March 1, 2024

Harnessing human evolution to advance precision medicine

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People who visit the Andes Mountains in South America may feel the physical effects of lower oxygen levels at higher altitudes. However, some people who live there have evolved over hundreds of generations to tolerate these low-oxygen conditions. Credit: Elysia Cook McDermott

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People who visit the Andes Mountains in South America may feel the physical effects of lower oxygen levels at higher altitudes. However, some people who live there have evolved over hundreds of generations to tolerate these low-oxygen conditions. Credit: Elysia Cook McDermott

Humans are still evolving, and Tatum Simonson, Ph.D., founder and co-director of the Center for Low-Oxygen Physiological Genomics at the University of California School of Medicine, plans to use evolution to improve health care for everyone.

His latest research, published on February 9, 2024 in Science Advances, reveals that a genetic variant in some Andean people is associated with reduced red blood cell counts at high altitudes, allowing them to live safely high in the mountains in low-oxygen conditions. Simonson’s lab at UC San Diego is applying these findings to understand whether there may be a genetic component that explains why some people with sleep apnea or lung diseases such as chronic obstructive pulmonary disease (COPD) fare better than others. .

Simonson explained, “There are people with COPD who breathe a lot and maintain a higher oxygen saturation. Others with the same disease don’t breathe as much and their oxygen saturation is low. Researchers suspect there may be genetic differences underlying this variation, similar to the variation we found in pathways important for oxygen sensing and responses underlying natural selection at high altitudes.”

Our cells need oxygen to survive. When there is not enough of it in the environment, our body produces extra red blood cells, which carry oxygen throughout the body. Too many red blood cells, however, create a dangerous condition called excessive erythrocytosis (EE), which makes the blood viscous, which can cause stroke or heart failure.

His previous research has shown that many Tibetans who live in the mountains and are exposed to low-oxygen situations are born with innate mechanisms that protect them from poor outcomes at high altitudes, including the overproduction of red blood cells. Part of this is due to changes in regulatory EPAS1 gene, which reduces hemoglobin concentrations by regulating the pathway that responds to changes in oxygen levels. Advances in genetics have demonstrated that modern Tibetans received this genetic advantage from their ancestors who mixed with archaic humans living in Asia tens of thousands of years ago – a unique evolutionary history confined to this population.

For her latest research, Dr. EPAS1 region of the genome. She and her team focused on a gene mutation that is present in some people living in the Andes but absent in all other human populations. When they scanned entire Andean genomes, they found a pattern around this variant, suggesting that the genetic change, which alters just a single amino acid in the protein product, happened by chance relatively recently (9,000 to 13,000 years ago) and spread. very recently. rapidly through hundreds of generations within the Andean population.

Similar to the Tibetans, the EPAS1 The gene is associated with lower red blood cell counts in Andeans who have it. However, researchers were surprised to discover that the variant works in a completely different way than the Tibetan version of the gene; Instead of regulating its levels, the Andean variant alters the genetic makeup of the protein, altering the DNA of each cell.


UC San Diego researchers have found that a genetic variant in some Andean people is associated with reduced red blood cell counts at high altitudes, allowing them to live safely high in the mountains in low-oxygen conditions. The results could help scientists improve precision medicine for sleep apnea and lung diseases such as chronic obstructive pulmonary disease (COPD). Credit: Elysia Cook McDermott

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UC San Diego researchers have found that a genetic variant in some Andean people is associated with reduced red blood cell counts at high altitudes, allowing them to live safely high in the mountains in low-oxygen conditions. The results could help scientists improve precision medicine for sleep apnea and lung diseases such as chronic obstructive pulmonary disease (COPD). Credit: Elysia Cook McDermott

“Tibetans generally have a lower average hemoglobin concentration, and their physiology deals with low oxygen in a way that does not increase their red blood cells to excessively high levels. following this path, involving the same gene, but with a change in the protein code. Evolution worked in these two populations, on the same gene, but in different ways,” Simonson said.

This study exemplifies a current approach to research that links genetic targets of natural selection with complex disease genes – understanding, for example, how natural genetic variation contributes to adaptive and maladaptive responses to low oxygen, as this study reveals.

In Simonson’s lab, this means figuring out which downstream target genes are being activated in response to low oxygen, among other things. Said Simonson: “This paper shows one gene associated with a specific phenotype, but we think there are many different oxygen transport genes and components involved. It’s just one piece of that puzzle and could provide researchers with information relevant to other populations.”

Simonson and his team are working with Latino populations in San Diego and El Centro, California, as well as Tijuana and Ensenada, Mexico, taking them to high altitudes and recording their breathing while they are awake and asleep. They are cross-referencing their findings with publicly available databases to determine whether discoveries made in Andeans are also found in local Latinos, who may share some genetic variants with Andeans.

“In precision medicine, it is important to recognize variation in genetic background, specifically in historically understudied populations,” Simonson said. “If we can find some shared genetic factors in populations in an extreme environment, it could help us understand aspects of health and disease in that group and in groups more locally. In this way, this study aims to push research forward and towards a comprehensive approach and personalized medical approaches in clinics here in San Diego.”

More information:
Elijah S. Lawrence et al, EPAS1/HIF2A functional missense variant is associated with hematocrit in Andean highlanders, Science Advances (2024). DOI: 10.1126/sciadv.adj5661

Diary information:
Science Advances

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