Selection in Andean genomes appears to be pushing haemoglobin down, not up

The textbook version of high-altitude adaptation has two contrasting cases. Andean highlanders respond to chronic hypoxia with elevated haemoglobin concentration, a trait that closely resembles the acclimatisation response seen in lowlanders who travel to altitude [s1]. Tibetan highlanders do not: their haemoglobin sits near sea-level normal values, and their adaptation runs through ventilation and circulation instead [s1][s2].

A genome-wide analysis of Peruvian Andeans published in Genome Biology and Evolution complicates that contrast in a specific and unexpected direction. The alleles it finds under recent positive selection are associated with lower haemoglobin, not higher [s1].

What was analysed

The study used genome-wide array data from Peruvian Andeans and identified two genomic regions containing three genes — PDE1B, PPP1R1A and RASGEF1B — that show evidence of recent positive selection and are associated with haemoglobin concentration [s1].

The direction of effect is the finding. Andean alleles within these regions are associated with lowered haemoglobin concentration, which the authors read as recent polygenic selection acting to reduce haemoglobin within this population [s1].

The greatest divergence of Andean allele frequencies from other global populations falls within the PDE1B/PPP1R1A region [s1]. To work out what selection might be doing there, the authors brought in whole-genome sequencing data along with publicly available expression and Hi-C data [s1]. They report a selective sweep favouring 11 PDE1B expression-decreasing alleles, positioned at the boundary of a topologically associating domain that spans several haemoglobin-linked genes [s1].

That last detail is the mechanistic hook. Topologically associating domains organise which regulatory elements can physically contact which genes. A sweep sitting at a domain boundary next to haemoglobin-linked genes is a plausible place for regulatory change to alter a haematological trait — but the study identifies the location and the association, not the causal chain.

Why this was an open question

Recent candidate-gene efforts to understand the role of natural selection in shaping Andean haemoglobin have produced conflicting results, leaving it unclear what role selection played in this hematopoietic response [s1]. That is the gap the paper sets out to fill, and it is worth noting what changed methodologically: a genome-wide scan does not require guessing in advance which genes matter, which is precisely the failure mode of the candidate-gene era.

The result is described by the authors as novel evidence that polygenic natural selection may be acting to lower Andean haemoglobin in a manner phenotypically convergent with Tibetan populations [s1]. Convergent, in this usage, means arriving at a similar phenotype by a different genetic route — not that Andeans and Tibetans share the adaptation.

Where it sits against the physiology

A review published in Experimental Physiology in September 2025 compared the oxygen transport cascade across three well-characterised high-altitude populations: Andeans (Aymara and Quechua), Tibetans and Sherpa, and Ethiopians (Amhara and Oromo) [s2].

The Andean profile it describes is not only haematological. Andeans show a blunted ventilatory response and marked remodelling of the pulmonary circulation, producing elevated pulmonary arterial pressure and mild but persistent right ventricular hypertrophy, alongside lifelong sympathetic overactivity — and strong haematological adaptation with increased haemoglobin concentration [s2]. Tibetans exhibit a robust hypoxic ventilatory response, efficient pulmonary diffusion capacity, preserved cardiac function with optimised muscle energetics, enhanced tissue blood flow and greater muscle capillary density [s2]. Ethiopian Amhara highlanders show ventilatory status close to sea-level values with limited pulmonary and cerebral vasoreactivity to hypoxia [s2].

Read alongside the genomic result, the picture is less tidy than the standard dichotomy suggests. The measured Andean phenotype is high haemoglobin [s2], while the alleles apparently favoured by recent selection push haemoglobin down [s1]. One reading is that elevated haemoglobin is largely a plastic acclimatisation response — the same one lowlanders show [s1] — and that selection has been working against its costs rather than for its benefits. The paper does not assert that interpretation, and nothing in either source measures the fitness consequences directly.

The limits

This is an association study on array data with a functional annotation layered on top. It establishes that specific regions carry signatures of recent positive selection and that alleles in those regions associate with haemoglobin concentration [s1]. It does not demonstrate that the PDE1B expression change causes the haemoglobin difference, and it does not establish what selective pressure was involved.

Sample composition also constrains generalisation. The data are from Peruvian Andeans [s1]; the Andean Altiplano spans several countries and multiple Indigenous populations, and the review notes that data on some highland groups remain limited [s2]. Selection signals are also sensitive to demographic history — population bottlenecks and admixture can mimic sweeps — and disentangling those is a standing difficulty in the field rather than a flaw unique to this paper.

What it would take to firm this up

The direct test is functional: showing that the PDE1B expression-decreasing alleles change haemoglobin regulation in the relevant cell types, rather than merely sitting near genes that do. The population test is replication in independent Andean samples, including groups outside Peru, with phenotype measured rather than imputed.

For now the contribution is narrower and still worth having. A trait long treated as the defining Andean adaptation now has genomic evidence that recent selection may be pulling in the opposite direction [s1] — which is the kind of result that makes a settled story worth re-examining.

Sources

• Genomic Evidence for Natural Selection Underlying High-Altitude Adaptive Hemoglobin Levels Among Peruvian Andeans, Genome Biology and Evolution, published online 5 July 2026 (August 2026 issue)
• Human adaptation to high-altitude: A contemporary comparison of the oxygen cascade in Andean, Tibetan and Ethiopian highlanders, Experimental Physiology, published online 24 September 2025