Un gruppo di ricercatori americani ha certificato che i popoli di montagna sono geneticamente diversi dagli altri: nel corso dei secoli il loro organismo è mutato in modo da garantire la sopravvivenza della specie anche in condizioni estreme – di GIAMPAOLO VISETTI

PECHINO – Vivere in alta quota allunga e migliora la vita. Ad assicurare longevità e vecchiaia più attiva non sono solo aria pulita, cibi sani, movimento quotidiano e ritmi meno stressanti. Un gruppo di ricercatori americani ha certificato che i popoli di montagna sono geneticamente diversi dagli altri. Il loro organismo, nel corso dei secoli, ha subìto un mutamento biologico, capace di garantire la sopravvivenza della specie anche in condizioni estreme.

Lo studio dell’Università di Berkeley, pubblicato sull’ultimo numero della rivista Science, è riuscito a spiegare perché la resistenza alla rarefazione dell’aria, dove la concentrazione dell’ossigeno è inferiore fino al 40% rispetto a quella sul livello del mare, rallenta gli effetti dell’invecchiamento e migliora le prestazioni degli organi interni. La ricerca è stata effettuata in Tibet e ha messo a confronto il Dna di cinquanta abitanti dell’Himalaya con quello di altrettanti cinesi di etnia han nati in pianura. Fino ad oggi la scienza aveva già scoperto dieci geni che distinguono i due popoli. L’équipe del professor Rasmus Nielsen ne ha rilevati ora trenta, individuando per la prima volta nei discendenti di chi da generazioni si è insediato sopra i 3500 metri di quota una sorta di “umanità parallela”. La scoperta del “segreto dei tibetani” non stabilisce solo una diversità genetica, politicamente assai

delicata, tra i nativi di Lhasa e quelli di Pechino. Si estende ai 13 milioni di esseri umani che in tutto il mondo vivono fino a 5 mila metri sopra il livello del mare ed è destinata a dare nuovo impulso agli studi sulle malattie causate dalla privazione di ossigeno nel grembo materno, tra cui epilessia e schizofrenia. … Secondo gli scienziati californiani, i popoli delle vette sono protagonisti “della più rapida mutazione genetica mai accertata” e questo cambiamento è “direttamente connesso al modo con cui l’organismo utilizza l’ossigeno”.
La razza selezionata sul “tetto del mondo”, dove si concentrano tutti gli Ottomila del pianeta, ha avuto origine in Asia 2800 anni fa, quando tibetani e han si sono separati. Clima e isolamento hanno evitato contaminazioni di sangue, consegnandoci il popolo che può oggi condurre oltre il mistero della consunzione fisica. I tibetani, come altre genti degli altipiani andini, non vengono colpiti dal cosiddetto “mal di montagna”. La carenza cronica di ossigeno non causa in loro edemi polmonari, o cerebrali, nemici anche degli alpinisti più allenati. Problemi cardiaci e di pressione, affaticamento rapido, neonati sottopeso e alta mortalità infantile, non colpiscono come dovrebbero chi da sempre vive tra i 3700 e i 5200 metri di quota.
Fra i 30 geni della “vita rafforzata” uno in particolare è mutato fino a disegnare il profilo di un super-uomo. Si chiama “Epas1″ ed è noto come il “gene dell’atleta”. Le due varianti principali favoriscono le prestazioni sotto sforzo e codificano la proteina che, grazie alla capacità di regolare i livelli di ossigeno nel sangue, bilancia il metabolismo aerobico e anaerobico.

Che la selezione naturale dell’altitudine avesse fissato delle “varianti umane vantaggiose” non è una novità. Gli sportivi ricorrono da anni alla preparazione in quota per aumentare globuli rossi, emoglobina, eritropoietina ed ematocrito, così da migliorare le prestazioni agonistiche. Lo studio di Berkeley si spinge più in là, individuando per la prima volta i geni che trasformano l’ipossia nel motore di una serie di adattamenti cellulari che, oltre che la resistenza atletica, migliorano la salute e rallentano l’invecchiamento. Non potremo andare tutti a vivere in Tibet. Scienza e medicina si apprestano però a portare l’Everest verso valle, affinché chiunque possa mutare un essere dell’Himalaya.

TIBETANS ADAPTED TO HIGH ALTITUDE IN LESS THAN 3,000 YEARS

By Robert Sanders, Media Relations | 01 July 2010

University of California – Berkeley (2010, July 2). Tibetan adaptation to high altitude occurred in less than 3,000 years. ScienceDaily. Retrieved July 25, 2010, from http://www.sciencedaily.com­ /releases/2010/07/100701145519.htm

BERKELEY — A comparison of the genomes of 50 Tibetans and 40 Han Chinese shows that ethnic Tibetans split off from the Han less than 3,000 years ago and since then rapidly evolved a unique ability to thrive at high altitudes and low oxygen levels.

The genome-wide comparison, performed by evolutionary biologists at the University of California, Berkeley, uncovered more than 30 genes with DNA mutations that have become more prevalent in Tibetans than Han Chinese, nearly half of which are related to how the body uses oxygen. One mutation in particular spread from fewer than 10 percent of the Han Chinese to nearly 90 percent of all Tibetans.

A Chinese researcher collects a blood sample from an ethnic Tibetan man participating in the DNA study. (Beijing Genomics Institute photo)

This is the fastest genetic change ever observed in humans,” said Rasmus Nielsen, UC Berkeley professor of integrative biology, who led the statistical analysis. “For such a very strong change, a lot of people would have had to die simply due to the fact that they had the wrong version of a gene.”

The widespread mutation in Tibetans is near a gene called EPAS1, a so-called “super athlete gene” identified several years ago and named because some variants of the gene are associated with improved athletic performance, Nielsen said. The gene codes for a protein involved in sensing oxygen levels and perhaps balancing aerobic and anaerobic metabolism.

The new findings could steer scientists to till-now unknown genes that play a role in how the body deals with decreased oxygen, and perhaps explain some diseases, including schizophrenia and epilepsy, associated with oxygen deprivation in the womb, he said.

Nielsen and his colleagues in China and Europe report their findings in the July 2 issue of the journal Science.

A research first

Nielsen, a computational evolutionary biologist, mines genomic information to discover genetic changes driven by natural selection as humans and animals have adapted to new environments. Changes in the frequency of DNA mutations are one clue.

“You look for rapid evolution in genes because there must be something important about that gene forcing it to change so fast,” he said. “The new finding is really the first time evolutionary information alone has helped us pinpoint an important function of a gene in humans.”

Adaptation to low oxygen levels has allowed many peoples, from Andeans to Tibetans, to live at high altitude. When people from lower elevations move above about 13,000 feet, where oxygen levels are about 40 percent lower than at sea level, they typically tire easily, develop headaches, produce babies with lower birth weights and have a higher infant mortality rate. Tibetans have none of these problems, despite lower oxygen saturation in the blood and lower hemoglobin levels. Hemoglobin, which gives blood its red color, binds and transports oxygen to the body’s tissues.

Nielsen used genome data produced by the Beijing Genomics Institute (BGI) in Shenzhen, China’s flagship genome center, to tease out the genetic changes associated with these physiological changes.

“We’re looking for footprints of past selection to find something functional in our genome,” Nielsen said

Study methods

BGI researchers obtained DNA from 50 Tibetans living in the Tibet Autonomous Region of China and 40 Han Chinese from Beijing. The Tibetans lived in two villages located at elevations of 4,300 meters (14,100 feet) and 4,600 meters (15,100 feet). All reported at least three generations of ancestors had lived at the same site. After obtaining informed consent, the Chinese researchers took blood samples from the participants and measured oxygen saturation, red blood cell concentration and hemoglobin content in their blood.

Back in the lab, the BGI team isolated only the active genes, or exons, from each individual, then used next-generation sequencing technology to sequence these so-called exomes. This involved cutting the DNA into many short pieces, sequencing each about 18 times with state-of-the-art Illumina sequencing machines, and then using overlaps to help reassemble the complete genome of each person. That work was directed by Jun Wang of BGI and the University of Copenhagen in Denmark.

Nielsen and post-doctoral fellows John E. Pool, Emilia-Huerta Sanchez and Nicolas Vinckenbosch conducted the analysis at UC Berkeley, locating all point mutations, called single-nucleotide polymorphisms (SNPs), in the 90 genomes and then comparing Tibetan and Han separately to a control group of 100 Europeans (Danes).

The analysis revealed that the common ancestors of Tibetans and Han Chinese split into two populations about 2,750 years ago, with the larger group moving to the Tibetan plateau. That group eventually shrank, while the low-elevation Han population expanded dramatically. Today, the Han Chinese are the dominant ethnic group in mainland China. The Tibetan branch either merged with the people’s already occupying the Tibetan plateau, or replaced them.

“We can’t distinguish intermixing and replacement,” Nielsen said. “The Han Chinese and Tibetans are as different from one another as if the Han completely replaced the Tibetans about 3,000 years ago.”

The Tibetan and Han Chinese genomes are essentially identical in terms of the frequency of polymorphisms in the roughly 20,000 genes, though some 30 genes stood out because of dramatic differences between the Tibetans and the Han.

“We made a list of the genes that changed the most,” Nielsen said, “and what was fascinating was that, bing!, at the top of that list was a gene that had changed very strongly, and it was related to the response to oxygen.”

The SNP with the most dramatic change in frequency, from 9 percent in Han Chinese to 87 percent in Tibetans, was associated with lower red blood cell count and lower hemoglobin levels in Tibetans. That variation occurred near a gene called EPAS1, which earlier studies suggest is involved in regulating hemoglobin in the blood as a response to oxygen levels. The mutation may be in a transcription factor that regulates the activity of EPAS1.

Tibetans carrying only one allele with this mutation had about the same hemoglobin concentration as Han Chinese, but those with two mutated alleles had significantly lower hemoglobin concentration. However, they all have about the same oxygen concentration in the blood. For some reason, individuals with two copies of the mutation function well in high altitude with relatively low hemoglobin concentration in their blood. The mutation seems to provide an alternative inborn mechanism for dealing with the low oxygen levels, Nielsen said.

Other strongly selected variants were near the genes for the fetal and adult versions of the globin genes, which produce the structural proteins of hemoglobin.

Two other genes showing a dramatic shift in frequency have been linked to anemia, while several other genes have been linked to diseases, including schizophrenia and epilepsy, possibly caused by low oxygen levels in the womb.

A large team of researchers from BGI contributed to the study, some of whom are also associated with the Graduate University of the Chinese Academy of Sciences.

The research was funded by various Chinese, American and Danish organizations, including the U.S. National Institutes of Health and the National Science Foundation. The sequenced genomes were part of the international 1000 Genomes Project, which now aims to sequence 2,500 human genomes by the end of 2011.

http://berkeley.edu/news/media/releases/2010/07/01_tibetan_genome.shtml

Reference:

1. Xin Yi, Yu Liang, Emilia Huerta-Sanchez, Xin Jin, Zha Xi Ping Cuo, John E. Pool, Xun Xu, Hui Jiang, Nicolas Vinckenbosch, Thorfinn Sand Korneliussen, Hancheng Zheng, Tao Liu, Weiming He, Kui Li, Ruibang Luo, Xifang Nie, Honglong Wu, Meiru Zhao, Hongzhi Cao, Jing Zou, Ying Shan, Shuzheng Li, Qi Yang, Asan, Peixiang Ni, Geng Tian, Junming Xu, Xiao Liu, Tao Jiang, Renhua Wu, Guangyu Zhou, Meifang Tang, Junjie Qin, Tong Wang, Shuijian Feng, Guohong Li, Huasang, Jiangbai Luosang, Wei Wang, Fang Chen, Yading Wang, Xiaoguang Zheng, Zhuo Li, Zhuoma Bianba, Ge Yang, Xinping Wang, Shuhui Tang, Guoyi Gao, Yong Chen, Zhen Luo, Lamu Gusang, Zheng Cao, Qinghui Zhang, Weihan Ouyang, Xiaoli Ren, Huiqing Liang, Huisong Zheng, Yebo Huang, Jingxiang Li, Lars Bolund, Karsten Kristiansen, Yingrui Li, Yong Zhang, Xiuqing Zhang, Ruiqiang Li, Songgang Li, Huanming Yang, Rasmus Nielsen, Jun Wang, and Jian Wang. Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude. Science, 2 July 2010: Vol. 329. no. 5987, pp. 75 – 78 DOI: 10.1126/science.1190371