A single nucleotide mutation in the dual-oxidase 2 (DUOX2) gene causes some of the panda's unique metabolic phenotypes

Abstract

The giant panda (Ailuropoda melanoleuca) is an iconic bear native to China, famous for eating almost exclusively bamboo. This unusual dietary behavior for a carnivore is enabled by several key adaptations including low physical activity, reduced organ sizes and hypothyroidism leading to lowered energy expenditure. These adaptive phenotypes have been hypothesised to arise from a panda-unique single-nucleotide mutation in the dual-oxidase 2 (DUOX2) gene, involved in thyroid hormone synthesis. To test this hypothesis we created genome edited mice carrying the same point mutation as the panda and investigated its effects on metabolic phenotype. Homozygous mice were 27% smaller than heterozygous and wild-type ones, had 13% lower body mass-adjusted food intake, 55% decreased physical activity, lower mass of kidneys (11%) and brain (5%), lower serum thyroxine (T4: 36%), decreased absolute (12%) and mass-adjusted (5%) daily energy expenditure, and altered gut microbiota. Supplementation with T4 reversed the effects of the mutation. This work uses a state of the art genome editing approach to demonstrate the link between a single-nucleotide mutation in a key endocrine related gene leading to profound adaptive changes in the metabolic phenotype, with great importance in ecology and evolution.

Fuwen Wei—Recipient of the 2021 Molecular Ecology Prize

“…This research is a paradigm of integrative biology research, systematically illustrating the adaptive mechanism of giant panda maintaining low energy expenditure. Furthermore, a collaborative study between his team and John Speakman's team confirmed the functional effects of DUOX2 pseudogenization by the creation and analysis of gene‐edited mice with the same mutation as that found in giant panda (Rudolf et al, 2021).…”

Molecular mechanisms of adaptive evolution in wild animals and plants

“…For example, the giant panda exhibits an exceptionally low daily energy expenditure, possibly controlled by a unique mutation in the DUOX2 gene that reduces thyroid hormone levels (Nie et al, 2015). This physiological change was confirmed through a mutated mouse model (Rudolf et al, 2022). This might be one of the reasons why the giant panda can survive on a specialized bamboo diet.…”

NOX family NADPH oxidases in mammals: Evolutionary conservation and isoform-defining sequences

“…Indeed, thyroid hormone levels are extremely low in this species compared to their mammalian norm. DUOX2 is essential for thyroid hormone synthesis and this specific hypothyroidism has been attributed to the presence of a unique mutation in the DUOX2 gene of the giant panda [ 24 , 25 ]. As DUOXA2 is essential for DUOX2 function [ 26 ]-and cannot be complemented by DUOXA1, our findings bring a so far unexplored possibility for the low thyroid hormone levels found in the giant panda.…”