How can Tibetans survive high altitudes that leave lowlanders gasping? The answer is found in broken genes. A new paper on the Tibetan genome vindicates what Michael Behe said in Darwin Devolves: evolution breaks things, but sometimes, like in the case of polar bears, the result can allow organisms to thrive in specific environments. Yes, this follows on the heels of last week’s Behe vindication; see here.
A team of 16 scientists, writing in PNAS, sought to understand the genetic basis for Tibetan high-altitude adaptation in more detail. Tibetans and Nepalese, many of whom serve as guides for lowlanders wanting to conquer Mount Everest, routinely carry heavy burdens at altitudes above 14,000 feet, the average elevation on the Tibetan plateau. In its entry on Sherpa people, Wikipedia notes,
Many Sherpa are highly regarded as elite mountaineers and experts in their local area. They were immeasurably valuable to early explorers of the Himalayan region, serving as guides at the extreme altitudes of the peaks and passes in the region, particularly for expeditions to climb Mount Everest. Today, the term is often used by foreigners to refer to almost any guide or climbing supporter hired for mountaineering expeditions in the Himalayas, regardless of their ethnicity. Because of this usage, the term has become a slang byword for a guide or mentor in other situations. Sherpas are renowned in the international climbing and mountaineering community for their hardiness, expertise, and experience at very high altitudes. [Emphasis added.]
This sounds like a study in the evolution of higher fitness. Wikipedia goes on to say,
Released in 2010 by U.C. Berkeley, a study identified more than 30 genetic factors that make Tibetans’ bodies well-suited for high-altitudes, including EPAS1, referred to as the “super-athlete gene” which regulates the body’s production of hemoglobin, allowing for greater efficiency in the use of oxygen.
Association and Causation
The news from UC Berkeley about the paper, however, does not specify any random mutation that “causes” super-athletes to be born in the competition for survival, but rather that the “super-athlete gene” was “named because some variants of the gene are associated with improved athletic performance.” Association is not causation. Those variants already existed in the human genome. Wikipedia’s misleading statement that “30 genetic factors that make Tibetans’ bodies well-suited” needs to be qualified:
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.
Nowhere in the two papers published in this 2010 study did the authors establish that beneficial mutation(s) and positive natural selection actually conferred the high-altitude adaptation.1,2 Their measures of “positive selection” are inferences relying on the assumption, “if a gene persists, it must be under positive selection” — whether or not it shows any benefit to the organism. Even if an adaptation is demonstrated, the variations show association, not causation. For instance:
It is plausible that the diminished Hb levels found in Tibetans offset complications associated with sustained high Hb levels (for instance, hyperviscosity) seen in non-Tibetans exposed to high-altitude conditions. Alternatively, decreased Hb levels could be a side effect of other phenotypes that are the actual targets of natural selection.
The second paper2 touts the EPAS1 gene as the strongest case for positive selection, but they qualify that claim with, “Selection may have acted directly on this variant, or another linked noncoding variant, to influence the regulation of EPAS1.” Consider this nebulous conclusion:
EPAS1 may therefore represent the strongest instance of natural selection documented in a human population, and variation at this gene appears to have had important consequences for human survival and/or reproduction in the Tibetan region.
The authors write with escape clauses like this, denying knowledge of “actual targets” of natural selection, hoping that “further research” will confirm them someday.
Does this research actually help Darwinism? All human beings are interfertile, members of a single species! There is no origin of species going on. We already know that some people are born with better athletic ability than others. The 2010 study appears to speak of the sorting out of existing alleles among populations of people, some of which worked out well for those living at high altitudes. Moreover, this sorting occurred within the past 3,000 years. Odd, isn’t it, how human families tend to move together and marry within the group.
The Last Gasp
Positive selection for fitness, though, is not what the current paper in PNAS found.3 In “Tibetan PHD2, an allele with loss-of-function properties,” a team led by Daisheng Song found two broken genes that propped each other up.
Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, PHD2 and HIF2A. The product of the former induces the degradation of the product of the latter. Key issues regarding Tibetan PHD2 are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that Tibetan PHD2 is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the Tibetan Phd2 allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal.
How can two defective genes confer a benefit to Tibetans, protecting them from hypoxia? Picture two walls in a construction project that fall in such a way as to prop each other up, protecting workers underneath from rain. Another analogy might be a leak in a gas line that is compensated for by a slowdown in the gas supply line by an accidental shunt that diverts more of it elsewhere. That’s a bit like this situation.
We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude.
The two broken genes end up facilitating the intake of oxygen in the lungs. At elevations that have only 60 percent of the oxygen present at sea level, that is beneficial to someone with the mutations.
Remember the Polar Bear?
It’s a bit like the story of polar bear evolution in Michael Behe’s book, Darwin Devolves. Broken genes conferred on polar bears a better capacity to eat fat and tolerate cold, which has worked well for them in Arctic regions, where fatty seal meat is more abundant than berries that brown bears eat. Natural selection did not create these genes; mutations broke them. Sometimes things work out in certain environments, like Behe’s proverbial car that gets better gas mileage without the hood and rear seat when gas mileage is the most important concern at the time.
Nowhere do the authors argue for a gain-of-function genetic mutation. There is no mention of positive selection. In fact, the authors undermine earlier claims, saying that loss of function is the primary reason the Tibetans gained an advantage.
Previous studies examining Phd2 loss of function due to either point mutations in or genetic deletion of the Phd2 gene have consistently shown that Phd2 loss of function is associated with increases in either HVR or hypoxia-induced tidal volume, respiratory frequency, or minute ventilation, or a combination of these. These findings therefore support the notion that the Tibetan Phd2 allele is a loss-of-function allele, consistent with the biochemical studies demonstrating impaired interaction of Tibetan PHD2 with p23.
Another Loss-of-Function Mutation
The loss of function in PHD2 is hypomorphic; in other words, it makes the protein weaker but not completely inactive. Intriguingly, another loss-of-function mutation helps compensate for the first one by minimizing damage that would otherwise result from the first break.
We propose that the Tibetan PHD2 allele is a hypomorphic loss-of-function allele that leads to an augmented HVR, while the Tibetan HIF2A allele is a loss-of-function allele that provides protection against pulmonary hypertension and erythrocytosis (Fig. 5C). Lowlanders have a robust HVR [hypoxic ventilatory response], but after long-term acclimatization to high altitude, their HVR declines. Tibetans have an augmented HVR that approaches the ancestral response of lowlanders, which may allow them to maintain high oxygen delivery from the lungs. In contrast to Tibetans, Andeans exhibit a blunted HVR. Thus, this study provides evidence that Tibetans possess a distinct combination of PHD2 and HIF2A alleles that reconfigures the HIF pathway in a manner that facilitates adaptation to the chronic hypoxia of high altitude.
Mistakes just work out sometimes.
Tibetans display augmented hypoxic ventilatory response (HVR), resistance to pulmonary hypertension, and relatively low hemoglobin (Hb) levels. These are considered to be adaptive. For example, the resistance to pulmonary hypertension lessens the risk of right heart failure, while the relatively low Hb levels (which approach that of lowlanders) may decrease the risk of thrombotic events associated with blood hyperviscosity. The augmented HVR can facilitate the intake of oxygen into the lungs.
Although this worked out for Tibetans, one could argue that fully functioning genes are there for a purpose, perhaps to warn humans not to migrate up so high on mountains, which is not their ideal habitat. Normally, human physiology responds by making them gasp for air and get sick.
Thus, the two genes conventionally used to illustrate adaptation by natural selection in Tibetans, PHD2 and HIF2A, are both loss-of-function genes. This reinforces Behe’s thesis that Darwin “devolves” by breaking existing genetic information. Darwin needs his magic wand of natural selection to create novelty and bring innovation to the world. He won’t get very far by breaking things. Sherpas might be able to help him get up Mount Everest, but not Mount Improbable.
- Xing Ji et al., “Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude,” Science 02 Jul 2010: Vol. 329, Issue 5987, pp. 75-78. DOI: 10.1126/science.1190371.
- Simonson et al., “Genetic Evidence for High-Altitude Adaptation in Tibet,” Science 02 Jul 2010: Vol. 329, Issue 5987, pp. 72-75. DOI: 10.1126/science.1189406.
- Song et al., “Tibetan PHD2, an allele with loss-of-function properties,” Proceedings of the National Academy of Sciences, May 15, 2020. DOI: 10.1073/pnas.1920546117.
Photo: Climbers on Mount Everest, by Lloyd Smith, via Wikimedia Commons.