P, H"7+7
!@>?B!A>?P7,!"#$,/&(+2,04,.+-("'&("0-,($+/+40/+,$+'3,1&"-(&"-,&,$"#$
&'.+0'&/,!>?:,($+,3/+22)/+,$+&*,40/,*"44)2"0-,&5/022,($+,9'00*B#&2
"-(+/4&5+7, D$+, /&(+, 04, >? (/&-230/(, &5/022, ($+, 9'00*B#&2, "-(+/4&5+
5&-,9+,*+25/"9+*,&2,($+,3/0*)5(,04,3)'10-&/6,>? *"44)2"0-,5&3&5"(6
H"IP, &-*, ($+, &'.+0'&/B9'00*, !>? *"44+/+-5+, H!A>?B!9>?P7, D$+
*+5/+1+-(, "-, !9>? "2, ($+/+40/+, 1"("#&(+*, 96, &-, +-$&-5+*
3)'10-&/6, >? *"44)2"0-, 5&3&5"(6:, =$"5$, "2, *+(+/1"-+*, 96, ')-#
10/3$0'0#6,&-*,3)'10-&/6,3+/4)2"0-7
D$+,102(,"130/(&-(,4&5(0/2,&44+5("-#,.+-("'&("0-,&(,$"#$,&'("()*+
&/+,($+,3&/("&',3/+22)/+2,04,>? &-*,F>? &-*,($+,3!,04,&/(+/"&',9'00*
HQ50((,&-*,V"'201:,?UUKP7,T/+&($"-#,"2,2("1)'&(+*,=$+-,&,*+5'"-+
"-,&/(+/"&',!>? H!&>?N,$630;+1"&P,"2,2+-2+*,96,5$+10/+5+3(0/2,"($+, 5&/0("*, 90*"+27, !0=+.+/:, ($"2, $630;"5, .+-("'&(0/6, /+230-2+
"-5/+&2+2, /+23"/&(0/6, F>? '022:, 5&)2"-#, &, 2+50-*&/6, $6305&3-"&
H'0=,F>?P,&-*,&'C&'02"2,H$"#$,3!P,"-,($+,9'00*7,T+5&)2+,F>? &-*
!b -0/1&''6, 2("1)'&(+, 9/+&($"-#, #$% 5+-(/&', &-*, 3+/"3$+/&'
5$+10/+5+3(0/2:, 2+50-*&/6, $6305&3-"&, &-*, &'C&'02"2, /+2(/&"-, ($+
.+-("'&(0/6,/+230-2+7,D$+,-+(,+44+5(,"2,&-,"-5/+&2+,"-,.+-("'&("0-,($&(
"2,*+3+-*+-(,0-,($+,2+.+/"(6,04,$630;"&:,9)(,($+,1&#-"()*+,04,($"2
"-5/+&2+, "2, '+22, ($&-, "4, 9'00*, F>? '+.+'2, $&*, /+1&"-+*, 50-2(&-(
H8"#7?P,HQ50((,&-*,V"'201:,?UUKP7,D$+,1&#-"()*+,04,($+,$630;"5
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
Myoglobin binds iron and oxygen in muscle tissue, related to hemoglobin
High-altitude adaptation
Total ventilation (ml kg–1 min–1)
3000
Bar-headed goose
Pekin duck
2000
Isocapnia
1000
Polikilocapnia
0
20
40
60
80
Arterial O2 tension (Torr)
100
Fig.2. The ventilatory response to environmental hypoxia causes a
secondary loss of CO2, and the resulting hypocapnia (low arterial CO2
tension) and alkalosis (high arterial pH) inhibit breathing. As a result, the
hypoxic ventilatory response (HVR) when CO2 is experimentally maintained
(isocapnia, white symbols) is higher than in the environmentally realistic
situation when CO2 is uncontrolled and allowed to fall (poikilocapnia, filled
symbols). However, bar-headed geese (orange triangles) are less sensitive
to hypocapnia than are low-altitude birds, and thus exhibit an enhanced
ventilatory response to acute environmental hypoxia (gray arrow). This is
reflected by a higher poikilocapnic HVR in bar-headed geese than in pekin
ducks (green squares) but a similar isocapnic HVR. Data are means ±
s.e.m., modified from Scott and Milsom (Scott and Milsom, 2007).
1Torr!133 Pa.
.+-("'&(0/6,/+230-2+,"2,&'20,*+3+-*+-(,0-,($+,*)/&("0-,04,$630;"&
H\0=+'',+(,&'7:,JKKMP7,F013&/+*,="($,($+,/&3"*,/+230-2+,($&(,055)/2
="($"-, 1"-)(+2, 04, ($+, 0-2+(, 04, $630;"&:, 2+.+/&', *&62, 04
&55'"1&("<&("0-,5&-,4)/($+/,"-5/+&2+,.+-("'&("0-,0="-#,(0,3'&2("5"(6
"-,($+,>? 2+-2"-#,4)-5("0-,04,($+,5&/0("*,90*6,5$+10/+5+3(0/2,&-*
"-, 5+-(/&', "-(+#/&("0-, 2"(+2, ="($"-, ($+, -+)/&', 4++*9&5C, '003, ($&(
/+#)'&(+2,9/+&($"-#,HT'&5C,&-*,D+--+6:,JKMUN,\0=+'':,?UUOP7,>.+/
1&-6,10-($2,&(,$"#$,&'("()*+:,($"2,$630;"5,.+-("'&(0/6,/+230-2+,5&9+,#/&*)&''6,&((+-)&(+*,96,$630;"5,*+2+-2"("<&("0-,H\0=+'',+(,&'7:
JKKMN, T/)(2&+/(:, ?UUOP7, @(, "2, *"44"5)'(, (0, &25/"9+, &*&3(".+
2"#-"4"5&-5+, (0, ($+2+, .&/"0)2, /+230-2+2, 0="-#, (0, ($+, 1)'("3'+
4)-5("0-2, 04, 9/+&($"-#7, @-5/+&2+2, "-, 9/+&($"-#, *)/"-#, ($+, &5)(+
/+230-2+, &-*, +&/'6, 3$&2+2, 04, &55'"1&("<&("0-, 5'+&/'6, "13/0.+, >?
)3(&C+,*)/"-#,$630;"&7,F0-.+/2+'6:,$630;"5,*+2+-2"("<&("0-,1"#$(
$+'3, (0, 1&"-(&"-, 9'00*, F>?`3!, $01+02(&2"2:, /+*)5+, /+23"/&(0/6
=&(+/,'022:,0/,/+*)5+,($+,1+(&90'"5,502(,04,9/+&($"-#,&(,($+,+;3+-2+
04,*"1"-"2$+*,>? )3(&C+,H\0=+'':,?UUOP7
D$+,10/3$0'0#"5&',5&3&5"(6,40/,>? *"44)2"0-,&5/022,($+,')-#2,"2
#+-+/&''6, "-5/+&2+*, "-, '0='&-*+/2, &4(+/, &55'"1&("<&("0-, (0, $"#$%
&'("()*+, $630;"&7, [+.+'031+-(, 0/, 3/0'0-#+*, /+2"*+-5+, &(, $"#$
&'("()*+, 5&-, "-5/+&2+, 3)'10-&/6, *"44)2"0-, 5&3&5"(6, 96, "-5/+&2"-#
($+, 2)/4&5+, &/+&, &.&"'&9'+, 40/, *"44)2"0-, &-*, 96, /+*)5"-#, ($+
($"5C-+22,04,($+,3)'10-&/6,9'00*B#&2,"-(+/4&5+,H!2"&,+(,&'7:,?UUYN
!2"&,+(,&'7:,?UUON,^&."C)1&/,+(,&'7:,?UUKP7,A'($0)#$,/+'&(".+'6,'"(('+
"2,C-0=-,&90)(,$0=,>? '+.+'2,50-(/0',')-#,10/3$0#+-+2"2,*)/"-#
*+.+'031+-(,0/,*)/"-#,&*)'(,'"4+,2(&#+2,HV+(<#+/,+(,&'7:,?UUMP:,($+2+
"-*)5+*, 5$&-#+2, "-, ')-#, 10/3$0'0#6, 5'+&/'6, $+'3, "13/0.+, >?
(/&-230/(,*)/"-#,$630;"&7
@-, '0='&-*, 23+5"+2:, ($+, &55'"1&("<&("0-, /+230-2+, (0, $630;"&
#+-+/&''6,"-.0'.+2,&,1&'&*&3(".+,5$&-#+,"-,3)'10-&/6,3+/4)2"0-:
($+,3$62"0'0#"5&',50130-+-(,04,3)'10-&/6,>? *"44)2"0-7,!630;"&
*"/+5('6, 2("1)'&(+2, ($+, +-*0($+'"&', &-*, 2100($, 1)25'+, 5+''2, "-
4127
3)'10-&/6,9'00*,.+22+'2:,5&)2"-#,.&2050-2(/"5("0-,($/0)#$0)(,($+
')-#2,&-*,&-,"-5/+&2+,"-,3)'10-&/6,9'00*,3/+22)/+,($&(,5&-,3+/2"2(
40/,3/0'0-#+*,*)/&("0-2,&(,$"#$,&'("()*+,H^++.+2,&-*,Z/0.+/:,JKOYN
Z)/-+6:,?UU?P7,D$"2,#'09&',.&2050-2(/"5("0-,"13&"/2,>? *"44)2"09+5&)2+, "(, 5&-, *".+/(, 9'00*, 4'0=, &=&6, 4/01, ($+, #&2, +;5$&-#+
2)/4&5+,(0,3)'10-&/6,2$)-(,.+22+'2,HI0.+/"-#,+(,&'7:,?UUMP:,&-*,($+
/+2)'(&-(,3)'10-&/6,$63+/(+-2"0-,5&-,5&)2+,4')"*,'+&C&#+,"-(0,($+
&"/, 23&5+2:, =$"5$, "-, ()/-, 5&)2+2, &, ($"5C+-"-#, 04, ($+, >? *"44)2"09&//"+/, HV&##"0/"-", +(, &'7:, ?UUJN, W'*/"*#+, +(, &'7:, ?UULP7, !630;"5
3)'10-&/6,$63+/(+-2"0-,5&-,&'20,0.+/9)/*+-,($+,/"#$(,.+-(/"5'+,04
($+,$+&/(,&-*,5&-,50-(/"9)(+,(0,3&($03$62"0'0#"5&',50-*"("0-2:,2)5$
&2, 5$/0-"5, 10)-(&"-, 2"5C-+22, HV0-#+, &-*, I+c-%X+'&/*+:, JKKJN
I+c-%X+'&/*+,+(,&'7:,?UJUP7
Q01+, 4+&()/+2, 04, ($+, &55'"1&("<&("0-, /+230-2+, (0, $630;"&, 5&"13/0.+, 3)'10-&/6, >? (/&-230/(, &(, $"#$, &'("()*+:, =$+/+&2, 0($+/
4+&()/+2, 5&-, 9+, 50)-(+/3/0*)5(".+7, \03)'&("0-2, &(, $"#$, &'("()*+
50)'*,($+/+40/+,9+-+4"(,4/01,+-$&-5"-#,($+,4&5"'"(&(0/6,1+5$&-"212
0/, 2)33/+22"-#, ($+, "-$"9"(0/6, 0-+27, Q01+, $"#$'&-*, 23+5"+2, 0/
303)'&("0-2, &/+, 5$&/&5(+/"<+*, 96, &, $+"#$(+-+*, &5)(+, $630;"5
.+-("'&(0/6, /+230-2+:, &, 10/+, +44+5(".+, 9/+&($"-#, 3&((+/-:, &
1&"-(&"-+*, &55'"1&("<&("0-, /+230-2+:, &-*`0/, &, 3/+.+-("0-, 04
$630;"5, *+2+-2"("<&("0-, HT'&5C, &-*, D+--+6:, JKMUN, T+&'', +(, &'7:
JKKON, E), &-*, d&62+/:, ?UULN, T/)(2&+/(:, ?UUON, Q50((, &-*, V"'201:
?UUON, \"5$0-, +(, &'7:, ?UUKP7, D$+, )-*+/'6"-#, 5$+10/+5+3(".+
1+5$&-"212,&/+,-0(,-+5+22&/"'6,50-.+/#+-(,&(,($+,5+'')'&/,'+.+'7,80/
+;&13'+:,($+,+-$&-5+*,.+-("'&(0/6,/+230-2+,(0,&5)(+,$630;"&,"-,($+
$"#$%&'("()*+,9&/%$+&*+*,#002+,H&'()*+$',$-.(P,"2,3&/('6,*)+,(0,&"-2+-2"("."(6,(0,$6305&3-"&,H8"#7?P,HQ50((,&-*,V"'201:,?UUON,Q50((
&-*, V"'201:, ?UUKP:, =$+/+&2, /+230-2+2, 04, $"#$%&'("()*+, $)1&-2
#+-+/&''6,"-.0'.+,5$&-#+2,"-,>? 2+-2"("."(6,HT/)(2&+/(:,?UUOP7,>($+/
$"#$'&-*, 23+5"+2, 0/, 303)'&("0-2, +;$"9"(, &, 9')-(+*, .+-("'&(0/6
/+230-2+,(0,&5)(+,$630;"&,HT'&C+,&-*,T&-5$+/0:,JKMYN,T/)(2&+/(,+(
&'7:, ?UUYP:, =$"5$, =0)'*, 9+, 1&'&*&3(".+, &(, $"#$, &'("()*+2, ="($0)(
5013+-2&(0/6,5$&-#+2,&(,0($+/,2(+32,"-,($+,>? (/&-230/(,3&($=&6
($&(,1&"-(&"-,3+/"3$+/&',>? 2)33'67,A2,1"#$(,&'20,9+,($+,5&2+,40/
$630;"5,*+2+-2"("<&("0-:,($"2,9')-(+*,/+230-2+,1"#$(,$+'3,1&"-(&"9'00*,F>?`3!,$01+02(&2"2,0/,"(,1"#$(,/+*)5+,($+,502(2,04,9/+&($"-#
H!05$&5$C&:,JKKMN,\0=+'':,?UUOP7
D$+, &-5+2(/&', &55'"1&("<&("0-, /+230-2+, 40/, ($+, 10/3$0'0#"5&'
50130-+-(,04,3)'10-&/6,>? *"44)2"0-,="'',4&5"'"(&(+,3)'10-&/6,>?
(/&-230/(, &(, $"#$, &'("()*+7, !0=+.+/:, 3)'10-&/6, >? *"44)2"05&3&5"(6, 5&-, 9+, +-$&-5+*, 4)/($+/, "-, 201+, $"#$%&'("()*+, &*&3(+*
#/0)32, ($&(, $&.+, '&/#+/, ')-#2, ($&-, '0='&-*+/2, HT/)(2&+/(, +(, &'7:
JKKKN,E),&-*,d&62+/:,?UULN,T/)(2&+/(:,?UUON,Q50((,+(,&'7:,?UJUP7
D$"2,"2,3&/("5)'&/'6,(/)+,"-,9"/*2,9+5&)2+,($+"/,')-#2,&/+,/"#"*,&-*
&/+,.+-("'&(+*,96,&"/,2&527,D$+,'&/#+/,')-#2,04,($+,$"#$%&'("()*+,9&/%
$+&*+*, #002+, HQ50((, +(, &'7:, ?UJUP:, 40/, +;&13'+:, 2$0)'*, &440/*, &
#/+&(+/, 2)/4&5+, &/+&, 40/, *"44)2"0-, &-*, ($)2, /+*)5+, ($+, !>?
*"44+/+-5+, 9+(=++-, 3&/&9/0-5$"&', #&2, &-*, &/(+/"&', 9'00*7, T6
50-(/&2(:, ($+, &-5+2(/&', &55'"1&("<&("0-, /+230-2+, 40/, ($+
3$62"0'0#"5&',50130-+-(,04,3)'10-&/6,>? *"44)2"0-,="'',"13+*+
3)'10-&/6, >? (/&-230/(, &(, $"#$, &'("()*+27, e0(, 2)/3/"2"-#'6:, ($+
3)'10-&/6,.&2050-2(/"5("0-,/+230-2+,"2,9')-(+*,0/,'02(,&'(0#+($+/
"-,23+5"+2,($&(,&/+,&*&3(+*,(0,$"#$,&'("()*+2,H8&/&5",+(,&'7:,JKMf&N
[)/10="5<,+(,&'7:,JKKRN,Z/0.+2,+(,&'7:,JKKRN,Z+,+(,&'7:,JKKMN,Q&C&"
+(, &'7:, ?UURP:, =$"5$, 50)'*, /+3/+2+-(, &-, +;&13'+, 04, #+-+("5
5013+-2&("0-7
Blood O2 transport
_-*+/,50-*"("0-2,04,$630;"5,$630;+1"&:,=$+-,($+,!>? 04,&/(+/"&'
9'00*,H!&>?P,"2,/+*)5+*:,(/&-230/(,04,>? 96,9'00*,1)2(,1++(,&,*)&'
5$&''+-#+g,HJP,"(,1)2(,1&"-(&"-,&-,&*+])&(+,*+'".+/6,04,>? (0,($+
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
4128 J. F. Storz, G. R. Scott and Z. A. Cheviron
A
Arterial
Blood O2 content (mmol l–1)
&*.&-(&#+2, 04, &-, "-5/+&2+*, !9, 50-5+-(/&("0-, 40/, >? 5&//6"-#
5&3&5"(6,1"#$(,9+,10/+,($&-,0442+(,96,&,50//+230-*"-#,/+*)5("0"-,Q7
B
βbO2
Venous
PaO2–PvO2
Blood PO2 (Torr)
CaO2–CvO2
.
VO2
mmol min–1
.
Q
Blood flow (l min–1)
Fig.3. Schematic illustration of blood O2 transport. (A)O2-equilibrium curve
under physiochemical conditions prevailing in arterial blood (a, solid curve,
open symbol) and venous blood (v, dashed curve, closed symbol). The xaxis measures blood PO2 and the y-axis measures blood O2 content.
CaO2–CvO2 denotes the arterial–venous difference in O2 content,
PaO2–PvO2, denotes the corresponding difference in PO2, bO2 denotes the
blood O2 capacitance coefficient (see text for details), Q denotes cardiac
output, and VO2 denotes the rate of O2 consumption. (B)The area of the
rectangle is proportional to total O2 consumption, which can be enhanced
by increasing Q and/or by increasing the bO2. Increases in the bO2
produce a corresponding increase in CaO2–CvO2through shifts in the shape
or position of the O2-equilibrium curve.
3+/"3$+/&',("22)+2N,&-*,H?P,"(,1)2(,1&"-(&"-,&-,&*+])&(+,!>? &(,($+
.&25)'&/, 2)33'6, 20)/5+, (0, 3+/1"(, >? *"44)2"0-, (0, ($+, ("22)+
1"(05$0-*/"&7
A(,&,#".+-,!&>?:,>? *+'".+/6,5&-,9+,+-$&-5+*,96,"-5/+&2"-#,($+
(0(&',5&/*"&5,0)(3)(:,Q:,&-*,96,"-5/+&2"-#,($+,9'00*,>? 5&3&5"(&-5+
50+44"5"+-(:,9>? H8"#7RP7,D$+,'&((+/,3&/&1+(+/,"2,*+4"-+*,&2,($+,/&("0
H/&>?B/.>?P`H!&>?B!.>?P:,=$+/+,/&>?B/.>? "2,($+,&/(+/"&'B.+-0)2
*"44+/+-5+, "-, >? 50-5+-(/&("0-, &-*, !&>?B!.>? "2, ($+
&/(+/"&'B.+-0)2, *"44+/+-5+, "-, !>?7, E"($, /+#&/*, (0, ($+, 2+50-*
5$&''+-#+,1+-("0-+*,&90.+:,($+,'0=+/,5/"("5&',!>? &(,($+,.&25)'&/
2)33'6, 20)/5+, 40/, ("22)+, 0;6#+-&("0-, 5&-, 9+, +;3/+22+*, &2
!.>?!&>?Bh9>?!HQ`V>?PiBJ:, =$+/+, V>? "2, ($+, /&(+, 04, >?
50-2)13("0-, 96, ($+, ("22)+2, &-*, ($+, 3/0*)5(, 9>?!HQ`V>?P, "2, ($+
23+5"4"5, 9'00*, >? 50-*)5(&-5+, H[+a0)/2, +(, &'7:, JKOUN, T0).+/0(:
JKMYP7, T+5&)2+, !&>? "2, *+(+/1"-+*, 96, .+-("'&("0-, &-*, >?
+])"'"9/&("0-,&(,($+,9'00*B#&2,"-(+/4&5+:,($"2,+])&("0-,2$0=2,($&(,&"-5/+&2+,"-,($+,23+5"4"5,9'00*,>? 50-*)5(&-5+,1"-"1"<+2,($+,*+5'"-+
"-,!.>? )-*+/,$630;"&:,($+/+96,1&"-(&"-"-#,&-,&*+])&(+,3/+22)/+
$+&*,40/,>? *"44)2"0-,(0,($+,("22)+,1"(05$0-*/"&7
_-*+/,2+.+/+,$630;"&:,&-,"-5/+&2+*,9'00*B>? &44"-"(6,="'',(+-*
(0,1&;"1"<+,9>? 9+5&)2+,($+,&/(+/"&'B.+-0)2,!>? *"44+/+-5+,23&-2
($+,2(++3+2(,30/("0-,04,($+,2"#10"*&',>?%+])"'"9/")1,5)/.+,H8"#7RP7
D$"2, 5&-, 9+, ."2)&'"<+*, &2, &-, "-5/+&2+, "-, ($+, 2'03+, 04, ($+, '"-+
50--+5("-#, ($+, &/(+/"&', &-*, .+-0)2, 30"-(2, 0-, ($+, 5)/.+7, D$+
/+2)'(&-(,"-5/+&2+,"-,($+,23+5"4"5,9'00*,>? 50-*)5(&-5+,$+'32,1++(
($+,*)&',5$&''+-#+,1+-("0-+*,&90.+g,"(,1"-"1"<+2,($+,"-+."(&9'+,!>?
*+5/+1+-(, "-, ($+, ("22)+, 5&3"''&/"+2, =$"'+, 3/+2+/."-#, &, 50-2(&-(
/&>?B/.>? *"44+/+-5+,&-*:,$+-5+:,&,50-2(&-(,-+(,>? 4');7,I"C+="2+:
&-, "-5/+&2+*, $+10#'09"-, H!9P, 50-5+-(/&("0-, "-5/+&2+2, /&>?:
($+/+96, "-5/+&2"-#, 9'00*, >? 50-*)5(&-5+, "4, !&>?:, Q &-*, V>? &''
/+1&"-,50-2(&-(7,E"($,+;5+22".+,30'656($+1"&:,$0=+.+/:,30(+-("&'
Erythropoeitic activity
E$+-,'0='&-*,-&(".+2,&25+-*,(0,$"#$,&'("()*+:,($+,&55'"1&("<&("0/+230-2+, (0, $630;"&, #+-+/&''6, +-(&"'2, 50//+'&(+*, "-5/+&2+2, "$+1&(05/"(, H!5(P, &-*, !9, 50-5+-(/&("0-:, 9)(, ($+, &*&3(".+
2"#-"4"5&-5+, 04, ($"2, +/6($/030+"("5, /+230-2+, "2, ])+2("0-&9'+
HT)''&/*:, JKO?N, V0-#+, &-*, E$"((+-9)/6:, JKOLN, E"-2'0=, &-*
V0-#+:,JKMON,V0-#+,&-*,I+0-%X+'&/*+:,JKKJP7,_-*+/,-0/10;"&:
&, 10*+/&(+'6, "-5/+&2+*, !5(, &)#1+-(2, &/(+/"&', >? 50-(+-(, &-*
($+/+40/+, +-$&-5+2, &+/09"5, 5&3&5"(6, HWC9'01, &-*, !+/1&-2+-:
JKLMN,d&-2(/)3,&-*,WC9'01:,JKMfN,WC9'01,&-*,T+/#')-*:,JKKJP7
!0=+.+/:, ($+, $"#$+2(, &((&"-&9'+, !5(, "2, -0(, -+5+22&/"'6, &2205"&(+*
="($, ($+, $"#$+2(, &((&"-&9'+, &+/09"5, 30=+/, 0)(3)(, HF/0=+'', +(, &'7:
JKYKN,F/0=+'',&-*,Q1"($:,JKLON,X"''&4)+/(+,+(,&'7:,?UUfN,Q5$)'+/,+(
&'7:,?UJUP7,D$"2,"2,9+5&)2+,($+,&2205"&(+*,"-5/+&2+,"-,9'00*,."2502"(6
3/0*)5+2, &, $"#$+/, 3+/"3$+/&', .&25)'&/, /+2"2(&-5+, ($&(, 1"#$(
5013/01"2+,Q:,($+/+96,/+*)5"-#,0>?:1&; HZ)6(0-,&-*,^"5$&/*20-:
JKLJN, F0--+2, +(, &'7:, ?UULP7, @(, "2, /+&20-&9'+, (0, +;3+5(, ($&(, &
10*+/&(+'6,"-5/+&2+*,!5(,50)'*,50-4+/,&,3$62"0'0#"5&',&*.&-(&#+
)-*+/,$630;"&,9+5&)2+,&,#/+&(+/,])&-("(6,04,>? 5&-,9+,5&//"+*,&(
3&/("&', 2&()/&("0-2:, 9)(, +;3+/"1+-(&', /+2)'(2, *0, -0(, 2)330/(, ($"2
HV5Z/&($,&-*,E+"':,JKOMN,E"-2'0=,+(,&'7:,JKMYP7,@-,$)1&-2,&(,$"#$
&'("()*+:,+."*+-5+,2)##+2(2,($&(,($+,03("1&',!9,50-5+-(/&("0-,1"#$(
&5()&''6,9+,])"(+,5'02+,(0,($+,(63"5&',2+&,'+.+',.&')+,HX"''&4)+/(+,+(
&'7:,?UUfP7
@-,$)1&-2,'"."-#,&(,$"#$,&'("()*+:,$630;"&%"-*)5+*,30'656($+1"&
04(+-, .&2('6, +;5++*2, ($+, 03("1&', !5(7, 80/, +;&13'+:, "-, A-*+&-&(".+2,'"."-#,&(,&'("()*+2,04,jRUUU1:,!5(,&-*,!9,50-5+-(/&("0-2
5&-,/+&5$,.&')+2,04,)3,(0,U7MR,&-*,?OU#'BJ:,/+23+5(".+'6,HT0).+/0(:
JKMYP7,D$"2,+;5+22".+,30'656($+1"&,'"1"(2,+;+/5"2+,3+/40/1&-5+:,Q
&-*, 3)'10-&/6, 4)-5("0-:, &-*, &33+&/2, (0, 3'&6, &, C+6, /0'+, "-, ($+
3&($0#+-+2"2,04,5$/0-"5,10)-(&"-,2"5C-+22,HE"-2'0=,+(,&'7:,JKMYN
V0-#+,&-*,I+c-%X+'&/*+:,JKKJN,^".+/&%F$,+(,&'7:,?UUOP7,^"5$&/*2
H^"5$&/*2:, JKLUP, 3/0."*+*, &, ."."*, *+25/"3("0-, 04, ($+, +44+5(2, 04
$630;"&%"-*)5+*, 30'656($+1"&, "-, 3&("+-(2, 2)44+/"-#, 4/01, 5$/0-"5
3)'10-&/6, *"2+&2+g, kD$+, "-5/+&2+*, /+*, 5+'', 1&22, 3/0*)5+2
"-5/+&2+*,9'00*,.0')1+:,=$"5$,0.+/4"''2,($+,$+&/(N,&-*,($"2,0/#&-:
&'/+&*6, )-*+/, 2(/&"-, =0/C"-#, &#&"-2(, &, /+2(/"5(+*, 3)'10-&/6
.&25)'&/,9+*:,#0+2,"-(0,50-#+2(".+,$+&/(,4&"')/+:,=$"5$,2("'',4)/($+/
"-5/+&2+2, 9'00*, .0')1+7, A(, ($+, 2&1+, ("1+, ($+, &**+*, 3)'10-&/6
.&25)'&/,+-#0/#+1+-(,4)/($+/,&##/&.&(+2,($+,h$630;"&i:,($)2,2+(("-#
)3,&,2+50-*,."5"0)2,565'+7l
@-, $)1&-2:, ($+, 30(+-("&', 4"(-+22, 50-2+])+-5+2, 04, +;5+22".+
30'656($+1"&, 2++1, +23+5"&''6, 5'+&/, 5)(, =$+-, 50-2"*+/"-#, ($+
+44+5(2,0-,3/+#-&-56,0)(501+2,&(,$"#$,&'("()*+,HV00/+,+(,&'7:,?UUfN
Z0-<&'+2, +(, &'7:, ?UUKN, S)'"&-, +(, &'7:, ?UUK&N, S)'"&-, +(, &'7:, ?UUK9P7
!023"(&'%9&2+*, 2()*"+2, $&.+, *05)1+-(+*, ($&(, ($+, /"2C, 04, &*.+/2+
3+/"-&(&',0)(501+2,"2,"-5/+&2+*,="($,+;(/+1+,1&(+/-&',!5(2,HV00/+
+(,&'7:,?UUJ&N,Z0-<&'+2,+(,&'7:,?UUKP,H8"#7fP7,[)/"-#,3/+#-&-56,&(
$"#$, &'("()*+:, +'+.&(+*, !5(, &-*, ($+, &2205"&(+*, "-5/+&2+, "-, 9'00*
."2502"(6,50-(/"9)(+,(0,&-,"-5/+&2+*,/"2C,04,2("''9"/($:,3/+(+/1,9"/($:
&-*, /+*)5+*, 9"/($, =+"#$(:, &'', 04, =$"5$, &33+&/, (0, 2(+1, 4/01, &
/+*)5+*,)(+/"-+,&/(+/6,9'00*,4'0=,&-*:,50-2+])+-('6:,&,/+*)5+*,/&(+
04,>? *+'".+/6,(0,($+,)(+/03'&5+-(&',5"/5)'&("0-,HV00/+,+(,&'7:,JKM?N
V00/+, +(, &'7:, ?UUJ&N, V00/+, +(, &'7:, ?UUJ9N, m&1)*"0, +(, &'7:, JKKYN
E"'20-, +(, &'7:, ?UUON, S)'"&-, +(, &'7:, ?UUMN, S)'"&-, +(, &'7:, ?UUK9P7, 80/
($"2, /+&20-:, &55'"1&("<+*, '0='&-*+/2, &(, $"#$, &'("()*+, #+-+/&''6
+;3+/"+-5+,+23+5"&''6,$"#$,/&(+2,04,&*.+/2+,3/+#-&-56,0)(501+27,@$)1&-2,'"."-#,&(,$"#$,&'("()*+:,($+,&.&"'&9'+,+."*+-5+,2)##+2(2,($&(
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
Stillbirth OR
High-altitude adaptation
7
6
5
4
3
2
1
0
A
Preterm birth OR
5
5
4
3
2
1
0
SGA OR
7
B
5
6
5
4
3
2
1
0
y=0.11x2–2.85x+19.39, R2=0.85
C
5
9
11
13
2
15
17
19
17
19
17
19
2
y=0.07x –1.64x+11.14, R =0.96
7
9
11
13
15
y=–0.001x3+0.01x2–1.73x+9.30, R2=0.95
7
9
11
13
15
Maternal hemoglobin (g dl–1)
Fig.4. Odds ratios (OR) for stillbirths (A), preterm births (B) and small-forgestational-age (SGA) births (C) as a function of maternal Hb
concentration. Data are compiled from 37,377 women residing at low
(150m) and high (>3000m) altitudes (2003–2006) (modified from Gonzales
et al., 2009).
$630;"&%"-*)5+*, 30'656($+1"&, /+3/+2+-(2, &-, +;&13'+, 04
1&'&*&3(".+,3'&2("5"(67
Blood–O2 affinity
8"-+%()-+*,&*a)2(1+-(2,"-,9'00*B>? &44"-"(6,5&-,3'&6,&,C+6,/0'+,"1&(5$"-#,>? 2)33'6,&-*,>? *+1&-*,96,2$"4("-#,($+,2(++3+2(,30/("004, ($+, >?%+])"'"9/")1, 5)/.+, ="($"-, ($+, /&-#+, 04, $'+ #$#1 !>?2
HT0).+/0(:,JKMYN,Q&1&a&,+(,&'7:,?UURP7,D$+2+,&*a)2(1+-(2,50)'*,9+
1+*"&(+*,96,5$&-#+2,"-,($+,"-(/"-2"5,!9B>? &44"-"(6:,5$&-#+2,"-,($+
2+-2"("."(6, 04, !9, (0, &''02(+/"5, 504&5(0/2, ($&(, 10*)'&(+, !9B>?
&44"-"(6:,&-*`0/,5$&-#+2,"-,($+,50-5+-(/&("0-,04,&''02(+/"5,504&5(0/2
="($"-, ($+, +/6($/056(+, He"C"-1&&:, ?UUJN, E+9+/, &-*, 8&#0:, ?UUfN
E+9+/:, ?UUON, Q(0/<, &-*, V0/"6&1&:, ?UUMP7, D$+, '&((+/, 1+5$&-"21
"-.0'.+2, /+#)'&(0/6, 5$&-#+2, "-, ($+, 5$+1"5&', 1"'"+), ="($"-, ($+
+/6($/056(+,&-*,*0+2,-0(,/+])"/+,2(/)5()/&',10*"4"5&("0-2,04,($+,!9
3/0(+"-,"(2+'47,@-,($+,+-)5'+&(+*,+/6($/056(+2,04,102(,1&11&'2:,($+
102(,30(+-(,&''02(+/"5,504&5(0/,"2,?:R%*"3$023$0#'65+/&(+,H[\ZP:,&
1+(&90'"(+,04,#'650'62"2,h40/,+;5+3("0-2:,2++,T)--,HT)--:,JKMUPi7
@-, ($+, -)5'+&(+*, +/6($/056(+2, 04, 9"/*2:, ($+, 102(, 30(+-(, &''02(+/"5
504&5(0/,"2,(63"5&''6,"-02"(0',3+-(&3$023$&(+,H@-2!YP:,&,1+(&90'"(+
04, 0;"*&(".+, 3$023$0/6'&("0-7, W5(0($+/1"5, .+/(+9/&(+2, (63"5&''6
1&C+, )2+, 04, 0($+/, -)5'+0("*+, (/"3$023$&(+2, He"C"-1&&:, ?UUJP7
D$+2+,.&/"0)2,&''02(+/"5,504&5(0/2,#+-+/&''6,/+*)5+,!9B>? &44"-"(6
96,3/+4+/+-("&''6,9"-*"-#,&-*,2(&9"'"<"-#,($+,*+0;6#+-&(+*:,n(+-2+%
2(&(+G,50-40/1&("0-,04,($+,!9,(+(/&1+/7,>($+/,504&5(0/2,2)5$,&2,!b
&-*,F'B "0-2,+;+/(,2"1"'&/,&''02(+/"5,+44+5(2:,($+/+96,4&5"'"(&("-#,>?
)-'0&*"-#,"-,($+,("22)+,5&3"''&/"+2,H^"##2:,JKMMN,e"C"-1&&:,?UUJN
Vo"/9&)/':,JKKfN,S+-2+-:,?UUfN,E+9+/,&-*,8&#0:,?UUfP7
4129
@-, 1&11&'2, ($&(, &/+, -&(".+, (0, '0='&-*, +-."/0-1+-(2:, ($+
&55'"1&("<&("0-, /+230-2+, (0, $630;"&, (63"5&''6, "-.0'.+2, &, [\Z%
"-*)5+*,/+*)5("0-,"-,!9B>? &44"-"(6,H&,/"#$(=&/*,2$"4(,"-,($+,>?%
+])"'"9/")1, 5)/.+P:, =$"5$, 1"#$(, 9+, 1+*"&(+*, 3/"1&/"'6, 96, &"-5/+&2+,"-,($+,+/6($/056("5,50-5+-(/&("0-,04,[\Z,HI+-4&-(,+(,&'7:
JKLMN,I+-4&-(,+(,&'7:,JKOJN,Vo"/9&)/',+(,&'7:,JKKRP7,@-,$)1&-2:,40/
+;&13'+:,&,/&3"*,"-5/+&2+,"-,($+,"-(/&5+'')'&/,[\Z,50-5+-(/&("0055)/2,="($"-,?f$,04,&25+-(,(0,$"#$,&'("()*+,HjfYUU1P:, &-*, ($+
/+2)'(&-(, *+5/+&2+, "-, !9B>? &44"-"(6, "2, 3&/("&''6, 0442+(, 96, ($+
/+23"/&(0/6,&'C&'02"2,"-*)5+*,96,"-5/+&2+*,.+-("'&("0-,HI+-4&-(,+(
&'7:, JKLMN, I+-4&-(, +(, &'7:, JKOJN, E+"2C034, &-*, Q+.+/"-#$&)2:
JKO?P7
V0*)'&("-#,($+,+/6($/056("5,50-5+-(/&("0-,04,&''02(+/"5,504&5(0/2
5&-,9+,50-2"*+/+*,(0,9+,&,1+5$&-"21,04,3$+-0(63"5,3'&2("5"(6,9+5&)2+
($+,2&1+,#+-0(63+,H1&-"4+2(,&2,!9,2(/)5()/+P,5&-,+;3/+22,&,/&-#+,04
*"44+/+-(, 3$+-0(63+2, H9'00*B>? &44"-"("+2P, *+3+-*"-#, 0-, ($+
3/+.&"'"-#, 5"/5)12(&-5+27, D$+, &*&3(".+, 2"#-"4"5&-5+, 04, ($+, [\Z%
"-*)5+*, *+5/+&2+, "-, !9B>? &44"-"(6, &(, $"#$, &'("()*+, $&2, 9++-, ($+
2)9a+5(, 04, 1)5$, *+9&(+7, _-*+/, 50-*"("0-2, 04, 10*+/&(+, $630;"&:, &
/+*)5("0-,"-,!9B>? &44"-"(6,5&-,+-$&-5+,'+.+'2,04,("22)+,0;6#+-&("096,1&;"1"<"-#,($+,5&3"''&/6B("22)+,!>? *"44+/+-5+7,!0=+.+/:,)-*+/
50-*"("0-2,04,2+.+/+,$630;"&,=$+-,!&>? "2,2)92(&-("&''6,/+*)5+*:,&
'+4(=&/*, 2$"4(, 04, ($+, >?%+])"'"9/")1, 5)/.+, "2, /+])"/+*, (0, &''0=, >?
'0&*"-#,&-*,)-'0&*"-#,0.+/,($+,2(++3+2(,30/("0-,04,($+,5)/.+,HD)/+C
+(,&'7:,JKORN,D)/+C,+(,&'7:,JKOM&N,D)/+C,+(,&'7:,JKOM9N,Q&1&a&,+(,&'7:
JKMLN,Q&1&a&,+(,&'7:,?UURP7,W.+-,&(,'0=,&'("()*+:,&,'+4(%2$"4(+*,5)/.+
1"#$(, 9+, &*.&-(&#+0)2, =$+-, ($+, /&(+, 04, >? (/&-24+/, &5/022, ($+
9'00*B#&2,"-(+/4&5+,"2,*"44)2"0-,'"1"(+*:,&2,"2,($+,5&2+,*)/"-#,"-(+-2+
+;+/5"2+, HT+-50="(<, +(, &'7:, JKM?P7, @-, /&(2:, &, 3$&/1&50'0#"5&''6
"-5/+&2+*, !9B>? &44"-"(6, =&2, 2$0=-, (0, #/+&('6, +-$&-5+, 1+(&90'"5
3+/40/1&-5+, &-*, 2)/.".&', )-*+/, 50-*"("0-2, 04, +;(/+1+, $630;"&
HW&(0-, +(, &'7:, JKOfN, D)/+C, +(, &'7:, JKOM&N, D)/+C, +(, &'7:, JKOM9P:, &-*
$)1&-,2)9a+5(2,="($,1)(&-(,!92,($&(,+;$"9"(,"-5/+&2+*,>? &44"-"(6
H!9, A-*/+=2%V"--+&30'"2P, 1&"-(&"-, -0/1&', &/(+/"&', >? 2&()/&("0&-*,)-*"1"-"2$+*,&+/09"5,5&3&5"(6,&(,$"#$,&'("()*+,HRJUU1P,/+'&(".+
(0, 2)9a+5(2, ="($, ="'*%(63+, !9, H!+99+', +(, &'7:, JKOMP7, @(, ($+/+40/+
&33+&/2,($&(,($+,[\Z,/+230-2+,04,'0='&-*+/2,1"#$(,9+,1&'&*&3(".+
&(,$"#$,&'("()*+27
@-, 50-(/&2(, (0, ($+, $+1&(0'0#"5&', 5$&-#+2, ($&(, &/+, (63"5&''6
&2205"&(+*,="($,($+,&55'"1&("<&("0-,/+230-2+,(0,$630;"&,"-,'0='&-*
1&11&'2:,#+-+("5&''6,9&2+*,5$&-#+2,"-,!9,2(/)5()/+,($&(,"-5/+&2+
"-(/"-2"5, >? &44"-"(6, 0/, ($&(, 2)33/+22, 2+-2"("."(6, (0, &''02(+/"5
504&5(0/2, &/+, #+-+/&''6, ($0)#$(, (0, 1&C+, 10/+, "130/(&-(
50-(/"9)("0-2,(0,$630;"&,(0'+/&-5+,"-,23+5"+2,($&(,&/+,$"#$%&'("()*+
-&(".+2,HT)--:,JKMUN,V0-#+,&-*,I+c-%X+'&/*+:,JKKJN,Q(0/<:,?UUON
E+9+/:, ?UUON, Q(0/<, &-*, V0/"6&1&:, ?UUMP7, D$"2, "2, 9+5&)2+, &"-5/+&2+*, !9B>? &44"-"(6, 3/010(+2, 3)'10-&/6, >? '0&*"-#, &(, '0=
!>?:,&-*,5&-,($)2,&13'"46,($+,+44+5(2,04,3)'10-&/6,&*&3(&("0-2,(0
"-5/+&2+,!&>?7,!0=+.+/:,&-,"-5/+&2+*,!9B>? &44"-"(6,&'20,$"-*+/2
>? )-'0&*"-#,"-,($+,("22)+,5&3"''&/"+27,>($+/,10*)'&(0/2,04,!9B>?
9"-*"-#,1"#$(,9+,"130/(&-(,"-,($"2,/+#&/*:,2)5$,&2,($+,T0$/,+44+5(
H/+*)5("0-, "-, !9B>? &44"-"(6, &(, '0=, 3!P7, D$"2, (/&*+%044, "-, !9
4)-5("0-,9+(=++-,-0/10;"5,&-*,$630;"5,+-."/0-1+-(2,5&-,#".+,/"2+
(0,(/&*+%0442,"-,=$0'+%0/#&-"21,&+/09"5,3+/40/1&-5+,H!+99+',+(,&'7:
JKOMN,F$&33+'',&-*,Q-6*+/:,JKMfN,F$&33+'',+(,&'7:,JKMMP7
Tissue O2 transport
Q"1"'&/,(0,($+,2"()&("0-,40/,3)'10-&/6,>? *"44)2"0-:,($+,/&(+,04,>?
(/&-230/(,4/01,9'00*,(0,1"(05$0-*/"&,"-,("22)+2,5&-,9+,*+25/"9+*,&2
($+, 3/0*)5(, 04, ("22)+, >? *"44)2"0-, 5&3&5"(6, H"DP, &-*, ($+
9'00*B1"(05$0-*/"&,!>? *"44+/+-5+,H!9>?B!1"(>?P7,_-*+/,$630;"&:
($+,*+5/+1+-(,"-,!>? &(,1"(05$0-*/"&,"2,1"("#&(+*,96,&-,+-$&-5+*
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
4130 J. F. Storz, G. R. Scott and Z. A. Cheviron
Fig.5. The diffusion capacity for O2 is enhanced in the flight muscle of the
bar-headed goose, a species that lives at elevation and migrates over the
Himalayas at extremely high altitudes. This is accomplished by an increase
in capillarity and a redistribution of mitochondria towards the cell
membrane. (A)Histological staining for alkaline phosphatase activity
identifies abundant capillaries in the pectoralis muscle of a bar-headed
goose (scale bar: 50m). (B)Transmission electron micrograph of a fastoxidative muscle fiber in a bar-headed goose showing the abundant
subsarcolemmal mitochondria (arrow) and the less common intermyofibrillar
mitochondria (arrowhead) (scale bar: 5m). See Scott et al. (Scott et al.,
2009a) for details.
>? *"44)2"0-, 5&3&5"(67, >? *"44)2"0-, &(, 3+/"3$+/&', ("22)+2, $&2, 90($
10/3$0'0#"5&',&-*,3$62"0'0#"5&',50130-+-(27,D$+,10/3$0'0#"5&'
5&3&5"(6, 40/, >? *"44)2"0-, "2, *+(+/1"-+*, 96, ($+, *+-2"(6, &-*
*"2(/"9)("0-, 04, 5&3"''&/"+2, "-, 3+/"3$+/&', ("22)+2:, &2, =+'', &2, 96, ($+
5+'')'&/, &//&-#+1+-(, 04, 1"(05$0-*/"&, H8"#7YP7, ^+#"0-&', ("22)+
3+/4)2"0-, H5&3"''&/6, /+5/)"(1+-(P, /+3/+2+-(2, ($+, 3$62"0'0#"5&'
50130-+-(:, =$"5$, *+(+/1"-+2, ($+, +;(+-(, (0, =$"5$, ($+
10/3$0'0#"5&', 5&3&5"(6, 40/, >? *"44)2"0-, "2, /+&'"<+*7, D"22)+, >?
(/&-230/(, ="'', 9+, 03("1"<+*, &(, $"#$, &'("()*+2, 96, 4)'', 3+/4)2"0-, 04
&9)-*&-(, &-*, $010#+-+0)2'6, 23&5+*, 5&3"''&/"+2:, &-*, 96
1"(05$0-*/"&,($&(,&/+,302"("0-+*,5'02+,(0,5&3"''&/"+27
@(,"2,)-5'+&/,=$+($+/,($+,10/3$0'0#"5&',5&3&5"(6,40/,>? *"44)2"0"2,&'(+/+*,96,$"#$%&'("()*+,&55'"1&("<&("0-,"-,'0=%&'("()*+,23+5"+27
@-, #+-+/&':, ($+/+, "2, &, 2(/0-#, /+'&("0-2$"3, 9+(=++-, 5&3"''&/"(6, &-*
1+(&90'"5,*+1&-*,h+7#7,1"(05$0-*/"&',&9)-*&-5+,H!+33'+:,?UUUPi:
9)(, 5&3"''&/"(6, 1)2(, "-5/+&2+, /+'&(".+, (0, *+1&-*, 40/, ("22)+, >?
(/&-230/(, (0, 9+, "13/0.+*, "-, $630;"&7, D$+, "22)+, 04, =$+($+/, $"#$%
&'("()*+,&55'"1&("<&("0-,"-5/+&2+2,5&3"''&/"(6,$&2,9++-,50-(+-("0)2'6
*+9&(+*:, 9&2+*, 0-, 1+($0*0'0#"5&', &-*, 50-5+3()&', &/#)1+-(2
/+'&(+*,(0,90($,>? 2)33'6,&-*,1+(&90'"5,*+1&-*,HV&($"+)%F02(+''0:
?UUJP7, D$+/+, &/+, +;&13'+2, =$+/+, 5&3"''&/"(6, "-, ($+, 1)25'+, $&2
"-5/+&2+*,*)/"-#,$"#$%&'("()*+,&55'"1&("<&("0-,="($0)(,&-6,5$&-#+
"-, 1"(05$0-*/"&', &9)-*&-5+, HV&($"+)%F02(+''0, &-*, A#+6:, JKKOP:
9)(,"(,"2,#+-+/&''6,($0)#$(,($&(,&-6,5$&-#+2,"-,5&3"''&/"(6,055)/,&2
&,2+50-*&/6,50-2+])+-5+,04,&'(+/&("0-2,"-,1+(&90'"5,*+1&-*,0/,5+''
2"<+,HI+="2,+(,&'7:,JKKKN,!+33'+:,?UUUN,!033+'+/,&-*,X0#(:,?UUJP7
D$+, &//&-#+1+-(, 04, 1"(05$0-*/"&, ="($"-, 5+''2, 1)2(, (/&*+%044
9+(=++-, /+*)5"-#, ($+, "-(/&5+'')'&/, *"44)2"0-, *"2(&-5+, 40/, >? &-*
/+*)5"-#,($&(,40/,"-(/&5+'')'&/,1+(&90'"(+2:,=$"5$,="'',9+,03("1"<+*
=$+-,1"(05$0-*/"&,&/+,2"()&(+*,"-,3/+*01"-&-('6,2)92&/50'+11&'
H"7+7, 5')2(+/+*, -+&/, ($+, 5+'', 1+19/&-+P, 0/, "-(+/164"9/"''&/, H"7+7
*"2(/"9)(+*, ($/0)#$0)(, ($+, 5+''P, '05&("0-2:, /+23+5(".+'6, H8"#7YTP
Hd"-2+6,+(,&'7:,?UUOP7,A55'"1&("<&("0-,(0,$"#$%&'("()*+,$630;"&,*0+2
-0(,&33+&/,(0,&'(+/,1"(05$0-*/"&',*"2(/"9)("0-,"-,1)25'+:,9&2+*,0&, 2()*6, 04, 5$/0-"5, $630;"&, +;302)/+, "-, /&(2, H.&-, WC+/+-, +(, &'7:
JKK?P7, D$"2, 50-(/&2(2, ="($, ($+, 3/0'"4+/&("0-, 04, 2)92&/50'+11&'
1"(05$0-*/"&, ($&(, "2, "-*)5+*, =$+-, $630;"&, "2, +;3+/"+-5+*, 0-'6
*)/"-#, 2$0/(, *&"'6, 90)(2, 04, +;+/5"2+, HQ5$1)(<, +(, &'7:, ?UJUP7
A'($0)#$, 5013/+$+-2".+, 2)330/(, /+1&"-2, (0, 9+, 50''+5(+*:, '0=%
&'("()*+, 23+5"+2, &33+&/, (0, +;$"9"(, -+#'"#"9'+, 3'&2("5"(6, "-, ($+
10/3$0'0#"5&', 5&3&5"(6, 40/, >? *"44)2"0-, *)/"-#, $"#$%&'("()*+
&55'"1&("<&("0-7
I0='&-*+/2, &(, $"#$, &'("()*+, 1"#$(, 2&5/"4"5+, 3+/4)2"0-, 04
1)25'+, &-*, 201+, 0($+/, 3+/"3$+/&', ("22)+27, ^+#"0-&', ("22)+
3+/4)2"0-,*)/"-#,$630;"&,"2,/+#)'&(+*,96,'05&',3&/&5/"-+,2"#-&'2
($&(, 3/010(+, .&20*"'&("0-, H+7#7, -"(/"5, 0;"*+P, &-*, 5+-(/&', 2"#-&'2
($&(, /+#)'&(+, .&20&5("."(6, "-, &, ("22)+%23+5"4"5, 1&--+/, H+7#7
2613&($+("5, -+)/&', &5("."(6P7, D$+, 40/1+/, 1+5$&-"21, (+-*2, (0
"-5/+&2+, 9'00*, 4'0=, &-*, 5&3"''&/6, /+5/)"(1+-(:, 3&/("5)'&/'6, (0
1+(&90'"5&''6,&5(".+,("22)+2,H!+"-0-+-,+(,&'7:,?UJUP7,T6,50-(/&2(:
($+,'&((+/,1+5$&-"21,5&-,3/010(+,&,/+*"2(/"9)("0-,04,9'00*,4'0=
&=&6,4/01,3+/"3$+/&',("22)+2,*)/"-#,$630;"&,"-,4&.0/,04,$630;"&%
2+-2"(".+,("22)+2:,2)5$,&2,($+,$+&/(,&-*,9/&"-,H!05$&5$C&:,JKMYP7
D$"2, /+*)5("0-, "-, 9'00*, 4'0=, (0, 3+/"3$+/&', ("22)+2, 1"#$(, $+'3
&-"1&'2,(0'+/&(+,2$0/(,3+/"0*2,04,>? '&5C:,9)(,"(,"2,-0(,0.+/501+
&4(+/,3/0'0-#+*,&55'"1&("<&("0-,(0,$"#$,&'("()*+,Hd&1"(010,+(,&'7:
JKKRN, !&-2+-, &-*, Q&-*+/:, ?UURP7, \+/"3$+/&', >? 2)33'6, 5&/+1&"-, "13&"/+*, +.+-, =$+-, 3)'10-&/6, &-*, $+1&(0'0#"5&'
&*a)2(1+-(2, /+2(0/+, &/(+/"&', 0;6#+-&("0-, (0, -0/10;"5, '+.+'2
HF&'9+(,+(,&'7:,?UURP:,3022"9'6,9+5&)2+,04,($+,5013'+;,"-(+#/&("004,4++*40/=&/*,&-*,4++*9&5C,"-4')+-5+2,4/01,($+,5+-(/&',-+/.0)2
262(+1:,($+,$+&/(,&-*,($+,3+/"3$+/&',("22)+2,He0&C+2,+(,&'7:,?UUfP7
D$+, /+*"2(/"9)("0-, 04, 9'00*, 4'0=, 1"#$(, ($+/+40/+, /+3/+2+-(, &
1&'&*&3(".+,/+230-2+,(0,$"#$%&'("()*+,$630;"&7
@-, 3/"-5"3'+:, ("22)+, >? (/&-230/(, 50)'*, 9+, "13/0.+*, &(, $"#$
&'("()*+, 96, +-$&-5+*, 10/3$0'0#"5&', 5&3&5"("+2, 40/, >? *"44)2"0-7
D$"2, $&2, 055)//+*, "-, 201+, $"#$%&'("()*+, 23+5"+2:, 2)5$, &2, ($+, 9&/%
$+&*+*,#002+:,=$"5$,$&2,+;3&-*+*,5&3"''&/"(6,"-,($+,4'"#$(,1)25'+
&-*,$+&/(:,&2,=+'',&2,1"(05$0-*/"&,($&(,&/+,/+*"2(/"9)(+*,5'02+/,(0
($+,10/+,&9)-*&-(,5&3"''&/"+2,H8"#7YP,HQ50((,+(,&'7:,?UUK&N,Q50((,+(
&'7:,?UJUP7,D$+2+,)-"])+,(/&"(2,&/+,5&-&'"<+*:,055)//"-#,="($0)(,&-6
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
High-altitude adaptation
3/"0/,+;302)/+,(0,$"#$,&'("()*+7,D$+,9+-+4"(,04,($+2+,23+5"&'"<&("0-2
"2,3/09&9'6,/+2(/"5(+*,(0,("22)+2,($&(,&/+,&5(".+,*)/"-#,4'"#$(:,9+5&)2+
/)--"-#,+;+/5"2+,"2,-0(,=+'',2)2(&"-+*,"-,9&/%$+&*+*,#++2+,*)/"-#
$630;"&, H8+**+, +(, &'7:, JKMKP7, !0=+.+/:, ($"2, 3$+-0(63+, *0+2, -0(
&33+&/, (0, 9+, &, )-".+/2&', +.0')("0-&/6, /+230-2+, (0, $"#$, &'("()*+:
9+5&)2+, 1)25'+, 5&3"''&/"(6, "2, -0(, &'(+/+*, "-, 201+, $"#$%&'("()*+
1&11&'2, HV&($"+)%F02(+''0:, JKMKN, T/)(2&+/(:, ?UUMP7, D"22)+, >?
(/&-230/(,50)'*,&'20,9+,"13/0.+*,96,/+2(/"5("-#,($+,$630;"&%"-*)5+*
/+*"2(/"9)("0-, 04, 9'00*, 4'0=7, D$"2, $630($+2"2, $&2, -0(, 9++($0/0)#$'6, "-.+2("#&(+*:, &-*, ($+, 1"-"1&', 2)330/(, 40/, ($"2
3022"9"'"(6, "2, 50-40)-*+*, 96, *"44+/+-5+2, "-, &/(+/"&', >? '0&*"-#
H8&/&5",+(,&'7:,JKMf9N,8&/&5",+(,&'7:,JKMYP7
Tissue O2 utilization
D"22)+, >? )("'"<&("0-, "2, &'(+/+*, "-, .&/"0)2, =&62, 96, $"#$%&'("()*+
&55'"1&("<&("0-,"-,'0=%&'("()*+,23+5"+27,A,/+*)5("0-,"-,=$0'+%("22)+
1+(&90'"5,5&3&5"(6,H"7+7,1&;"1&',>? *+1&-*P,055)/2,"-,1)25'+,&-*
0($+/,("22)+2,*)/"-#,5$/0-"5,$630;"&,($/0)#$,/+*)5("0-2,"-,5+'',2"<+
&-*,1"(05$0-*/"&',&9)-*&-5+,H!033+'+/,&-*,X0#(:,?UUJN,V&($"+)%
F02(+''0:, ?UUJP7, ^+*)5("0-2, "-, 1"(05$0-*/"&', 5&3&5"(6, '+&*, (0, &
2$"4(, "-, 4)+', 3/+4+/+-5+, "-, 4&.0)/, 04, 5&/90$6*/&(+, 0;"*&("0-, &(, &
#".+-, /&(+, 04, AD\, ()/-0.+/, HV5F'+''&-*, +(, &'7:, JKKMP:, =$"5$
/+*)5+2,($+,/+])"/+1+-(,40/,>? 96,J?BJfp,HW2203:,?UUON,F&'9+(,+(
&'7:, ?UUKP7, F$/0-"5, $630;"&, 1"#$(, "-, 201+, 5&2+2, "13/0.+, ($+
+44"5"+-56,04,1"(05$0-*/"&',>? )("'"<&("0-,H"7+7,A[\`>? 50-2)1+*P
Hm)-#), +(, &'7:, ?UUMP, 9)(:, "-, #+-+/&':, 1"(05$0-*/"&', 4)-5("0-, "2
2)2(&"-+*, 0/, +.+-, "13&"/+*, )-*+/, 2)5$, 50-*"("0-2, HW2203:, ?UUOP7
D$+,)2+,04,&-&+/09"5,1+(&90'"21,"-,($+,1)25'+,(0,26-($+2"<+,AD\
*)/"-#, +;+/5"2+, #+-+/&''6, *+5'"-+2, &4(+/, $"#$%&'("()*+
&55'"1&("<&("0-:, 3022"9'6, 9+5&)2+, 04, &-, "13/0.+*, 500/*"-&("09+(=++-, >? 2)33'6:, #'650'6("5, 4');, &-*, 5+'')'&/, AD\, *+1&-*
H!05$&5$C&,+(,&'7:,?UU?P7,T6,50-(/&2(:,5$/0-"5,$630;"&,$&2,-0,+44+5(
0-, 201+, (/&"(2, ($&(, 50)'*, $&.+, &, 3/040)-*, "-4')+-5+, 01"(05$0-*/"&',1+(&90'"21,*)/"-#,>? '&5C:,2)5$,&2,($+,2+-2"("."(6,04
1"(05$0-*/"&', /+23"/&("0-, (0, '0=, >? H1"(05$0-*/"&', >? C"-+("52P
HF02(&,+(,&'7:,JKKOP,&-*,($+,&5("."(6,04,($+,5/+&("-+,C"-&2+,2$)(('+
H[&-+2$/&*,+(,&'7:,?UUJP7,D$+,#+-+/&',/+2)'(,"2,($&(,201+,1+(&90'"5
(/&"(2, /+230-*, (0, $630;"&, (0, $+'3, 1&(5$, 5+'')'&/, >? 2)33'6, &-*
*+1&-*:,=$+/+&2,0($+/2,+;$"9"(,-+#'"#"9'+,3'&2("5"(67
[+3+-*"-#,0-,($+,23+5"+2,"-,])+2("0-:,&-5+2(/&',&55'"1&("<&("0/+230-2+2,"-,("22)+,>? )("'"<&("0-,50)'*,+"($+/,4&5"'"(&(+,0/,"13+*+
$"#$%&'("()*+,&*&3(&("0-7,D$+,/+*)5("0-,"-,1+(&90'"5,5&3&5"(6,1"#$(
9+,9+-+4"5"&',"-,23+5"+2,($&(,)2)&''6,2)2(&"-,2)9%1&;"1&',/&(+2,04
&+/09"5, 1+(&90'"217, V"(05$0-*/"&', &9)-*&-5+, "2, 50-2("()(".+'6
/+*)5+*, "-, ($+, 1)25'+, 04, D"9+(&-, $)1&-2, 5013&/+*, ="($, ($&(, 04
-&(".+, '0='&-*+/2:, &-*, "2, -0(, &44+5(+*, 96, +-."/0-1+-(&', >?
&.&"'&9"'"(6,Hd&62+/,+(,&'7:,JKKJN,d&62+/,+(,&'7:,JKKLP7,D$"2,1"#$(
/+3/+2+-(,&-,+;&13'+,04,#+-+("5,&22"1"'&("0-,H\"#'")55",+(,&'7:,?UULP:
9+5&)2+, ($+, 3$+-0(63"5, 3'&2("5"(6, +;$"9"(+*, 96, '0='&-*+/2, $&2
9+501+, 50-2("()(".+'6, +;3/+22+*, "-, D"9+(&-27, F0-.+/2+'6:
/+*)5("0-2, "-, 1+(&90'"5, 5&3&5"(6, 1"#$(, 9+, 1&'&*&3(".+, "-, $"#$%
&'("()*+,9"/*2:,=$"5$,-++*,(0,2)2(&"-,-+&/%1&;"1&',/&(+2,04,&+/09"5
1+(&90'"21, *)/"-#, 4'"#$(7, @-, ($+, 9&/%$+&*+*, #002+:, 40/, +;&13'+:
&+/09"5,5&3&5"(6,04,($+,4'"#$(,1)25'+,"2,+;3&-*+*,96,&-,"-5/+&2+*
3/030/("0-, 04, 0;"*&(".+, 4"9+/2:, =$+/+&2, ($+, "-$+/+-(, /+23"/&(0/6
5&3&5"("+2:, >? C"-+("52:, &-*, 3$023$0/6'&("0-, +44"5"+-5"+2, 04, ($+"/
1"(05$0-*/"&,&/+,)-&'(+/+*,HQ50((,+(,&'7:,?UUK&N,Q50((,+(,&'7:,?UUK9P7
!)1&-,303)'&("0-2,&(,$"#$,&'("()*+,$&.+,&'20,+.0'.+*,&-,+-$&-5+*
3/+4+/+-5+, 40/, 5&/90$6*/&(+, 0;"*&("0-, "-, ($+, 1)25'+, &-*, $+&/(:
&'0-#,="($,&,*+5/+&2+*,3/03+-2"(6,40/,&-&+/09"5,'&5(&(+,3/0*)5("0*)/"-#,+;+/5"2+,H!05$&5$C&,+(,&'7:,JKKJN,!05$&5$C&:,JKKMP7,_-'"C+
($+, 2"()&("0-, "-, '0='&-*+/2:, ($+2+, 3$+-0(63+2, +;$"9"(, .+/6, '"(('+
4131
3'&2("5"(6,"-,$"#$'&-*,-&(".+2,*)/"-#,&55'"1&("<&("0-,(0,$630;"&,&-*
1"#$(, ($+/+40/+, /+3/+2+-(, &-0($+/, 5&2+, 04, #+-+("5, &22"1"'&("0-7, @&**"("0-:,201+,(/&"(2,50)'*,9+,+-$&-5+*,"-,$"#$%&'("()*+,23+5"+2,($&(
&/+,-0(,3'&2("5,"-,'0='&-*+/2:,2)5$,($+,5/+&("-+,C"-&2+,2$)(('+,HQ50((
+(, &'7:, ?UUK9P:, =$+/+&2, 0($+/, (/&"(2, /+1&"-, )-&'(+/+*:, 2)5$, &2
1"(05$0-*/"&',3$023$0/6'&("0-,+44"5"+-56,&-*,>? C"-+("52,HQ50((,+(
&'7:,?UUK&P7
A-0($+/,"130/(&-(,&23+5(,04,>? )("'"<&("0-,&(,$"#$,&'("()*+2,($&(
$&2,"130/(&-(,50-2+])+-5+2,40/,5+'')'&/,4)-5("0-:,9)(,=$"5$,"2,-0(
23+5"4"5&''6, /+'&(+*, (0, 1&(5$"-#, >? 2)33'6, &-*, *+1&-*:, "2, ($+
3/0*)5("0-, 04, /+&5(".+, >? 23+5"+2, H^>QP7, ^>Q, 3/0*)5("0-, 5&"-5/+&2+,&(,$"#$,&'("()*+2,"4,>? '"1"(&("0-,(0,56(05$/01+,- 0;"*&2+
HF>qP:,($+,+-<61+,($&(,5&(&'6<+2,($+,(+/1"-&',/+*)5("0-,04,>? "0;"*&(".+, 3$023$0/6'&("0-:, 5&)2+2, &, 2$"4(, "-, 1"(05$0-*/"&', /+*0;
(0=&/*2, &, 10/+, /+*)5+*, 2(&(+, HA0-, +(, &'7:, ?UJUP7, A'($0)#$
+-*0#+-0)2, &-("0;"*&-(, 262(+12, +;"2(, (0, $+'3, 3/+.+-(, ^>Q, 4/01
5&)2"-#,0;"*&(".+,*&1&#+:,($+,&55'"1&("<&("0-,/+230-2+,(0,$630;"&
"-,'0='&-*,-&(".+2,04(+-,"-.0'.+2,&,*0=-/+#)'&("0-,04,&-("0;"*&-(
5&3&5"(6,H[02+C,+(,&'7:,?UUOP7,E"($,*"1"-"2$+*,3/0(+5("0-:,0;"*&(".+
*&1&#+,(0,.&/"0)2,5+'')'&/,50130-+-(2,"-5/+&2+2,&(,$"#$,&'("()*+2:
&2, "-*"5&(+*, 96, "-5/+&2+*, /&(+2, 04, '"3"*, 3+/0;"*&("0-, &-*, [eA
2(/&-*,9/+&C2,HF)//"+:,JKKKN,[02+C,+(,&'7:,?UUOP7
V+5$&-"212, (0, /+*)5+, ^>Q, 3/0*)5("0-, 0/, (0, 3/0(+5(, &#&"-2(
0;"*&(".+,*&1&#+,=0)'*,9+,9+-+4"5"&',&(,$"#$,&'("()*+7,>-+,3022"9'+
1+&-2,04,/+*)5"-#,^>Q,3/0*)5("0-,"2,(0,1&"-(&"-,&,10/+,0;"*"<+*
+'+5(/0-, (/&-230/(, 5$&"-, HT/0=-, +(, &'7:, ?UUKP7, D$"2, 50)'*, 9+, ($+
#+-+/&',2(/&(+#6,+13'06+*,96,9&/%$+&*+*,#++2+:,&2,/+4'+5(+*,96,&&'(+/&("0-,"-,F>q,+-<61+,C"-+("52,H$"#$+/,2)92(/&(+,&44"-"(6P,($&(
1"#$(,&''0=,($+,+'+5(/0-,(/&-230/(,5$&"-,(0,03+/&(+,&(,&,'0=+/,/+*0;
2(&(+,="($,'+22,/+*)5+*%56(05$/01+,- HQ50((,+(,&'7:,?UJUP7,D$"2,1"#$(
9+,5&)2+*,96,&,2"-#'+,&1"-0,&5"*,2)92("()("0-,"-,2)9)-"(,R,04,($+
3/0(+"-,($&(,&'(+/2,"-(+/%2)9)-"(,"-(+/&5("0-2,HQ50((,+(,&'7:,?UJUP7,D$+
"130/(&-5+, 04, /+*)5"-#, ^>Q, 3/0*)5("0-, "-, 3/+.+-("-#, 0;"*&(".+
*&1&#+,"2,+13$&2"<+*,96,2()*"+2,5013&/"-#,$"#$%,&-*,'0=%&'("()*+
$)1&-,303)'&("0-2g,0;"*&(".+,*&1&#+,&(,$"#$,&'("()*+2,"2,#+-+/&''6
'+22, "-, $"#$'&-*+/2, +.+-, ($0)#$, 102(, H9)(, -0(, &''P, &-("0;"*&-(
+-<61+,'+.+'2,&/+,/+*)5+*,HZ+'4",+(,&'7:,?UUfN,Q"-$&,+(,&'7:,?UUK&N
Q"-$&,+(,&'7:,?UUK9N,Q"-$&,+(,&'7:,?UJUP7,@(,"2,3/+2+-('6,)-5'+&/,$0=
($+2+, +.0')("0-&/6, 5$&-#+2, /+'&(+, (0, ($+, &-5+2(/&', &55'"1&("<&("0/+230-2+:,9)(,($+6,2$0)'*,-0-+($+'+22,9+,"130/(&-(,40/,"13/0."-#
5+'',4)-5("0-,&(,$"#$,&'("()*+27
Maladaptive plasticity, countergradient variation and
high-altitude adaptation
T)''&/*,HT)''&/*:,JKO?P,&-*,V0-#+,&-*,I+c-%X+'&/*+,HV0-#+,&-*
I+c-%X+'&/*+:, JKKJP, *+25/"9+*, &, 3$62"0'0#"5&', 26-*/01+
5$&/&5(+/"2("5,04,9"/*2,&-*,1&11&'2,($&(,&/+,#+-+("5&''6,&*&3(+*,(0
$"#$%&'("()*+,$630;"&7,D$+2+,&-"1&'2,&/+,(63"5&''6,5$&/&5(+/"<+*,96
&-,+'+.&(+*,!9B>? &44"-"(6:,&,-0/1&',0/,2'"#$('6,"-5/+&2+*,!5(:,($"-%
=&''+*, 3)'10-&/6, .+22+'2, ($&(, /+230-*, (0, $630;+1"&, ="($
10*+/&(+, $63+/(+-2"0-:, &-*, "-5/+&2+*, 1)25'+, 5&3"''&/6, *+-2"(67
Q01+, 04, ($+2+, 4+&()/+2, &/+, 2$&/+*, ="($, 9)//0="-#, 1&11&'2, ($&(
&/+,&*&3(+*,(0,($+,5$/0-"5,$630;"&,04,2)9(+//&-+&-,9)//0=,262(+12
H!&'':, JKLLN, S+'C1&--, +(, &'7:, JKMJN, F&139+'', +(, &'7:, ?UJUP7, T6
50-(/&2(:, "-, '0='&-*%&*&3(+*, &-"1&'2:, &55'"1&("<&("0-, (0, $630;"&
(63"5&''6, "-.0'.+2, "-5/+&2+*, +/6($/030+"("5, &5("."(6:, *+5/+&2+*
9'00*B>? &44"-"(6:,3)'10-&/6,&/(+/"&',$63+/(+-2"0-:,&-*,-)1+/0)2
0($+/, /+230-2+2, ($&(, 5&-, 30(+-("&''6, "13&"/, >? (/&-230/(7, D$+2+
3$62"0'0#"5&',/+230-2+2,5&-,0.+/9)/*+-,($+,/"#$(,2"*+,04,($+,&/(+/"&'
5"/5)'&("0-, &-*, 5&-, 50-(/"9)(+, (0, 3&($03$62"0'0#"5&', 50-*"("0-2
2)5$, &2, 5$/0-"5, 10)-(&"-, 2"5C-+22:, 2)##+2("-#, ($&(, &(, '+&2(, 201+
4+&()/+2, 04, ($+, (63"5&', &55'"1&("<&("0-, /+230-2+, (0, $630;"&, &/+
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
4132 J. F. Storz, G. R. Scott and Z. A. Cheviron
1&'&*&3(".+7,V0/+0.+/:,+."*+-5+,2)##+2(2,($&(,1&-6,/+230-2+2,(0
$630;"&:,2)5$,&2,30'656($+1"&,&-*,/+*)5+*,!9B>? &44"-"(6:,*0,-0(
2"13'6, /+3/+2+-(, 3&($0'0#"5&', 0.+/2$00(2, 04, ($+, 3$+-0(63"5
03("1)1N,"-2(+&*:,($+,&-5+2(/&',-0/1,04,/+&5("0-,"2,&5()&''6,30"-(+*
"-,($+,=/0-#,*"/+5("0-7
@-, $)1&-2:, ($+, &55'"1&("<&("0-, /+230-2+, (0, 2+.+/+, $630;"&
"-5')*+2,&-,"-5/+&2+,"-,!5(,H1+*"&(+*,96,"-5/+&2+*,3/0*)5("0-,04
+/6($/030+"("-P, &-*, &, *+5/+&2+, "-, !9B>? &44"-"(6, H1+*"&(+*, 96
"-5/+&2+*, /+*, 5+'', 50-5+-(/&("0-2, 04, [\Z, &-*, &, /+*)5+*
"-(/&5+'')'&/, 3!P7, 80/, /+&20-2, +;3'&"-+*, &90.+:, 90($, 04, ($+2+
$+1&(0'0#"5&',&*a)2(1+-(2,&/+,50)-(+/3/0*)5(".+,)-*+/,50-*"("0-2
04,2+.+/+,$630;"&7,E$&(,&550)-(2,40/,($"2,044%(&/#+(,/+230-2+r,>-+
3022"9'+,+;3'&-&("0-,"2,($&(,($+,"-5/+&2+*,!5(,&-*,*+5/+&2+*,!9B>?
&44"-"(6,&/+,3&/(,04,&,1"2*"/+5(+*,/+230-2+,(0,+-."/0-1+-(&',$630;"&
($&(,0/"#"-&''6,+.0'.+*,&2,&,/+230-2+,(0,&-+1"&,H!+99+',+(,&'7:,JKOMN
Q(0/<:, ?UJUP7, W-."/0-1+-(&', $630;"&, &-*, &-+1"&, 90($, /+2)'(, "/+*)5+*,'+.+'2,04,("22)+,0;6#+-&("0-:,9)(,($+6,$&.+,*"44+/+-(,/00(
5&)2+27,@-,($+,5&2+,04,&-+1"&:,/+*)5+*,("22)+,0;6#+-&("0-,"2,5&)2+*
96, &, 5)/(&"'+*, 0;6#+-, (/&-230/(, 5&3&5"(6, 04, ($+, 9'00*:, &-*, 5&($+/+40/+,9+,/+5("4"+*,96,"-5/+&2"-#,($+,!5(,H=$"5$,"-5/+&2+2,/&>?P
&-*, 96, *+5/+&2"-#, !9B>? &44"-"(6, h=$"5$:, )-*+/, -0/10;"&:
+-$&-5+2, >? )-'0&*"-#, ="($0)(, 5013/01"2"-#, >? )3(&C+, "-, ($+
')-#2, HT/&)-+/, &-*, E&-#:, JKKOPi7, @-, ($+, 5&2+, 04, +-."/0-1+-(&'
$630;"&:, 96, 50-(/&2(:, /+*)5+*, ("22)+, 0;6#+-&("0-, $&2, &-, +;(+/-&'
5&)2+g, ($+, /+*)5+*, !>? 04, "-23"/+*, &"/:, =$"5$, "-, ()/-, '+&*2, (0, &
/+*)5+*,>? 2&()/&("0-,04,&/(+/"&',9'00*7,_-*+/,($+2+,5"/5)12(&-5+2:
>? *+'".+/6, 1"#$(, 9+, 4)/($+/, 5013/01"2+*, 96, &-, +'+.&(+*, !9
50-5+-(/&("0-,H*)+,(0,($+,&2205"&(+*,"-5/+&2+,"-,9'00*,."2502"(6P,&-*
&,*+5/+&2+*,!9B>? &44"-"(6,H*)+,(0,/+*)5+*,3)'10-&/6,>? '0&*"-#
($&(, '+&*2, (0, &, 4)/($+/, *"1"-)("0-, 04, &/(+/"&', >? 2&()/&("0-P7, @$)1&-2,&-*,0($+/,'0='&-*,1&11&'2,($&(,+;3+/"+-5+,$630;"5,2(/+22
&(,$"#$,&'("()*+:,($+,a0"-(,"-5/+&2+,"-,!9,50-5+-(/&("0-,&-*,[\Z`!9
/&("0,3/0."*+,+;&13'+2,04,1&'&*&3(".+,3$+-0(63"5,3'&2("5"(6:,&2,($+
"-*)5+*,3$62"0'0#"5&',5$&-#+2,&/+,"-,($+,03302"(+,*"/+5("0-,04,($+
3$+-0(63"5,03("1)1,)-*+/,2+.+/+,$630;"&7
\)'10-&/6,.&2050-2(/"5("0-,"2,&-0($+/,+;&13'+,04,&,1"2*"/+5(+*
/+230-2+, (0, +-."/0-1+-(&', $630;"&:, =$"5$, 3/09&9'6, +.0'.+*, "(+//+2(/"&',.+/(+9/&(+2,(0,$+'3,1&(5$,3+/4)2"0-,(0,.+-("'&("0-7,A(,'0=
&'("()*+:,$+(+/0#+-+"(6,055)/2,($/0)#$0)(,($+,')-#2,&-*,5&-,'+&*,(0
201+,/+#"0-2,9+"-#,2'"#$('6,$630;"5,/+'&(".+,(0,0($+/27,\)'10-&/6
.&2050-2(/"5("0-, "-, ($+2+, "20'&(+*, /+#"0-2, "2, 9+-+4"5"&', 9+5&)2+, "(
5&)2+2,3/+4+/+-("&',2$)-("-#,04,9'00*,(0,($+,102(,0;6#+-&(+*,&/+&2
04, ($+, ')-#27, !0=+.+/:, &2, *+25/"9+*, &90.+:, ($"2, "2, 1&'&*&3(".+
=$+-, $630;"&, 055)/2, #'09&''6, ($/0)#$0)(, ($+, ')-#2:, 5&)2"-#
3)'10-&/6,$63+/(+-2"0-:,&,*".+/2"0-,04,9'00*,4'0=,&=&6,4/01,($+
#&2,+;5$&-#+,2)/4&5+,(0,3)'10-&/6,2$)-(,.+22+'2,HI0.+/"-#,+(,&'7:
?UUMP:, &-*, &, ($"5C+-"-#, 04, ($+, >? *"44)2"0-, 9&//"+/, *)+, (0, 4')"*
'+&C&#+,"-(0,($+,&"/,23&5+2,HV&##"0/"-",+(,&'7:,?UUJN,W'*/"*#+,+(,&'7:
?UULP7,A,9')-(+*,3)'10-&/6,3/+220/,/+230-2+,2$0)'*,($+/+40/+,9+
&*.&-(&#+0)2, 40/, >? )3(&C+, "-, $630;"&, &-*, ($"2, 9+-+4"(, 2$0)'*
0)(=+"#$, ($+, 30(+-("&', *"2/)3("0-, (0, .+-("'&("0-B3+/4)2"01&(5$"-#7
@-, 5&2+2, "-, =$"5$, ($+, &55'"1&("<&("0-, /+230-2+, (0, $630;"&, "2
1&'&*&3(".+:, 2+'+5("0-, ="'', 4&.0/, &-, &((+-)&("0-, 04, ($+, "-*)5+*
3$+-0(63"5, 5$&-#+7, D$"2, 5&-, #".+, /"2+, (0, &, 3&((+/-, 04
50)-(+/#/&*"+-(, .&/"&("0-, HF0-0.+/, &-*, Q5$)'(<:, JKKYN, Z/+($+/:
?UUYP,5&)2+*,96,2+'+5("0-,0-,#+-+("5&''6,9&2+*,(/&"(,.&/"&("0-,($&(
0442+(2, ($+, +-."/0-1+-(&''6, "-*)5+*, 5$&-#+27, D$+, 9')-(+*
+/6($/030"+("5, &-*, 3)'10-&/6, .&2050-2(/"5("0-, /+230-2+2, (0
$630;"&,"-,-)1+/0)2,$"#$%&'("()*+,23+5"+2,&-*,303)'&("0-2,3/0."*+
3022"9'+,+;&13'+2,04,($"2,3$+-01+-0-7
^+5+-(,#+-01"5,2)/.+62,04,-)5'+0("*+,30'610/3$"21,"-,D"9+(&$"#$'&-*+/2, /+.+&'+*, 2(/0-#, +."*+-5+, 40/, &, $"2(0/6, 04, 302"(".+
2+'+5("0-,&(,2!&34 &-*,0($+/,#+-+2,"-,($+,$630;"&%"-*)5"9'+,4&5(0/
H!@8P,0;6#+-%2"#-&'"-#,3&($=&6,HT+&'',+(,&'7:,?UJUN,T"#$&1,+(,&'7:
?UUKN,T"#$&1,+(,&'7:,?UJUN,Q"10-20-,+(,&'7:,?UJUN,s",+(,&'7:,?UJUP7
D$+, !@8, 4&1"'6, 04, (/&-25/"3("0-, 4&5(0/2, /+#)'&(+2, 262(+1"5, &-*
5+'')'&/, 0;6#+-, $01+02(&2"2, 96, 500/*"-&("-#, ($+, (/&-25/"3("0-&'
/+230-2+,(0,$630;"&7,2!&34 H&'20,C-0=-,&2,5678P,+-50*+2,($+
0;6#+-%2+-2"(".+, 2)9)-"(,04,($+,$+(+/0*"1+/"5,!@8?,(/&-25/"3("04&5(0/, &-*, 3'&62, &-, +23+5"&''6, "130/(&-(, /0'+, "-, /+#)'&("-#
+/6($/030+"2"2, H^&-C"-, +(, &'7:, ?UUOP7, D$+, 2()*"+2, 96, T+&'', +(, &'7
HT+&'',+(,&'7:,?UJUP,&-*,s",+(,&'7,Hs",+(,&'7:,?UJUP,/+.+&'+*,&,2(/"C"-#
2"#-&', 04, 302"(".+, 2+'+5("0-, &(, 2!&34:, &-*, *05)1+-(+*, ($&(
-0-50*"-#,-)5'+0("*+,.&/"&-(2,"-,&-*,&/0)-*,($+,2!&34 #+-+,&/+
2(/0-#'6, &2205"&(+*, ="($, &, /+*)5+*, !9, 50-5+-(/&("0-, "-, D"9+(&$"#$'&-*+/27, \/+."0)2, 2()*"+2, *+10-2(/&(+*, ($&(, D"9+(&$"#$'&-*+/2,&/+,5$&/&5(+/"<+*,96,'0=,!9,50-5+-(/&("0-2,/+'&(".+,(0
&55'"1&("<+*,'0='&-*+/2:,&2,=+'',&2,(0,A-*+&-,$"#$'&-*+/2,($&(,&/+
/+2"*+-(, &(, 5013&/&9'+, &'("()*+2, HT+&'', &-*, ^+"5$21&-:, JKMfN
E"-2'0=,+(,&'7:,JKMKN,T+&'',+(,&'7:,JKKUN,T+&'',+(,&'7:,JKKMN,Z&//)(0
+(,&'7:,?UURN,E),+(,&'7:,?UUYN,T+&'':,?UUOP7,^+1&/C&9'6:,D"9+(&-2
'"."-#,&(,+'+.&("0-2,04,)3,(0,fUUU1,3/+2+-(,&,$+1&(0'0#"5&',3/04"'+
2"1"'&/,(0,=$&(,=0)'*,9+,+;3+5(+*,&(,2+&,'+.+'7,W."*+-5+,2)##+2(2
($&(,($"2,2&1+,9')-(+*,+/6($/030+"("5,/+230-2+,=0)'*,9+,9+-+4"5"&'
"-, 0($+/, $"#$%&'("()*+, $)1&-, 303)'&("0-2, &2, =+''7, A550/*"-#, (0
X"''&4)+/(+, +(, &'7, HX"''&4)+/(+, +(, &'7:, ?UUfPg, kt($+, 0.+/&''
2613(01&("5,&-*,3$62"5&',"13/0.+1+-(,($&(,501+2,4/01,/+*)5"-#
!5(,(0,2+&,'+.+',.&')+2,=$"'+,&(,$"#$,&'("()*+,2)##+2(,($&(,A-*+&$)1&-2,=0)'*,9+,9+((+/,2)"(+*,40/,'"4+,&(,$"#$,&'("()*+,"4,($+6,50)'*
1&"-(&"-, &, h!9i, ="($"-, ($+, 2+&, '+.+', /&-#+l7, @(, "2, 3022"9'+, ($&(
A-*+&-, $"#$'&-*+/2, $&.+, -0(, +.0'.+*, &, 2"1"'&/, 1+5$&-"21, 40/
&((+-)&("-#,($+,+/6($/030"+("5,/+230-2+,(0,$630;"&,9+5&)2+,04,($+"/
2$0/(+/, $"2(0/6, 04, /+2"*+-5+, &(, $"#$, &'("()*+, HT+&'', +(, &'7:, JKKMN
V00/+:,?UUJN,T+&'':,?UULN,T+&'':,?UUOP7
D$+, !9, 50-5+-(/&("0-, 04, D"9+(&-, $"#$'&-*+/2, *0+2, -0(, 4&''
0)(2"*+, ($+, &-5+2(/&', /&-#+, 04, .&/"&("0-, 5$&/&5(+/"2("5, 04, 5'02+'6
/+'&(+*, '0='&-*+/2:, 2)5$, &2, ($+, !&-, F$"-+2+7, @-2(+&*:, 2+'+5("0&33+&/2,(0,$&.+,4&.0/+*,&,9')-(+*,+/6($/030"+("5,/+230-2+,2)5$,($&(
!9, 50-5+-(/&("0-, &(, $"#$, &'("()*+, "2, 1&"-(&"-+*, &(, ($+, 2+&%'+.+'
(9%9.(+ :.17, D$"2, /+3/+2+-(2, &, 30(+-("&', +;&13'+, 04, #+-+("5
5013+-2&("0-, HZ/+($+/:, ?UUYP, "-, =$"5$, &, 1&'&*&3(".+
&55'"1&("<&("0-, /+230-2+, /+])"/+2, 2+'+5("0-, 0-, #+-+("5&''6, 9&2+*
(/&"(, .&/"&("0-, (0, /+2(0/+, ($+, &-5+2(/&', 3$+-0(63+7, A'($0)#$, ($+
1+5$&-"21,$&2,6+(,(0,9+,)-50.+/+*:,"(,"2,3022"9'+,($&(,-0-50*"-#
5$&-#+2,($&(,&'(+/,($+,+;3/+22"0-,04,2!&34 &-*,0($+/,!@8%/+'&(+*
#+-+2, $&.+, /+5&'"9/&(+*, ($+, $01+02(&("5, 2+(, 30"-(, 40/, $630;"&%
"-*)5+*,+/6($/030+"2"2,"-,D"9+(&-27,@(,/+1&"-2,(0,9+,2++-,=$+($+/
!9, 50-5+-(/&("0-, /+3/+2+-(2, ($+, *"/+5(, 3$+-0(63"5, (&/#+(, 04
2+'+5("0-, "-, D"9+(&-2:, 0/, =$+($+/, 5$&-#+2, "-, !9, 50-5+-(/&("02"13'6, /+3/+2+-(, &-, &-5"''&/6, +44+5(, 04, 2+'+5("0-, 0-, 201+, 0($+/
3$62"0'0#"5&',(/&"(,($&(,"2,&'(+/+*,96,/+#)'&(0/6,5$&-#+2,"-,($+,!@8
5&25&*+,Hm$)&-#,+(,&'7:,JKKRN,V00/+,+(,&'7:,?UULP7
D$+, 5+'')'&/, /+#)'&("0-, 04, !9B>? &44"-"(6, "-, $"#$%&'("()*+, *++/
1"5+,3/0."*+2,&-0($+/,30(+-("&',+;&13'+,04,$0=,($+,&55'"1&("<&("0/+230-2+,(0,$630;"&,1"#$(,=0/C,&(,5/022,3)/302+2,="($,#+-+("5&''6
9&2+*,&*&3(&("0-7,F013&/"20-2,9+(=++-,$"#$'&-*,&-*,'0='&-*,*++/
1"5+, $&.+, /+.+&'+*, #+-+("5&''6, 9&2+*, *"44+/+-5+2, "-, 9&2+'"-+
[\Z`!9,/&("02,HQ-6*+/:,JKM?P,&-*,!9B>?, &44"-"(6,HQ-6*+/,+(,&'7:
JKM?N,Q-6*+/:,JKMYN,F$&33+'',&-*,Q-6*+/:,JKMfN,F$&33+'',+(,&'7:
JKMMN, Q(0/<, +(, &'7:, ?UUKN, Q(0/<, +(, &'7:, ?UJUP7, A*)'(, *++/, 1"5+
5&3()/+*,&(,$"#$,&'("()*+,2$0=+*,&,Jfp,/+*)5("0-,"-,[\Z`!9,/&("02
&4(+/,LY,*&62,&55'"1&("0-,(0,2+&,'+.+':,&-*,&,?Rp,/+*)5("0-,&4(+/
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
High-altitude adaptation
u?RU, *&627, F0110-, #&/*+-, +;3+/"1+-(2, )-*+/, -0/10;"5
50-*"("0-2,/+.+&'+*,($&(,($+,$"#$'&-*,1"5+,=+/+,5$&/&5(+/"<+*,96
'0=+/,9&2+'"-+,[\Z`!9,/&("02,($&-,'0='&-*,1"5+:,&-*,+;3+/"1+-(&'
5/022+2,/+.+&'+*,($&(,($+2+,*"44+/+-5+2,$&.+,&,#+-+("5,9&2"2,HQ-6*+/:
JKM?P7, V0/+0.+/:, 5013&/"20-2, 04, !9, 4)-5("0-, 9+(=++-, $"#$'&-*
&-*, '0='&-*, 1"5+, /+.+&'+*, ($&(, #+-+("5&''6, 9&2+*, *"44+/+-5+2, "!9B>? &44"-"(6, &/+, '&/#+'6, &((/"9)(&9'+, (0, &, /+*)5+*, 2+-2"("."(6, (0
[\Z,&-*,F'B "0-2,"-,($+,!92,04,$"#$'&-*,1"5+,HQ(0/<,+(,&'7:,?UUKN
Q(0/<, +(, &'7:, ?UJUP7, D$+, /+*)5+*, 9&2+'"-+, [\Z`!9, /&("02, &-*, ($+
2)33/+22+*, &-"0-, 2+-2"("."(6, 90($, &33+&/, (0, 9+, &*&3(".+
1+5$&-"212,40/,1&"-(&"-"-#,&-,+'+.&(+*,9'00*B>? &44"-"(6,&-*:,6+(:
$"#$%&'("()*+,*++/,1"5+,2("'',+;$"9"(,&,$630;"&%"-*)5+*,"-5/+&2+,"[\Z, '+.+'27, E$6, $&2-G(, 2+'+5("0-, &90'"2$+*, ($+, 2++1"-#'6
1&'&*&3(".+,[\Z,/+230-2+,"-,$"#$%&'("()*+,*++/,1"5+r,\+/$&32,40/
($+,2&1+,/+&20-,($&(,A-*+&-,$)1&-2,$&.+,-0(,6+(,+.0'.+*,&,9')-(+*
+/6($/030+"("5,/+230-2+,(0,$630;"&7,A550/*"-#,(0,Q-6*+/,HQ-6*+/:
JKM?Pg, kth"(, 1"#$(, 9+i, ($&(, ($+, 3$62"0'0#"5&''6, 1+*"&(+*, [\Z
/+230-2+,+.0'.+*,-0(,"-,($+,50-(+;(,04,$"#$%&'("()*+,$630;"&:,9)(,"/+230-2+, (0, 0($+/, 20/(2, 04, $630;"5, 2(/+22, +-50)-(+/+*, 96, &-"1&'2
'"."-#,&(,'0=,&'("()*+27,T6,($&(,'"-+,04,($0)#$(:,($+,[\Z,/+230-2+
"-,$"#$%&'("()*+,*++/,1"5+,"2,&-,"-+;(/"5&9'+,4+&()/+,04,($+,&-"1&'G2
3$62"0'0#"5&', &/5$"(+5()/+, ($&(, 5&--0(, 9+, 10*"4"+*, ="($0)(
3'+"0(/03"5,/+3+/5)22"0-2l7
F&2+2, "-, =$"5$, "-*)5+*, 3$62"0'0#"5&', /+230-2+2, /+])"/+
5013+-2&("0-, 96, #+-+("5&''6, 9&2+*, 5$&-#+2, 2)##+2(, ($&(, ($+
&-5+2(/&',&55'"1&("<&("0-,/+230-2+,1"#$(,&5(,&2,&,$"-*/&-5+,(0,$"#$%
&'("()*+, &*&3(&("0-7, Q)5$, 5&2+2, &'20, 2)##+2(, ($+, 3022"9"'"(6, ($&(
1&-6, 3$+-0(63"5, 2"1"'&/"("+2, 9+(=++-, $"#$'&-*, &-*, '0='&-*
303)'&("0-2,04,($+,2&1+,23+5"+2,50)'*,9+,&((/"9)(&9'+,(0,($+,+44+5(2
04,50)-(+/#/&*"+-(,2+'+5("0-7
Genomic approaches to the study of phenotypic plasticity
and genetic adaptation to high altitude
Q01+,04,($+,9+2(,3/023+5(2,40/,"*+-("46"-#,&*&3(".+,1+5$&-"212,04
$630;"&, (0'+/&-5+:, &-*, 40/, (+&2"-#, &3&/(, ($+, /+'&(".+, /0'+2, 04
#+-0(63"5,23+5"&'"<&("0-,&-*,3$+-0(63"5,3'&2("5"(6:,&/+,&440/*+*,96
#+-+("5,&-*,#+-01"5,2()*"+2,04,303)'&("0-%'+.+',.&/"&("0-,"-,23+5"+2
($&(,&/+,50-("-)0)2'6,*"2(/"9)(+*,&5/022,2(++3,&'("()*"-&',#/&*"+-(27
A'($0)#$, 1)5$, 3/+."0)2, =0/C, 0-, $"#$%&'("()*+, &*&3(&("0-, $&2
405)2+*, 0-, 5013&/"20-2, 9+(=++-, 2+3&/&(+, 23+5"+2, ($&(, $&.+
*"44+/+-(, &'("()*"-&', /&-#+, '"1"(2:, 5013&/"20-2, 9+(=++-, $"#$'&-*
&-*,'0='&-*,303)'&("0-2,04,($+,2&1+,23+5"+2,044+/,2+.+/&',"130/(&-(
&*.&-(&#+2,40/,"*+-("46"-#,#+-+("5,1+5$&-"212,04,&*&3(&("0-7,8"/2(:
($+, &9"'"(6, (0, 50-*)5(, 5/022+2, "2, 5/)5"&', 40/, *"2+-(&-#'"-#, #+-+("5
&-*, +-."/0-1+-(&', 20)/5+2, 04, 3$+-0(63"5, .&/"&("0-7, Q+50-*:
1+5$&-"2("5, 2()*"+2, 04, 303)'&("0-%'+.+', .&/"&("0-, 3/0."*+, ($+
#/+&(+2(,+;3+/"1+-(&',30=+/,40/,&22+22"-#,#+-0(63"5,*"44+/+-5+2,"4"(-+22%/+'&(+*, 3$62"0'0#"5&', 3+/40/1&-5+, HZ&/'&-*, &-*, A*0'3$:
JKKJN,Q(0/<,&-*,E$+&(:,?UJUP7,V&-6,1+5$&-"212,04,3$62"0'0#"5&'
&*&3(&("0-,"-.0'.+,10*"4"5&("0-2,04,/+#)'&(0/6,-+(=0/C2:,&-*,-+='6
*+.+'03+*,#+-01"5,(+5$-0'0#"+2,3/0."*+,&,1+&-2,04,"-.+2("#&("-#
($+, -&()/+, 04, ($+2+, 10*"4"5&("0-27, @-, 3&/("5)'&/:, ($+, 2"1)'(&-+0)2
&-&'62"2,04,2+])+-5+,.&/"&("0-,&-*,+;3/+22"0-,3/04"'+2,40/,&,2+(,04
#+-+2, "-, ($+, 2&1+, 3&($=&6, 3/0."*+2, &, 1+&-2, 04, "*+-("46"-#, 90($
2(/)5()/&',&-*,/+#)'&(0/6,1+5$&-"212,04,&*&3(&("0-7
A(,($+,10'+5)'&/,'+.+':,3$+-0(63"5,3'&2("5"(6,"2,&2205"&(+*,="($
5$&-#+2,"-,(/&-25/"3("0-&',/+#)'&("0-,HZ/&5+6,+(,&'7:,?UUMP7,^+5+-(
50110-, #&/*+-, +;3+/"1+-(2, ($&(, =+/+, *+2"#-+*, (0, ])&-("46, ($+
3/030/("0-,04,(/&-25/"3(01"5,.&/"&("0-,($&(,"2,*)+,(0,+-."/0-1+-(&'
&-*, #+-+("5, +44+5(2, $&.+, *+10-2(/&(+*, (/+1+-*0)2, 3'&2("5"(6, 04
#+-+, +;3/+22"0-, "-, 23+5"+2, ="($, 9/0&*, &'("()*"-&', *"2(/"9)("0-2
HA33+-<+''+/,+(,&'7:,?UULN,F$+."/0-,+(,&'7:,?UUMP7,@-,/)40)2%50''&/+*
4133
23&//0=2, H;1'19*$-<$%+ -%=)'($(P:, $)-*/+*2, 04, #+-+2, ($&(, &/+
"-.0'.+*,"-,&+/09"5,1+(&90'"21,&-*,0;"*&(".+,2(/+22,/+230-2+2,&/+
*"44+/+-("&''6, +;3/+22+*, "-, ($+, 2C+'+(&', 1)25'+, 04, 9"/*2, -&(".+, (0
$"#$,HjfUUU1P,&-*,'0=,Hv?UUU1P,&'("()*+,HF$+."/0-,+(,&'7:,?UUMP7
!0=+.+/:, -0-+, 04, ($+2+, (/&-25/"3("0-&', *"44+/+-5+2, 3+/2"2(2, &4(+/
0-+, =++C, 04, 2+&%'+.+', &55'"1&("0-7, D$+2+, /+2)'(2, *+10-2(/&(+
50-2"*+/&9'+, 3'&2("5"(6, "-, ($+, (/&-25/"3(01"5, 3/04"'+2, 04, /)40)2%
50''&/+*,23&//0=2>+&-*,2)##+2(,($&(,1&-6,#+-01+%="*+,+;3/+22"0*"44+/+-5+2, 9+(=++-, $"#$'&-*, &-*, '0='&-*, "-*"."*)&'2, &/+
+-."/0-1+-(&''6,"-*)5+*7
>-+, +23+5"&''6, 3/01"2"-#, #+-01"5, &33/0&5$, (0, +.&')&(+, ($+
/+'&(".+, 50-(/"9)("0-2, 04, 3$+-0(63"5, 3'&2("5"(6, &-*, #+-0(63"5
23+5"&'"<&("0-, "-, $"#$%&'("()*+, &*&3(&("0-, "2, =$0'+, (/&-25/"3(01+
2$0(#)-, 2+])+-5"-#, HEDQQP, 0/, ^eA%2+], HE&-#, +(, &'7:, ?UUKP7
^eA%2+], )2+2, -+;(%#+-+/&("0-, 2+])+-5"-#, (0, 2"1)'(&-+0)2'6
5$&/&5(+/"<+, (/&-25/"3(, &9)-*&-5+, &-*, 2+])+-5+, 30'610/3$"21, "($0)2&-*2,04,+;3/+22+*,1^eA27,D$"2,(63+,04,303)'&("0-,#+-01"5
&33/0&5$, ($+/+40/+, $0'*2, 1)5$, 3/01"2+, 40/, "*+-("46"-#, -0.+'
10'+5)'&/, 1+5$&-"212, 04, 3$+-0(63"5, 3'&2("5"(6, &-*, #+-+("5
&*&3(&("0-:, 3&/("5)'&/'6, 40/, '05", =$02+, 4)-5("0-, &-*, &*&3(".+
2"#-"4"5&-5+,=+/+,3/+."0)2'6,)-&-("5"3&(+*7,A4(+/,5&-*"*&(+,'05",40/
$630;"&, &*&3(&("0-, $&.+, 9++-, "*+-("4"+*:, "(, "2, ($+-, 3022"9'+, (0
50-*)5(,40''0=%)3,+;3+/"1+-(2,(0,1+&2)/+,($+,3$62"0'0#"5&',+44+5(2
04,&'(+/+*,3/0(+"-,4)-5("0-,H"-,($+,5&2+,04,&1"-0,&5"*,1)(&("0-2P,0/
3/0(+"-,+;3/+22"0-,H"-,($+,5&2+,04,/+#)'&(0/6,1)(&("0-2P,H8+*+/,&-*
E&'2+/:,?UUYN,Q(0/<,&-*,E$+&(:,?UJUP7
Implications for altitudinal range shifts in a warming world
Z'09&', 5'"1&(+, 5$&-#+, $&2, &'/+&*6, 9++-, 2$0=-, (0, "13&5(, ($+
3$62"0'0#"5&',(0'+/&-5+2,&-*,/&-#+,'"1"(2,04,1&-6,0/#&-"212:,&-*
90($, &'("()*"-&', &-*, '&("()*"-&', /&-#+, 2$"4(2, 5&-, 9+, +;3+5(+*, (0
50-("-)+,&2,=&/1"-#,9+501+2,10/+,2+.+/+,H[+)(25$,+(,&'7:,?UUMN
V0/"(<,+(,&'7:,?UUMN,!)+6,+(,&'7:,?UUKN,Q"-+/.0,+(,&'7:,?UJUN,Q01+/0:
?UJUP7,\03)'&("0-2,($&(,&/+,/+2(/"5(+*,(0,$"#$,&'("()*+2,50)'*,9+,&(
/"2C, 04, "-5/+&2+*, 5013+("("0-, &2, '0='&-*, 23+5"+2, 2$"4(, ($+"/
&'("()*"-&',/&-#+2,(0=&/*2,500'+/,+-."/0-1+-(2:,9)(,($"2,="'',*+3+-*
0-,($+,5&3&5"(6,04,'0='&-*+/2,(0,&55'"1&("<+,&-*`0/,&*&3(,(0,$"#$%
&'("()*+,$630;"&7,@-,9"/*2,&-*,1&11&'2,($&(,&/+,-&(".+,(0,'0='&-*
+-."/0-1+-(2:, 5+/(&"-, 4+&()/+2, 04, ($+, &55'"1&("<&("0-, /+230-2+, (0
$630;"&,1"#$(,50-2(/&"-,&*&3(&("0-,(0,$"#$%&'("()*+,+-."/0-1+-(27
D$"2, "2, 9+5&)2+, 201+, 04, ($+, "-*)5+*, 3$62"0'0#"5&', 5$&-#+2, H+7#7
30'656($+1"&:, "-5/+&2+*, +/6($/056("5, 3$023$&(+`!9, /&("02:, &-*
3)'10-&/6, .&2050-2(/"5("0-P, &/+, "-, ($+, 03302"(+, *"/+5("0-, 04, ($+
&33&/+-(,3$+-0(63"5,03("1)1,)-*+/,5$/0-"5,$630;"&7,@-2"#$(2,"-(0
($+, &55'"1&("<&("0-, /+230-2+, 04, '0='&-*, &-"1&'2, (0, $"#$%&'("()*+
$630;"&, 5&-, 3/0."*+, &, 9&2"2, 40/, 3/+*"5("-#, $0=, &'("()*"-&', /&-#+
'"1"(2, 1"#$(, 2$"4(, "-, /+230-2+, (0, 5'"1&(+, 5$&-#+7, E$+-, '0='&-*
&-"1&'2,50'0-"<+,$"#$%&'("()*+,+-."/0-1+-(2:,&*&3(".+,3$+-0(63"5
3'&2("5"(6, 5&-, 1"("#&(+, ($+, 502(2, 04, 2+'+5("0-:, ($+/+96, +-$&-5"-#
3/023+5(2,40/,303)'&("0-,+2(&9'"2$1+-(,&-*,3+/2"2(+-5+,HZ$&'&190/
+(, &'7:, ?UUOP7, T6, 50-(/&2(:, 1&'&*&3(".+, 3'&2("5"(6, $&2, ($+, 03302"(+
+44+5(,96,"-5/+&2"-#,($+,502(,04,2+'+5("0-:,($+/+96,*"1"-"2$"-#,($+
3/023+5(2,04,2)55+224)',50'0-"<&("0-7
List of abbreviations
9>?
/&>?
F>q
/.>?
"I
[D
[\Z
!9
9'00*,>? 5&3&5"(&-5+,50+44"5"+-(
&/(+/"&',>? 50-5+-(/&("056(05$/01+,- 0;"*&2+
.+-0)2,>? 50-5+-(/&("03)'10-&/6,>? *"44)2"0-,5&3&5"(6
("22)+,>? *"44)2"0-,5&3&5"(6
?:R%*"3$023$0#'65+/&(+
$+10#'09"-
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
4134 J. F. Storz, G. R. Scott and Z. A. Cheviron
!5(
!X^
>^
!>?
!&>?
!A>?
!9>?
!@>?
!1"(>?
!.>?
Q
^>Q
QZA
X
V>?
$+1&(05/"(
$630;"5,.+-("'&(0/6,/+230-2+
0**2,/&("0
3&/("&',3/+22)/+,04,>?
&/(+/"&',>? 3/+22)/+
&'.+0'&/,>? 3/+22)/+
9'00*,>? 3/+22)/+
"-23"/+*,>? 3/+22)/+
1"(05$0-*/"&',>? 3/+22)/+
.+-0)2,>? 3/+22)/+
5&/*"&5,0)(3)(
/+&5(".+,>? 23+5"+2
21&'',40/,#+2(&("0-&',&#+
.+-("'&("0/&(+,04,>? 50-2)13("0-,96,("22)+2
Acknowledgements
We thank W. Milson and two anonymous reviewers for helpful comments. J.F.S.
gratefully acknowledges grant support from the National Science Foundation and
the National Institutes of Health/NHLBI. G.R.S. is supported by the Natural
Sciences and Engineering Research Council of Canada. Deposited in PMC for
release after 12 months.
References
Aon, M. A., Cortassa, S. and O’Rourke, B. (2010). Redox-optimized ROS balance: a
unifying hypothesis. Biochim. Biophys. Acta (in press).
Appenzeller, O., Minko, T., Qualis, C., Pozharov, V., Gamboa, J. and Wang, Y.
(2006). Gene expression, autonomic function and chronic hypoxia: lessons from the
Andes. Clin. Auton. Res. 16, 217-222.
Beall, C. M. (2006). Andean, Tibetan, and Ethiopian patterns of adaptation to highaltitude hypoxia. Integr. Comp. Biol. 46, 18-24.
Beall, C. M. (2007). Two routes to functional adaptation: Tibetan and Andean highaltitude natives. Proc. Natl. Acad. Sci. USA 104, 8655-8660.
Beall, C. M. and Reichsman, A. B. (1984). Hemoglobin levels in a Himalayan high
altitude population. Am. J. Phys. Anthropol. 63, 301-306.
Beall, C. M., Brittenham, G. M., Macuaga, F. and Barragan, M. (1990). Variation in
hemoglobin concentration among samples of high-altitude natives in the Andes and
the Himalayas. Am. J. Hum. Biol. 2, 639-651.
Beall, C. M., Strohl, K. P., Blangero, J., Williams-Blangero, S., Almasy, L. A.,
Decker, M. J., Worthman, C. M., Goldstein, M. C., Vargas, E., Villena, M. et al.
(1997). Ventilation and hypoxic ventilatory response of Tibetan and Aymara high
altitude natives. Am. J. Phys. Anthropol. 104, 427-447.
Beall, C. M., Brittenham, G. M., Strohl, K. P., Blangero, J., Williams-Blangero, S.,
Goldstein, M. C., Decker, M. J., Vargas, E., Villena, M., Soria, R. et al. (1998).
Hemoglobin concentration of high altitude Tibetans and Bolivian Aymara. Am. J.
Phys. Anthropol. 106, 385-400.
Beall, C. M., Cavalleri, G. L., Deng, L., Elston, R. C., Gao, Y., Knight, J., Li, C., Li,
J. C., Liang, Y., McCormack, M. et al. (2010). Natural selection on EPAS1 (HIF2)
associated with low hemoglobin concentration in Tibetan highlanders. Proc. Natl.
Acad. Sci. USA 107, 11459-11464.
Bencowitz, H. Z., Wagner, P. D. and West, J. B. (1982). Effect of change in P50 on
exercise tolerance at high altitude: a theoretical study. J. Appl. Physiol. 53, 14871495.
Bigham, A., Mao, X., Mei, R., Brutsaert, T., Wilson, M. J., Julian, C. G., Parra, E.
J., Akey, J. M., Moore, L. G. and Shriver, M. D. (2009). Identifying positive
selection candidate loci for high-altitude adaptation in Andean populations. Hum.
Genomics 4, 79-90.
Bigham, A., Bauchet, M., Pinto, D., Mao, X., Akey, J. M., Mei, R., Scherer, S.,
Julian, C. G., Wilson, M. J. and López-Herráez, D. et al. (2010). Identifying
signatures of natural selection in Tibetan and Andean populations using dense
genome scan data. PLoS Genet. (in press).
Black, C. P. and Tenney, S. M. (1980). Oxygen transport during progressive hypoxia
in high altitude and sea level waterfowl. Respir. Physiol. 39, 217-239.
Blake, C. I. and Banchero, N. (1985). Effects of cold and hypoxia on ventilation and
oxygen consumption in awake guinea pigs. Respir. Physiol. 61, 357-368.
Bouverot, P. (1985). Adaptation to Altitude-Hypoxia in Vertebrates. Berlin: SpringerVerlag.
Brauner, C. J. and Wang, T. (1997). The optimal oxygen equilibrium curve: a
comparison between environmental hypoxia and anemia. Am. Zool. 37, 101-108.
Brown, J. C., McClelland, G. B., Faure, P. A., Klaiman, J. M. and Staples, J. F.
(2009). Examining the mechanisms responsible for lower ROS release rates in liver
mitochondria from the long-lived house sparrow (Passer domesticus) and big brown
bat (Eptesicus fuscus) compared to the short-lived mouse (Mus musculus). Mech.
Ageing Dev. 130, 467-476.
Brutsaert, T. D. (2007). Population genetic aspects and phenotypic plasticity of
ventilatory responses in high altitude natives. Respir. Physiol. Neurobiol. 158, 151160.
Brutsaert, T. D. (2008). Do high-altitude natives have enhanced exercise performance
at altitude? Appl. Physiol. Nutr. Metab. 33, 582-592.
Brutsaert, T. D., Soria, R., Caceres, E., Spielvogel, H. and Haas, J. D. (1999).
Effect of developmental and ancestral high altitude exposure on chest morphology
and pulmonary function in Andean and European North American natives. Am. J.
Hum. Biol. 11, 383-395.
Brutsaert, T. D., Parra, E. J., Shriver, M. D., Gamboa, A. and León-Velarde, F.
(2005). Ancestry explains the blunted ventilatory response to sustained hypoxia and
lower exercise ventilation of Quechua altitude natives. Am. J. Physiol. Reg. Integr.
Comp. Physiol. 289, R225-R234.
Bullard, R. W. (1972). Vertebrates at altitude. In Physiological Adaptations (ed. M. K.
Yousef, S. M. Horvath, R. W. Bullard), pp. 209-225. New York: Academic Press.
Bunn, H. F. (1980). Regulation of hemoglobin function in mammals. Am. Zool. 20,
199-211.
Calbet, J. A., Robach, P. and Lundby, C. (2009). The exercising heart at altitude.
Cell. Mol. Life Sci. 66, 3601-3613.
Calbet, J. A. L., Boushel, R., Rådegran, G., Søndergaard, H., Wagner, P. D. and
Saltin, B. (2003). Why is Vo2 max after altitude acclimatization still reduced despite
normalization of arterial O2 content? Am. J. Physiol. Reg. Integr. Comp. Physiol.
284, R304-R316.
Cambell, K. L., Storz, J. F., Signore, A. V., Moriyama, H., Catania, K. C., Payson,
A. P., Bonaventura, J., Stetefeld, J. and Weber, R. E. (2010). Molecular basis of a
novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole. BMC Evol. Biol.
10, 214.
Chappell, M. A. and Snyder, L. R. G. (1984). Biochemical and physiological
correlates of deer mouse -chain hemoglobin polymorphisms. Proc. Natl. Acad. Sci.
USA 81, 5484-5488.
Chappell, M. A., Hayes, J. P. and Snyder, L. R. G. (1988). Hemoglobin
polymorphisms in deer mice (Peromyscus maniculatus): physiology of -globin
variants and -globin recombinants. Evolution 42, 681-688.
Cheviron, Z. A., Whitehead, A. and Brumfield, R. T. (2008). Transcriptomic variation
and plasticity in rufous-collared sparrows (Zonotrichia capensis) along an elevational
gradient. Mol. Ecol. 17, 4556-4569.
Connes, P., Yalcin, O., Baskert, O., Brun, J. F. and Hardeman, M. (2006). In heath
and in a normoxic environment, VO2 max is/is not limited primarily by cardiac output
and locomotor muscle blood flow. J. Appl. Physiol. 100, 2099.
Conover, D. O. and Schultz, E. T. (1995). Phenotypic similarity and the evolutionary
significance of countergradient variation. Trends Ecol. Evol. 10, 248-252.
Costa, L. E., Mendez, G. and Boveris, A. (1997). Oxygen dependence of
mitochondrial function measured by high-resolution respirometry in long-term hypoxic
rats. Am. J. Physiol. Cell Physiol. 273, C852-C858.
Crowell, J. W. and Smith, E. E. (1967). Determinants of the optimal hematocrit. J.
Appl. Physiol. 22, 501-504.
Crowell, J. W., Ford, R. G. and Lewis, V. M. (1959). Oxygen transport in
hemorrhagic shock as a function of hematocrit ratio. Am. J. Physiol. 196, 1033-1038.
Currie, R. J. (1999). Ascites in poultry: recent investigations. Avian Pathol. 28, 313326.
Daneshrad, Z., Novel-Chaté, V., Birot, O., Serrurier, B., Sanchez, H., Bigard, A. X.
and Rossi, A. (2001). Diet restriction plays an important role in the alterations of
heart mitochondrial function following exposure of young rats to chronic hypoxia.
Pflügers Arch. 442, 12-18.
de Jong, G. and Behera, N. (2002). The influence of life-history differences on the
evolution of reaction norms. Evol. Ecol. Res. 4, 1-25.
Dejours, P., Garey, W. F. and Rahn, H. (1970). Comparison of ventilatory and
circulatory flow rates between animals in various physiological conditions. Respir.
Physiol. 9, 108-117.
Deutsch, C. A., Tewksbury, J. J., Huey, R. B., Sheldon, K. S., Ghalambor, C. K.,
Haak, D. C. and Martin, P. R. (2008). Impacts of climate warming on terrestrial
ectotherms across latitude. Proc. Natl. Acad. Sci. USA 105, 6668-6672.
Dosek, A., Ohno, H., Acs, Z., Taylor, A. W. and Radak, Z. (2007). High altitude and
oxidative stress. Respir. Physiol. Neurobiol. 158, 128-131.
Durmowicz, A. G., Hofmeister, S., Kadyraliev, T. K., Aldashev, A. A. and
Stenmark, K. R. (1993). Functional and structural adaptation of the yak pulmonary
circulation to residence at high altitude. J. Appl. Physiol. 74, 2276-2285.
Eaton, W. A., Skelton, T. D. and Berger, E. (1974). Survival at extreme altitude:
protective effect of increased hemoglobin affinity. Science 183, 743-744.
Ekblom, B. and Bergland, B. (1991). Effect of erythopoietin administration on
mammal aerobic power. Scand. J. Med. Sci. Sports 1, 88-93.
Ekblom, B. and Hermansen, L. (1968). Cardiac output in athletes. J. Appl. Physiol.
25, 619-625.
Eldridge, M. W., Braun, R. K., Yoneda, K. Y. and Walby, W. F. (2006). Effects of
altitude and exercise on pulmonary capillary integrity: evidence for subclinical highaltitude pulmonary edema. J. Appl. Physiol. 100, 972-980.
Essop, M. F. (2007). Cardiac metabolic adaptations in response to chronic hypoxia. J.
Physiol. 584, 715-726.
Faraci, F. M., Kilgore, D. L. and Fedde, M. R. (1984a). Attenuated pulmonary pressor
response to hypoxia in bar-headed geese. Am. J. Physiol. 247, R402-R403.
Faraci, F. M., Kilgore, D. L. and Fedde, M. R. (1984b). Oxygen delivery to the heart
and brain during hypoxia: pekin duck vs. bar-headed goose. Am. J. Physiol. 247,
R69-R75.
Faraci, F. M., Kilgore, D. L. and Fedde, M. R. (1985). Blood flow distribution during
hypocapnic hypoxia in pekin ducks and bar-headed geese. Respir. Physiol. 61, 2130.
Fedde, M. R., Orr, J. A., Shams, H. and Scheid, P. (1989). Cardiopulmonary function
in exercising bar-headed geese during normoxia and hypoxia. Respir. Physiol. 77,
239-262.
Feder, M. and Walser, J. (2005). The biological limitations of transcriptomics in
elucidating stress and stress response. J. Evol. Biol. 18, 901-910.
Fry, J. (1992). The mixed-model analysis of variance applied to quantitative genetics:
biological meaning of the parameters. Evolution 46, 540-550.
Garland, T. and Adolph, S. C. (1991). Physiological differentiation of vertebrate
populations. Annu. Rev. Ecol. Syst. 22, 193-229.
Garruto, R. M., Chin, C., -T., Weitz, C. A., Liu, J., -C., Liu, R., -L. and He, X. (2003).
Hematological differences during growth among Tibetans and Han Chinese born and
raised at high altitude in Qinghai, China. Am. J. Phys. Anthropol. 122, 171-183.
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
High-altitude adaptation
Ge, R. L., Kubo, K., Kobayashi, T., Sekiguchi, M. and Honda, T. (1998). Blunted
hypoxic pulmonary vasoconstrictive response in the rodent Ochotona curzoniae
(pika) at high altitude. Am. J. Physiol. Heart Circ. Physiol. 274, H1792-H1799.
Gelfi, C., De Palma, S., Ripamonti, M., Eberini, I., Wait, R., Bajracharya, A.,
Marconi, C., Schneider, A., Hoppeler, H. and Cerretelli, P. (2004). New aspects
of altitude adaptation in Tibetans: a proteomic approach. FASEB J. 18, 612-614.
Ghalambor, C. K., McKay, J., Carroll, S. P. and Reznick, D. (2007). Adaptive versus
non-adaptive phenotypic plasticity and the potential for contemporary adaptation in
new environments. Funct. Ecol. 21, 394-407.
Gonzales, G. F., Steenland, K. and Tapia, V. (2009). Maternal hemoglobin level and
fetal outcome at low and high altitudes. Am. J. Physiol. Regul. Integr. Comp. Physiol.
297, R1477-R1485.
Gracey, A. Y., Chaney, M. L., Boomhower, J. P., Tyburczy, W. R., Connor, K. and
Somero, G. N. (2008). Rhythms of gene expression in a fluctuating intertidal
environment. Curr. Biol. 18, 1-7.
Grether, G. (2005). Environmental change, phenotypic plasticity and genetic
compensation. Am. Nat. 166, E115-E123.
Groves, B. M., Droma, T., Sutton, J. R., McCullough, R. G., McCullough, R. E.,
Zhuang, J., Rapmund, G., Sun, S., Janes, C. and Moore, L. G. (1993). Minimal
hypoxic pulmonary hypertension in normal Tibetans at 3,658m. J. Appl. Physiol. 74,
312-318.
Gurney, A. M. (2002). Multiple sites of oxygen sensing and their contributions to
hypoxic pulmonary vasoconstriction. Respir. Physiol. Neurobiol. 132, 43-53.
Guyton, A. C. and Richardson, T. Q. (1961). Effect of hematocrit on venous return.
Circ. Res. 9, 157-164.
Hall, F. G. (1966). Minimal utilized oxygen and the oxygen dissociation curve of blood
of rodents. J. Appl. Physiol. 21, 375-378.
Hansen, J. and Sander, M. (2003). Sympathetic neural overactivity in healthy humans
after prolonged exposure to hypobaric hypoxia. J. Physiol. 546, 921-929.
Hebbel, R. P., Eaton, J. W., Kronenberg, R. S., Zanjani, E. D., Moore, L. G. and
Berger, E. M. (1978). Human llamas: adaptation to altitude in subjects with high
hemoglobin oxygen affinity. J. Clin. Invest. 62, 593-600.
Heinonen, I. H., Kemppainen, J., Kaskinoro, K., Peltonen, J. E., Borra, R.,
Lindroos, M., Oikonen, V., Nuutila, P., Knuuti, J., Boushel, R. et al. (2010).
Regulation of human skeletal muscle perfusion and its heterogeneity during exercise
in moderate hypoxia. Am. J. Physiol. Reg. Integr. Comp. Physiol. (in press).
Hepple, R. T. (2000). Skeletal muscle: microcirculatory adaptation to metabolic
demand. Med. Sci. Sports Exerc. 32, 117-123.
Hochachka, P. W. (1985). Exercise limitations at high altitude: the metabolic problem
and search for its solution. In Circulation, Respiration and Metabolism (ed. R. Gilles),
pp. 240-249. Berlin: Springer-Verlag.
Hochachka, P. W. (1998). Mechanism and evolution of hypoxia-tolerance in humans.
J. Exp. Biol. 201, 1243-1254.
Hochachka, P. W., Stanley, C., Matheson, G. O., McKenzie, D. C., Allen, P. S. and
Parkhouse, W. S. (1991). Metabolic and work efficiencies during exercise in Andean
natives. J. Appl. Physiol. 70, 1720-1730.
Hochachka, P. W., Beatty, C. L., Burelle, Y., Trump, M. E., McKenzie, D. C. and
Matheson, G. O. (2002). The lactate paradox in human high-altitude physiological
performance. News Physiol. Sci. 17, 122-126.
Hoppeler, H. and Vogt, M. (2001). Muscle tissue adaptations to hypoxia. J. Exp. Biol.
204, 3133-3139.
Hsia, C. C., Carbayo, J. J., Yan, X. and Bellotto, D. J. (2005). Enhanced alveolar
growth and remodeling in Guinea pigs raised at high altitude. Respir. Physiol.
Neurobiol. 147, 105-115.
Hsia, C. C. W., Johnson, R. L., McDonough, P., Dane, D. M., Hurst, M. D., Fehmel,
J. L., Wagner, H. E. and Wagner, P. D. (2007). Residence at 3,800-m altitude for 5
mo in growing dogs enhances lung diffusing capacity for oxygen that persists at
least 2.5 years. J. Appl. Physiol. 102, 1448-1455.
Huey, R. B., Deutsch, C. A., Tewksbury, J. J., Vitt, L., Hertz, P., Perez, A. and
Garland, T. (2009). Why tropical forest lizards are vulnerable to climate warming.
Proc. R. Soc. Lond. B. Biol. Sci. 276, 1939-1948.
Jelkmann, W., Oberthur, W., Kleinschmidt, T. and Braunitzer, G. (1981).
Adaptation of hemoglobin function to subterranean life in the mole, Talpa europaea.
Respir. Physiol. 46, 7-16.
Jensen, F. B. (2004). Red blood cell pH, the Bohr effect, and other oxygenation-linked
phenomena in blood O2 and CO2 transport. Acta Physiol. Scand. 182, 215-227.
Julian, C. G., Galan, H., Wilson, M. J., Desilva, W., Cioffi-Ragan, D., Schwartz, J.
and Moore, L. G. (2008). Lower uterine artery blood flow and higher endothelin
relative to nitric oxide metabolite levels are associated with reductions in birth weight
at high altitude. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R906-R915.
Julian, C. G., Wilson, M. J. and Moore, L. G. (2009a). Evolutionary adaptation to
high altitude: a view from in utero. Am. J. Hum. Biol. 21, 614-622.
Julian, C. G., Wilson, M. J., Lopez, M., Yamashiro, H., Tellez, W., Rodriguez, A.,
Bigham, A. W., Shriver, M. D., Rodiruguez, C., Vargas, E. et al. (2009b).
Augmented uterine artery blood flow and oxygen delivery protect Andeans from
altitude-associated reductions in fetal growth. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 296, R1564-R1575.
Kamitomo, M., Alonso, J. G., Okai, T., Longo, L. D. and Gilbert, R. D. (1993).
Effects of long-term, high-altitude hypoxemia on ovine fetal cardiac output and blood
flow distribution. Am. J. Obstet. Gynecol. 169, 701-707.
Kanstrup, I. L. and Ekblom, B. (1984). Blood volume and hemoglobin concentration
as determinants of maximal aerobic power. Med. Sci. Sports. Exerc. 16, 256-262.
Kayser, B., Hoppeler, H., Claassen, H. and Cerretelli, P. (1991). Muscle structure
and performance capacity of Himalayan Sherpas. J. Appl. Physiol. 70, 1938-1942.
Kayser, B., Hoppeler, H., Desplanches, D., Marconi, C., Broers, B. and Cerretelli,
P. (1996). Muscle ultrastructure and biochemistry of lowland Tibetans. J. Appl.
Physiol. 81, 419-425.
Kinsey, S. T., Hardy, K. M. and Locke, B. R. (2007). The long and winding road:
influences of intracellular metabolite diffusion on cellular organization and
metabolism in skeletal muscle. J. Exp. Biol. 210, 3505-3512.
4135
Lenfant, C., Torrance, J., English, E., Finch, C. A., Reynafarje, C., Ramos, J. and
Faura, J. (1968). Effect of altitude on oxygen binding by hemoglobin and on organic
phosphate levels. J. Clin. Invest. 47, 2652-2656.
Lenfant, C., Torrance, J. D. and Reynafarje, C. (1971). Shift of the O2-Hb
dissociation curve at altitude: mechanism and effect. J. Appl. Physiol. 30, 625-631.
León-Velarde, F., Villafuerte, F. C. and Richalet, J. P. (2010). Chronic mountain
sickness and the heart. Prog. Cardiovasc. Dis. 52, 540-549.
Levins, R. (1968). Evolution in Changing Environments: Some Theoretical
Explorations. Princeton, NJ: Princeton University Press.
Lewis, A. M., Mathieu-Costello, O., McMillan, P. J. and Gilbert, R. D. (1999).
Effects of long-term, high-altitude hypoxia on the capillarity of the ovine fetal heart.
Am. J. Physiol. Heart Circ. Physiol. 277, H756-H762.
Lovering, A. T., Romer, L. M., Haverkamp, H. C., Pegelow, D. F., Hokanson, J. S.
and Eldridge, M. W. (2008). Intrapulmonary shunting and pulmonary gas exchange
during normoxic and hypoxic exercise in healthy humans. J. Appl. Physiol. 104,
1418-1425.
Maggiorini, M., Melot, C., Pierre, S., Pfeiffer, F., Greve, I., Sartori, C., Lepori, M.,
Hauser, M., Scherrer, U. and Naeije, R. (2001). High-altitude pulmonary edema is
initially caused by an increase in capillary pressure. Circulation 103, 2078-2083.
Mairbäurl, H. (1994). Red blood cell function in hypoxia at altitude and exercise. Int. J.
Sports Med. 15, 51-63.
Mairbäurl, H., Oelz, O. and Bärtsch, P. (1993). Interactions between Hb, Mg, DPG,
ATP, and Cl determine the change in Hb-O2 affinity at high altitude. J. Appl. Physiol.
74, 40-48.
Mathieu-Costello, O. (1989). Muscle capillary tortuosity in high altitude mice depends
on sarcomere length. Respir. Physiol. 76, 289-302.
Mathieu-Costello, O. (2001). Muscle adaptation to altitude: tissue capillarity and
capacity for aerobic metabolism. High Alt. Med. Biol. 2, 413-425.
Mathieu-Costello, O. and Agey, P. J. (1997). Chronic hypoxia affects capillary density
and geometry in pigeon pectoralis muscle. Respir. Physiol. 109, 39-52.
McClelland, G. B., Hochachka, P. W. and Weber, J. M. (1998). Carbohydrate
utilization during exercise after high-altitude acclimation: a new perspective. Proc.
Natl. Acad. Sci. USA 95, 10288-10293.
McGrath, R. L. and Weil, J. V. (1978). Adverse effects of normovolemic polycythemia
and hypoxia on hemodynamics in the dog. Circ. Res. 43, 793-798.
Metzger, R. J., Klein, O. D., Martin, G. R. and Krasnow, M. A. (2008). The
branching programme of mouse lung development. Nature 453, 745-750.
Monge, C. and León-Velarde, F. (1991). Physiological adaptation to high altitude:
oxygen transport in mammals and birds. Physiol. Rev. 71, 1135-1172.
Monge, C. and Whittembury, J. (1976). High altitude adaptation in the whole animal.
In Environmental Physiology of Animals (ed. J. Blight J. Cloudsey-Thompson and A.
MacDonald). New York: Wiley.
Moore, L. G. (2001). Human genetic adaptation to high altitude. High Alt. Med. Biol. 2,
257-279.
Moore, L. G., Hershey, D. W., Jahnigen, D. and Bowes, W. (1982). The incidence of
pregnancy-induced hypertension is increased among Colorado residents at high
altitude. Am. J. Obstet. Gynecol. 144, 423-429.
Moore, L. G., Young, D., McCullough, R. E., Droma, T. and Zamudio, S. (2001a).
Tibetan protection from intrauterine growth restriction (IUGR) and reproductive loss
at high altitude. Am. J. Hum. Biol. 13, 635-644.
Moore, L. G., Zamudio, S., Zhuang, J., Sun, S. and Droma, T. (2001b). Oxygen
transport in Tibetan women during pregnancy at 3,658m. Am. J. Phys. Anthropol.
114, 42-53.
Moore, L. G., Shriver, M., Bemis, L., Hickler, B., Wilson, M., Brutsaert, T., Parra,
E. and Vargas, E. (2004). Maternal adaptation to high-altitude pregnancy: an
experiment of nature – a review. Placenta 25, S60-S71.
Moore, L. G., Shriver, M., Bemis, L. and Vargas, E. (2006). An evolutionary model
for identifying genetic adaptation to high altitude. In Hypoxia and Exercise (ed. R. C.
Roach, P. D. Wagner and P. H. Hackett), pp. 101-118. New York: Springer-Verlag.
Moran, N. (1992). The evolutionary maintenance of alternative phenotypes. Am. Nat.
139, 971-989.
Moritz, C., Patton, J., Conroy, C., Parra, J., White, G. and Beissinger, S. (2008).
Impact of a century of climate change on small-mammal communities in Yosemite
National Park, USA. Science 322, 261-264.
Nikinmaa, M. (2001). Haemoglobin function in vertebrates: evolutionary changes in
cellular regulation in hypoxia. Respir. Physiol. 128, 317-329.
Noakes, T. D., Calbet, J. A. L., Boushel, R., Sondergaard, H., Radegran, G.,
Wagner, P. D. and Saltin, B. (2004). Central regulation of skeletal muscle
recruitment explains the reduced maximal cardiac output during exercise in hypoxia.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R996-R1002.
Pichon, A., Zhenzhong, B., Favret, F., Jin, G., Shufeng, H., Marchant, D., Richalet,
J. P. and Ge, R. L. (2009). Long term ventilatory adaptation and ventilatory
response to hypoxia in Plateau pika (Ochotona curzoniae): role of nNOS and
dopamine. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R978-R987.
Pigliucci, M., Murren, C. J. and Schlichting, C. D. (2006). Phenotypic plasticity and
evolution by genetic assimilation. J. Exp. Biol. 209, 2362-2367.
Powell, F. L. (2007). The influence of chronic hypoxia upon chemoreception. Respir.
Physiol. Neurobiol. 157, 154-161.
Powell, F. L., Milsom, W. K. and Mitchell, G. S. (1998). Time domains of the hypoxic
ventilatory response. Respir. Physiol. 112, 123-134.
Price, T., Qvarnstrom, A. and Irwin, D. (2003). The role of phenotypic plasticity in
driving genetic evolution. Proc. R. Soc. Lond. B. Biol. Sci. 270, 1433-1440.
Ramirez, J.-M., Folkhow, L. P. and Blix, A. S. (2007). Hypoxia tolerance in mammals
and birds: from the wilderness to the clinic. Annu. Rev. Physiol. 69, 113-143.
Rankin, E. B., Biju, M. P., Liu, Q., Unger, T. L., Rha, J., Johnson, R. S., Simon, M.
C., Keith, B. and Haase, V. H. (2007). Hypoxia-inducible factor-2 (HIF-2) regulates
hepatic erythropoietin in vivo. J. Clin. Invest. 117, 1068-1077.
Ravikumar, P., Bellotto, D. J., Johnson, R. L. and Hsia, C. C. (2009). Permanent
alveolar remodeling in canine lung induced by high-altitude residence during
maturation. J. Appl. Physiol. 107, 1911-1917.
4(% */52.!, /& %80%2)-%.4!, ")/,/'9
4136 J. F. Storz, G. R. Scott and Z. A. Cheviron
Reeves, J. T. and Grover, R. F. (1975). High-altitude pulmonary hypertension and
pulmonary edema. Prog. Cardiol. 4, 99-118.
Richards, D. W. (1960). Homeostasis: its dislocations and perturbations. Perspect.
Biol. Med. 3, 238-251.
Riggs, A. F. (1988). The Bohr effect. Annu. Rev. Physiol. 50, 181-204.
Rivera-Ch, M., León-Velarde, F. and Huicho, L. (2007). Treatment of chronic
mountain sickness: Critical reappraisal of an old problem. Respir. Physiol. Neurobiol.
158, 251-265.
Sakai, A., Matsumoto, T., Saitoh, M., Matsuzaki, T., Koizumi, T., Ishizaki, T., Ruan,
Z. H., Wang, Z. G., Chen, Q. H. and Wang, X. Q. (2003). Cardiopulmonary
hemodynamics of blue-sheep, Pseudois nayaur, as high-altitude adapted mammals.
Jpn. J. Physiol. 53, 377-384.
Samaja, M., di Prampero, P. E. and Cerretelli, P. (1986). The role of 2,3-DPG in the
oxygen transport at altitude. Respir. Physiol. 64, 191-202.
Samaja, M., Crespi, T., Guazzi, M. and Vandegriff, K. D. (2003). Oxygen transport in
blood at high altitude: role of the hemoglobin-oxygen affinity and impact of the
phenomena related to hemoglobin allosterism and red cell function. Eur. J. Biochem.
90, 351-359.
Scheiner, S. (1993). Genetics and evolution of phenotypic plasticity. Annu. Rev. Ecol.
Syst. 24, 35-68.
Scheiner, S. (1998). The genetics of phenotypic plasticity. VII. Evolution in a spatially
structured environment. J. Evol. Biol. 11, 303-320.
Schmutz, S., Däpp, C., Wittwer, M., Durieux, A. C., Mueller, M., Weinstein, F.,
Vogt, M., Hoppeler, H. and Flück, M. (2010). A hypoxia complement differentiates
the muscle response to endurance exercise. Exp. Physiol. 95, 723-735.
Schuler, B., Arras, M., Keller, S., Rettich, A., Lundby, C., Vogel, J. and Gassmann,
M. (2010). Optimal hematocrit for maximal excercise performance in acute and
chronic erythropoietin-treated mice. Proc. Natl. Acad. Sci. USA 107, 419-423.
Scott, G. R. and Milsom, W. K. (2007). Control of breathing and adaptation to high
altitude in the bar-headed goose. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293,
R379-R391.
Scott, G. R. and Milsom, W. K. (2009). Control of breathing in birds: implications for
high altitude flight. In Cardio-Respiratory Control in Vertebrates: Comparative and
Evolutionary Aspects (ed. M. L. Glass and S. C. Wood), pp. 429-448. Berlin:
Springer-Verlag.
Scott, G. R., Egginton, S., Richards, J. G. and Milsom, W. K. (2009a). Evolution of
muscle phenotype for extreme high altitude flight in the bar-headed goose. Proc. R.
Soc. Lond. B. Biol. Sci. 276, 3645-3653.
Scott, G. R., Richards, J. G. and Milsom, W. K. (2009b). Control of respiration in
flight muscle from the high-altitude bar-headed goose and low-altitude birds. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 297, R1066-R1074.
Scott, G. R., Schulte, P. M., Egginton, S., Scott, A. L. M., Richards, J. G. and
Milsom, W. K. (2010). Molecular evolution of cytochrome c oxidase underlies highaltitude adaptation in the bar-headed goose. Mol. Biol. Evol. epub ahead of print.
Simonson, T. S., Yang, Y., Huff, C. D., Yun, H., Qin, G., Witherspoon, D. J., Bai,
Z., Lorenzo, F. R., Xing, J., Jorde, L. B. et al. (2010). Genetic evidence for highaltitude adaptation in Tibet. Science 329, 72-75.
Sinervo, B., Mendez-de-la-Cruz, F., Miles, D. B., Heulin, B., Bastiaans, E.,
Villagran-Santa Cruz, M., Lara-Resendiz, R., Martinez-Mendez, N., CalderonEspinosa, M. L., Meza-Lazaro, R. N. et al. (2010). Erosion of lizard diversity by
climate change and altered thermal niches. Science 328, 894-899.
Sinha, S., Ray, U., Saha, M., Singh, S. and Tomar, O. (2009a). Antioxidant and
redox status after maximal aerobic exercise at high altitude in acclimatized
lowlanders and native highlanders. Eur. J. Appl. Physiol. 106, 807-814.
Sinha, S., Ray, U. S., Tomar, O. S. and Singh, S. N. (2009b). Different adaptation
patterns of antioxidant system in natives and sojourners at high altitude. Respir.
Physiol. Neurobiol. 167, 255-260.
Sinha, S., Dutta, A., Singh, S. N. and Ray, U. S. (2010). Protein nitration, lipid
peroxidation and DNA damage at high altitude in acclimatized lowlanders and native
highlanders: relation with oxygen consumption. Respir. Physiol. Neurobiol. 171, 115121.
Snyder, L. R. G. (1982). 2,3-diphosphoglycerate in high- and low-altitude populations
of the deer mouse. Respir. Physiol. 48, 107-123.
Snyder, L. R. G. (1985). Low P50 in deer mice native to high altitude. J. Appl. Physiol.
58, 193-199.
Snyder, L. R. G., Born, S. and Lechner, A. J. (1982). Blood oxygen affinity in highand low-altitude populations of the deer mouse. Respir. Physiol. 48, 89-105.
Somero, G. (2010). The physiology of climate change: how potentials for
acclimatization and genetic adaptation will determine “winners” and “losers”. J. Exp.
Biol. 213, 912-920.
Storz, J. F. (2007). Hemoglobin function and physiological adaptation to hypoxia in
high-altitude mammals. J. Mammal. 88, 24-31.
Storz, J. F. (2010). Genes for high altitudes. Science 329, 40-41.
Storz, J. F. and Moriyama, H. (2008). Mechanisms of hemoglobin adaptation to highaltitude hypoxia. High Alt. Med. Biol. 9, 148-157.
Storz, J. F. and Wheat, C. W. (2010). Integrating evolutionary and functional
approaches to infer adaptation at specific loci. Evolution 64, 2489-2509.
Storz, J. F., Runck, A. M., Sabatino, S. J., Kelly, J. K., Ferrand, N., Moriyama, H.,
Weber, R. E. and Fago, A. (2009). Evolutionary and functional insights into the
mechanism underlying high-altitude adaptation of deer mouse hemoglobin. Proc.
Natl. Acad. Sci. USA 106, 14450-14455.
Storz, J. F., Runck, A. M., Moriyama, H., Weber, R. E. and Fago, A. (2010). Genetic
differences in hemoglobin function between highland and lowland deer mice. J. Exp.
Biol. 213, 2565-2574.
Sultan, S. and Spencer, H. (2002). Metapopulation structure favors plasticity over
local adaptation. Am. Nat. 160, 271-283.
Turek, Z., Kreuzer, F. and Hoofd, L. (1973). Advantage or disadvantage of a
decrease of blood oxygen affinity for tissue oxygen supply at hypoxia. A theoretical
study comparing man and rat. Pflügers Arch. 342, 185-187.
Turek, Z., Kreuzer, F. and Ringnalda, B. E. M. (1978a). Blood gases at several
levels of oxygenation in rats with a left-shifted blood oxygen dissociation curve.
Pflügers Arch. 376, 7-13.
Turek, Z., Kreuzer, F., Turek-Maischeider, M. and Ringnalda, B. E. M. (1978b).
Blood O2 content, cardiac output, and flow to organs at several levels of oxygenation
in rats with a left-shifted blood oxygen dissociation curve. Pflügers Arch. 376, 201207.
van Ekeren, G. J., Sengers, R. C. and Stadhouders, A. M. (1992). Changes in
volume densities and distribution of mitochondria in rat skeletal muscle after chronic
hypoxia. Int. J. Exp. Pathol. 73, 51-60.
van Tienderen, P. (1991). Evolution of generalists and specialists in spatially
heterogenous environments. Evolution 45, 1317-1331.
van Tienderen, P. (1997). Generalists, specialists, and the evolution of phenotypic
plasticity in sympatric populations of distinct species. Evolution 51, 1372-1380.
Via, S., Gomulkiewicz, R., de Jong, G., Scheiner, S., Schlichting, C. and van
Tienderen, P. (1995). Adaptive phenotypic plasticity: consensus and controversy.
Trends Ecol. Evol. 10, 212-217.
Villafuerte, F. C., Cárdenas, R. and Monge, C. C. (2004). Optimal hemoglobin
concentration and high altitude: a theoretical approach for Andean men at rest. J.
Appl. Physiol. 96, 1581-1588.
Wang, Z., Gerstein, M. and Snyder, M. (2009). RNA-Seq: a revolutionary tool for
transcriptomics. Nat. Rev. Genet. 10, 57-63.
Ward, S., Bishop, C. M., Woakes, A. J. and Butler, P. J. (2002). Heart rate and the
rate of oxygen consumption of flying and walking barnacle geese (Branta leucopsis)
and bar-headed geese (Anser indicus). J. Exp. Biol. 205, 3347-3356.
Weber, R. E. (2007). High-altitude adaptations in vertebrate hemoglobins. Respir.
Physiol. Neurobiol. 158, 132-142.
Weber, R. E. and Fago, A. (2004). Functional adaptation and its molecular basis in
vertebrate hemoglobins, neuroglobins and cytoglobins. Respir. Physiol. Neurobiol.
144, 141-159.
Weiskopf, R. B. and Severinghaus, J. W. (1972). Lack of effect of high altitude on
hemoglobin oxygen affinity. J. Appl. Physiol. 33, 276-277.
Wilson, M. J., Lopez, M., Vargas, M., Julian, C., Tellez, W., Rodriguez, A., Bigham,
A., Armaza, J. F., Niermeyer, S., Shriver, M. et al. (2007). Greater uterine artery
blood flow during pregnancy in multigenerational (Andean) than shorter-term
(European) high-altitude residents. Am. J. Physiol. Regul. Integr. Comp. Physiol.
293, R1313-R1324.
Winslow, R. and Monge, C. (1987). Hypoxia, Polycythemia, and Chronic Mountain
Sickness. Baltimore, MD: Johns Hopkins University Press.
Winslow, R., Monge, C., Brown, E., Klein, H., Sarnquist, F., Winslow, N. and
McNeally, S. (1985). Effects of hemodilution on O2 transport in high-altitdue
polycythemia. J. Appl. Physiol. 59, 1495-1502.
Winslow, R. M., Chapman, K. W., Gibson, C. C., Samaja, M., Monge, C. C.,
Goldwasser, E., Sherpa, M. and Blume, D. (1989). Different hematologic
responses to hypoxia in Sherpas and Quechua Indians. J. Appl. Physiol. 66, 15611569.
Wu, T. and Kayser, B. (2006). High altitude adaptation in Tibetans. High Alt. Med.
Biol. 7, 193-208.
Wu, T., Wang, X., Wei, C., Cheng, H., Wang, X., Li, Y., Ge-Dong Zhao, H., Young,
P., Li, G. and Wang, Z. (2005). Hemoglobin levels in Qinghai-Tibet: different effects
of gender for Tibetans vs. Han. J. Appl. Physiol. 98, 598-604.
Yi, X., Liang, Y., Huerta-Sanchez, E., Jin, X., Cuo, Z. X. P., Pool, J. E., Xu, X.,
Jiang, H., Vinckenbosch, N., Korneliussen, T. S. et al. (2010). Sequencing of fifty
human exomes reveals adaptation to high altitude. Science 329, 75-78.
Zamudio, S., Palmer, S. K., Droma, T., Stamm, E., Coffin, C. and Moore, L. G.
(1995). Effect of altitude on uterine artery blood flow during normal pregnancy. J.
Appl. Physiol. 79, 7-14.
Zhuang, J., Droma, T., Sun, S., Janes, C., McCullough, R. E., McCullough, R. G.,
Cymerman, A., Huang, S. Y., Reeves, J. T. and Moore, L. G. (1993). Hypoxic
ventilatory responsiveness in Tibetan compared with Han residents of 3,658m. J.
Appl. Physiol. 74, 303-311.
Zungu, M., Young, M. E., Stanley, W. C. and Essop, M. F. (2008). Expression of
mitochondrial regulatory genes parallels respiratory capacity and contractile function
in a rat model of hypoxia-induced right ventricular hypertrophy. Mol. Cell. Biochem.
318, 175-181.
4(% */52.!, /& %80%2)-%.4!, ")/,/'9