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. 2021 Jul 15;9(2):nwab125.
doi: 10.1093/nsr/nwab125. eCollection 2022 Feb.

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

Agata M Rudolf  1 , Qi Wu  2 , Li Li  1 , Jun Wang  3 , Yi Huang  1 , Jacques Togo  1 , Christopher Liechti  4 , Min Li  1 , Chaoqun Niu  1 , Yonggang Nie  2 , Fuwen Wei  2 , John R Speakman  1
Affiliations

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

Agata M Rudolf et al. Natl Sci Rev. .

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 hypothesized 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 effect 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 and profound adaptive changes in the metabolic phenotype, with great importance in ecology and evolution.

Keywords: DUOX2; DUOX2 mutation; giant panda; metabolic rate; mice and microbiota; thyroid hormones.

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Figures

Figure 1.
Figure 1.
(A) Body mass between 4 and 10 weeks old (g/week), (B) body-mass-adjusted daily energy expenditure (kJ/day) and (C) daily food intake (kJ/day) in respirometry chamber, and (D) accumulated daily distance moved (m/day) in mutant homozygous (Duox2A625T/A625T), heterozygous (Duox2+/A625T) and wild-type homozygous (Duox2+/+) mice carrying a giant-panda-specific mutation in the Duox2 gene; LSM with SE.
Figure 2.
Figure 2.
(A) Body-mass-adjusted liver, (B) kidneys and (C) brain mass, and (D) levels of T3-triiodothyronine and (E) T4-thyroxine (nmol/L) in mutant homozygous (Duox2A625T/A625T), heterozygous (Duox2+/A625T) and wild-type homozygous (Duox2+/+) mice carrying a giant-panda-specific mutation in the Duox2 gene.
Figure 3.
Figure 3.
PCA analysis of fecal microbiota in mutant homozygous (Duox2A625T/A625T), heterozygous (Duox2+/A625T) and wild-type homozygous (Duox2+/+) mice carrying a giant-panda-specific mutation in the Duox2 gene at the age of 10–11 weeks old: (A) PC1 and PC2 with microbiota genus; (B) PC1 and PC2 with genotype.
Figure 4.
Figure 4.
Reversal of the impact of the Duox2 mutation by supplementation with T4. (A) Body mass between 4 and 10 weeks old (g/week), (B) body-mass-adjusted daily energy expenditure (kJ/day) and (C) daily food intake (kJ/day) in respirometry chamber, (D) accumulated daily distance moved (m/day), (E) body-mass-adjusted kidney mass and (F) levels of T3-triiodothyronine and (G) T4-thyroxine (nmol/L) in mutant homozygous (Duox2A625T/A625T) mice carrying a giant-panda-specific mutation in the Duox2 gene; exposed (T4) and non-exposed (Co) to 0.5 µg/mL of T4 supplementation; LSM with SE.
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