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PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.com PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.com Rock, Blue Genes, and Rock, Blue Genes, and Getting High Getting High How we cope when Oxygen is

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Rock, Blue Genes, and Rock, Blue Genes, and Getting High Getting High

How we cope when Oxygen is scarce How we cope when Oxygen is scarce

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Pumori (7162m): 1998

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Early atmosphere

Composition of volcanic gases

  • Water (95-97%)
  • CO2 (1.1-1.9%)
  • Sulphur Dioxide (1.5-2.3%)
  • Hydrogen Sulphide (0.07-0.08%)
  • Hydrochloric Acid (0.004-0.006%)

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The Cradle?

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CYANOBACTERIA

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Photolysis generates ozone

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Catatumbo river empties into Lake Maracaiebo (Venezuela)

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Red Bands and Red Beds

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Eukaryotes 2bn years ago

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0.85–0.54 3.85–2.45Gyr 2.45–1.85 1.85–0.85 0.54-

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Complex life uses ATP as energy currency, and mints it using Oxygen.

Adenosine P P P

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...AND COMPLEX LIFE IS COSTLY

Making, maintaining and using multiple complex proteins, and their genes, is very expensive!

THIS REPRESENTED AN THIS REPRESENTED AN EVOLUTIONARY BOTTLENECK EVOLUTIONARY BOTTLENECK

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Prokaryote Power Production is via Plasma Membranes

Surface area = 4πr2 Volume = 4/3 πr3 SA/V = 3/r r 1µm -> 6µm SA/V ↓ 3 -> 0.5

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Rickettsia prowazekii (epidemic typhus) Nature 396, 133 - 140 (12 November 1998

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Pyruvate Dehydrogenase

KREBS CYCLE

OXIDATIVE PHOSPHORYLATION

PYRUVATE

Mitochondrion Proton shuttle H+ H+

GLUCOSE

H+ H+ H+ H+

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The electron transport chain in mitochondrial membranes

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A series of protein complex located at the inner mitochondrial membrane

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H+

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H+ H+

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H+ H+

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H+ H+

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H+ H+

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H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+

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H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+

Adenosine P P P

Oxygen Oxygen Water Water

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Power…with control

with control.

VAST POWER!

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H+ H+ H+ H+

UNCOUPLING PROTEINS (UCPs)

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0.85–0.54 3.85–2.45Gyr 2.45–1.85 1.85–0.85 0.54-

...DEPENDENT UPON O2 AVAILABILITY

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BUT THIS RISE WASN’T SO SMOOTH

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5 10 15 20 25 30 35

  • 600
  • 500
  • 400
  • 300
  • 200
  • 100

Now

Devonian Hypoxic events

Pacific 5-6ml/l now, 0-1 then

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Data from Budyko, Ronov and Yanshin (1987) The Journal of Experimental Biology 201, 1223–1232 (1998)

Superimposed anoxic events -> mass extinctions. Ocean current collapses from polar melts

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Elasmobranchs survived

Arose in Silurian-Devonian (400m years ago)

Sharks, Rays, Skates, Sawfish Shovelnose Ray

Comparative Biochemistry and Physiology, Part A 155 (2010) 417–434

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As did our ancestors......

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THEY FACED RECURRENT HYPOXIA AGAIN

Epaulette Shark (Hemiscyllium Oscellatum)

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Turtle

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Amazonian Oscar Fish

Astronotus Occellatus

Oyster Toadfish

Opasnus Tau

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Crucian Carp

Carassius carassius

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..and

  • Massive glycogen reserves…..because

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WE ALSO FACED RECURRENT HYPOXIA.....AND STILL DO

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And this can be a matter of life-or-death

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SO...ARE THEY (AND WE) ‘GENTICALLY EQUIPPED’ FOR HYPOXIC SURVIVAL? And, if so, how?

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Many genes ‘sense’ oxygen and respond to it

HIF HIF-

  • 1 consists of 2 subunits:

1 consists of 2 subunits: HIF HIF-

  • 1

1α α and HIF and HIF-

  • 1

1β β/ARNT /ARNT

This occurs through the action of

  • xygen-sensing transcription

factors: HIF-1

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Hypoxia protects HIF Hypoxia protects HIF-

  • 1

1α α from degradation from degradation

OH OH

HIF-alpha prolyl hydroxylase (HPH) HIF-alpha proloyl hydroxylase (HPH)

pVon Hippel Lindau Protein (pVHL) pVon Hippel Lindau Protein (pVHL)

Ub E3 lig Ub E3 lig

Degradation through ubiquisome- proteosome pathway NORMOXIA

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HIF-1α: NORMOXIA

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HYPOXIA

Phosphorylation

Nucleus

HIF-1 B

HRE

(5′-RCGTG-3′)

GENE TRANSCRIPTION ACTIVATED

CREBBP/ EP300

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Nucleic Acids Res. 2009 August; 37(14): 4587–4602.

81 HIF1-responsive genes suggested so far

?

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Nucleic Acids Res. 2009 August; 37(14): 4587–4602.

81 HIF1-responsive genes suggested so far

?

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You breathe harder

‘It’s all about increasing delivery’

RBC mass increases ERYTHROPOETIN

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And increasing the reservoir but lowering its height doesn’t help delivery much!!

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100 75 50 25 100 80 60 40 20 SATURATION PaO2 (mmHg)

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You breathe harder

It’s all about increasing delivery???

RBC mass increases The heart pumps harder ? Capillary density rises ? Mitochondria numbers rise ?

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Stanyon R et al Journal of Biology 2009, 8:18

So is Oxygen Content That Important?

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Three High Altitude Populations Andian Altiplano Ethiopian Highlands Tibetan Plateau

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60,000 years old

Y chromosome D-M174

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Andamanese: earliest settlers of SE Asia D-M174 56.25%

Shi H et al Y chromosome evidence of earliest modern human settlement in East Asia and multiple

  • rigins of Tibetan and Japanese populations. BMC Biol 2008, 6:45. (5000 males, 73 populations)

Y chromosome D-M174

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Shi H et al Y chromosome evidence of earliest modern human settlement in East Asia and multiple

  • rigins of Tibetan and Japanese populations. BMC Biol 2008, 6:45. (5000 males, 73 populations)

30-40%

<72.3% 30%

D-M174 also prevalent in…

JAPAN 30-40%

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Chusang (Near Lhasa) 20,000 years ago (optical stimulated luminescence dating of travertine stone and hearth)

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PLENTY OF TIME FOR NATURAL SELECTION

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“Prenatal and postnatal mortality rose with increasing elevation and were 3 fold higher across all altitudes in the Han than the Tibetans”

Tibetan protection from intrauterine growth restriction (IUGR) and reproductive loss at high altitude Am J Human Biol Vol 13 (5): 635-644

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TIBETANS VS HAN

Some alleles are far more frequent than they should be

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TIBETANS VS HAN

Some alleles are more frequent than they should be

Adam17 Adam17 EPAS2 EPAS2

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EPAS1 (encodes HIF2a) 1.8g/dl lower Hb

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Weight loss (Kg)

10.04% WEIGHT LOSS 10.04% WEIGHT LOSS

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In fact, it’s not pathological, but highly regulated

Amino acids Load IGF1 Sarcolemma PLD1 Rheb Phosphatidic acid mTOR Akt EIF3f (scaffold) FoXO

HYPOXIA

Myostatin MURF1

ANABOLISM ANABOLISM CATABOLISM CATABOLISM

TSC1/2 AMP kinase

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BUT WHY? BUT WHY?

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ADVANTAGES OF WEIGHT LOSS IN HYPOXIA?

  • Biomechanical efficiency?
  • Reduced diffusion distances for oxygen?
  • Reduced ‘maintenance’ costs?

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50-95% reduction in muscle/ liver protein synthesis 30-60% reduction in protein synthesis Reduction in protein synthesis Reduction in protein synthesis

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The response to hypoxia isn’t about delivering more, but

USING LESS USING LESS

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Angiotensinogen Renin

Angiotensin II

Angiotensin I

ACE ACE Kinin

#

BP

V/C

Aldosterone

Endocrine RAS

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Local (Paracrine) RAS

  • Phylogenetically ancient (millions of years)
  • Diverse species
  • Diverse human cells and tissues
  • Important role in cell growth
  • Metabolism
  • Inflammation

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The ACE I/D polymorphism

5’ 3’

1 5 8 15 17 21 26 exons

287 bp ALU repeat sequence

Intron 16

Insertion (I) : lower tissue ACE levels Deletion (D) : higher tissue ACE levels

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5 10 15 20 25 30 35 40 45 50 II ID DD

5 10 15 20 25 30 35 40 45 50 II ID DD

Elite UK Mountaineers

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80 82 84 86 88 90 92 94 96 98 100 DD ID II

%

  • MT. BLANC (4810m)

KILIMANJARO (5895m, 4 days)

SUCCESS IN CLIMBING.....

II

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‘Like DD’

‘Like II’

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H+ H+ H+ H+

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ACE regulates UCP expression

ACE, UCP2 and UCP3 are expressed in human endothelial cells

235 bp 228 bp 207 bp

1018bp 516/508 bp 394bp 344bp 298bp 220bp 200bp ACE UCP2 UCP3 GAPDH

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SO IS HYPOXIC ADAPTATION ACTUALLY

METABOLIC METABOLIC ADAPTATION?

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MITOCHONDRIAL MODELLING

  • Reconstructed human mitochondrial metabolic

network

  • Optimized with ATP synthesis capacity as objective

function

  • Subjected to hypoxia

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Flux heat map

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  • Hypothesized that, in hypoxia, positive

selective pressure would be driven by the need to restore ATP-producing capacity toward normoxic levels.

  • Found that glucose transport and oxygen

uptake limited ATP synthesis capacity in hypoxia, phospholipid biosynthesis loss would impede.

  • Thus predicted that the 25 genes encoding

the glycolysis co-set would be under positive selective, and 15 phospholipid genes under negative selective pressure.

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6-phosphofructokinase (glycolysis) Phosphoglycerate kinase 1 (glycolysis)

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ACADM ACADS ACSL1 CDS2 CHKB CHPT1 CPT1B CPT2 GK GK3P GPAM PISD PPA1 PPA2 SLC25A20

Phospholipid co-set

Mitochondrial acyl-Coenzyme A dehydrogenase (medium chain fatty acid metabolism) Pyrophosphatase

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Modelling can predict elements

  • f human evolution

Evidence of selection pressure

  • n ‘use’ not ‘delivery’

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Evidence of selection in the mitochondrial genome

  • Mitochondrial whole-genome comparison study in 40

Tibetan and 50 Han Chinese

  • Of 13 haplogroups, M9 differed: 8 variants, those in 4

genes likely to be associate with greater protein stability

  • Comparison of non-synonymous/synonymous variants
  • f 13 genes,
  • Evidence for ‘adaptive selection for a number of genes’:

Gu M, et al Gene. 2012 Mar 15;496(1):37-44

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tRNA alanine and 12S rRNA genes ATP6 & 8 (ATP synthase subunit 6 & 8) Cyt b (complex III) ND2 (NADH dehydrogenase) COX2 (cytochrome c

  • xidase subunit II)

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The yak genome and adaptation to life at high altitude Nature Genetics Published online 01 July 2012

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ETHIOPIA

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ETHIOPIA

Likely populated longer than Andes and Tibet Plausible gene flow via individuals from Sub- Saharan Africa, Northern Africa, and the Middle East

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ETHIOPIANS

  • BHLHE41 (DEC2) locus.
  • Regulated by HIF-1α

α α α

  • Negatively regulates HIF-1α

α α α-induced transcription of VEGF.

  • Candidate for hypoxic disruption of the

circadian clock.

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And finally…..

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