Genetics of Chronic Mountain Sickness in Andean Highlanders

Nov. 2, 2013

Roy RonenUniversity of California, San Diego

2

Acute Mountain Sickness• headaches• fatigue, weakness• dizziness• insomnia• …

Chronic Mountain Sickness• Polycythemia• Palpitations• Tinnitus• >> pulmonary hypertension• >> stroke• >> poor birth outcome• …

Me, circa 2006

YearsDays

Salt plains (Salar de Uyuni), Bolivia, 3800m

a ‘recent’ exampleAndean Mountains, Peru Himalaya Mountains, Tibet

Bale Mountains, Ethiopia

58% sea level O2

61% sea level O2

56% sea level O2

Positive Darwinian Selection

3

- Scheinfeldt et al. 2012- Alkorta-Aranburu et al. 2012- Huerta-Sanchez et al. 2013

- Beall et al. 2010- Bigham et al. 2010- Simonson et al. 2010- Yi et al. 2010

High Altitude Adaptation

migration to high altitude

High alt. population

Andean Mountains, Peru58% see level O2

Time

Now

Low alt. population

Time

MRCA

Out-group population

migration to high altitude

High alt. population

High Altitude Adaptation

Now

WGS (~30x) of 10 CMS, 10 non-CMS

Setup

ADMIXTURE, k=4

Control: 66 MXL (Mexican, LA)1000G, low pass WGS

Outgroup: 67 LWK (Luhya, Kenya)1000G, low pass WGS

Setup

‘all’ sites(approx. freq.)

few sites(accurate freq.)

Selection Scan

WGS

Arrays

- Scheinfeldt et al. 2012- Alkorta-Aranburu et al. 2012- Huerta-Sanchez et al. 2013

- Beall et al. 2010- Bigham et al. 2010- Simonson et al. 2010- Yi et al. 2010

8

Whole Genome Sequencing

Whole Genome Sequencing

Chromosome 19, Sπ SNP Frequency Profile (chr19)

Genotyping Array (Affy 6.0)

SNP Frequency Profile (chr19)Chromosome 19, Sπ

Low alt. population

Time

MRCA

Out-group population

migration to high altitude

High alt. population

Genome Wide Scan for Selection

Sπ , Sf , FST , PBS Sπ , Sf , FST , PBS

10

Chr12, q13.11

• SENP1– Regulates GATA1 and HIF1α (!!!)– Senp-/- mice show erythropoiesis defect

• PFKM– pfkm deficient mice show hyper vascularization,

muscle hypoxia, and exercise intolerance

• ANP32D – Oncogene…

Known Functions

Measure Expression

Experimental Results (1)

Normoxia controls

Fibroblast cell lines derived from CMS & nonCMS

Hypoxia 1.5% O2

Experimental Results (2)RNAi knock down of Drosophila orthologs

Normal (21 % O2)

Hypoxia (5 % O2)

% S

urvi

val

SENP1 ortholog

ANP32D ortholog Condition

Summary

1. WGS important for identifying signature of selection.

2. New (experimentally validated!) hypoxia-tolerance genes:

• Selection of ANP32D, SENP1 in non-CMS (vs. CMS/MXL).

• Transcripts highly expressed in CMS vs. non-CMS.

• Knock downs remarkably more tolerant to hypoxia.

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Whole Genome Sequencing Uncovers the Genetic Basis of Chronic Mountain Sickness in Andean Highlanders

American Journal of Human Genetics, Sept. 2013

UC San Diego• Vineet Bafna Lab

– Nitin Udpa

• Gabriel Haddad Lab– Dan Zhou– Tsering Stobdan– Huiwen Zhao

Acknowledgments

BGI• Junbin Liang• Yingrui Li• Yi Yin• Yuanping Du• Lixia Guo• Rui Cao• Yu Wang

New Mexico HEMC• Otto Appenzeller

Universidad Peruana Cayetano Heredia• Francisco Villafuerte• David Callacondo

• Xin Jin• Chen Huang• Wenlong Jia• Dandan Cao• Guangwu Guo• Siqi LiuVanderbilt Med. Center

• Jorge L. Gamboa