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Andean Genomes Provide Genetic Clues to Mountain Sickness

NEW YORK (GenomeWeb News) – A whole-genome sequencing study of 20 Andean highlanders is highlighting a pair of genes whose expression levels appear to influence chronic mountain sickness risk.

Researchers based at centers in the US and Peru did genome sequencing on 10 Andean individuals afflicted with chronic mountain sickness related to low oxygen levels found in their high altitude environments, and 10 individuals from the same location who do not have the condition. As they reported online today in the American Journal of Human Genetics, their analysis of the genomes unearthed almost a dozen loci showing signs of positive selection during adaptation to high altitude life in the Andes.

The team homed in on two genes in these regions that were more highly expressed in cells from Andean highlanders with chronic mountain sickness, suggesting adaptations that curb expression of the genes may be beneficial in high altitude, low oxygen environments. Indeed, follow-up experiments indicated that dialing down levels of orthologous genes in Drosophila boosts fruit fly survival in low oxygen conditions.

Together, such results support ties between the genes and mountain sickness symptoms, University of California at San Diego researcher Gabriel Haddad, the study's co-senior author, said in a statement. "[G]enes that were identified by the whole-genome scan were actually linked causally to sickness in low oxygen environments."

Past studies suggest that different high altitude populations have undergone distinct and varied physiological adaptions to life in high elevation and low oxygen environments, he and his co-authors noted. That, in turn, makes it likely that a range of genetic tweaks can also contribute to or interfere with successful adaptation to such hypoxic conditions.

To look at the genetic side of the equation in more detail, the researchers decided to focus on a population living in Cerro de Pasco in Peru's central highlands, where some members of local populations have not fully adapted to their high altitude surroundings.

In particular, some Andean highlanders are prone to chronic mountain sickness, sometimes called Monge disease, that is less common or absent in other high altitude populations, they noted.

"[Chronic mountain sickness] is common in Andeans, found occasionally in Tibetans, and absent from the Ethiopian population living on the East African high altitude plateau," Haddad and the co-authors said. "Therefore, the Andean high altitude population provides us with the opportunity to dissect the genetic mechanisms underlying high altitude adaptation by comparing genetic variation between individuals with [chronic mountain sickness] and adapted subjects without [chronic mountain sickness]."

Using the Illumina HiSeq 2000, the researchers sequenced the genomes of 10 men from Cerro de Pasco who had been diagnosed with chronic mountain sickness and 10 who had not. The sequence data generated covered each individual's genome to a mean depth of between 20-fold and 40-fold.

By comparing sequences from the 20 Andean individuals to one another and to the human reference genome, the team unearthed variant profiles that helped in the hunt for parts of the genome under selection in altitude-adapted Andeans.

As a stand-in for lowlander population controls, the team used 1000 Genomes Project data representing individuals from a Mexican population from Los Angeles, who clustered genetically in the same vicinity as the Andeans tested in the study.

The team's analysis uncovered 11 regions of the genome harboring significantly different SNP frequencies in the altitude-adapted Andeans compared to their chronic mountain sickness-afflicted counterparts, suggesting these sites had been subject to positive selection during altitude adaptation.

Amongst genes found in these regions, two stood out to the study's authors: the chromosome 12 gene ANP32D, which has previously been implicated in cancer risk, and SENP1, a blood-related gene located in another stretch of chromosome 12.

The haplotypes comprising the positively selected SNPs in and around these genes appear to be present in other populations, researchers noted, but they're found at far higher frequencies in individuals from the Andean highlands who don't have chronic mountain sickness — a pattern that they verified by Sanger sequencing.

To explore the functional consequences of these variants, the team compared ANP32D and SENP1 expression patterns in fibroblast cell lines generated from Andean highlanders with and without chronic mountain sickness. There, both genes showed enhanced expression in the cells from those who had chronic mountain sickness, hinting that it may be possible to rein in some features of altitude sickness by staunching their expression.

Consistent with that notion, researchers saw a boost in fruit fly survival in low oxygen conditions when they knocked down Drosophila orthologs of the ANP32D and SENP1 genes by RNA interference, fueling speculation that one or both of the genes might serve as useful targets for treating mountain sickness or other conditions linked to lower-than-usual oxygen availability.

"With further study, the two genes we identified and validated may become potential drug targets for treating conditions related to low oxygen levels, such as strokes and heart attacks," Haddad said in a statement. "In addition, they may also be considered as targets for a potential drug treatment for chronic mountain sickness."

He and his team are reportedly ramping up to sequence samples from more individuals with chronic mountain sickness, with an eye to coming up with additional genetic factors in the condition and markers for it.