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. 2018 Nov 26;9(1):4991.
doi: 10.1038/s41467-018-07529-8.

Genetic Variation in PTPN1 Contributes to Metabolic Adaptation to High-Altitude Hypoxia in Tibetan Migratory Locusts

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Free PMC article

Genetic Variation in PTPN1 Contributes to Metabolic Adaptation to High-Altitude Hypoxia in Tibetan Migratory Locusts

Ding Ding et al. Nat Commun. .
Free PMC article

Abstract

Animal and human highlanders have evolved distinct traits to enhance tissue oxygen delivery and utilization. Unlike vertebrates, insects use their tracheal system for efficient oxygen delivery. However, the genetic basis of insect adaptation to high-altitude hypoxia remains unexplored. Here, we report a potential mechanism of metabolic adaptation of migratory locusts in the Tibetan Plateau, through whole-genome resequencing and functional investigation. A genome-wide scan revealed that the positively selected genes in Tibetan locusts are predominantly involved in carbon and energy metabolism. We observed a notable signal of natural selection in the gene PTPN1, which encodes PTP1B, an inhibitor of insulin signaling pathway. We show that a PTPN1 coding mutation regulates the metabolism of Tibetan locusts by mediating insulin signaling activity in response to hypoxia. Overall, our findings provide evidence for the high-altitude hypoxia adaptation of insects at the genomic level and explore a potential regulatory mechanism underlying the evolved metabolic homeostasis.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Phylogenetics of migratory locust based on whole-genome SNPs. a Geographic distribution of collected locust samples used for whole-genome re-sequencing. Tibetan and lowland locusts are shown at the top-right corner. b Unrooted neighbor-joining tree of migratory locust. c Principle component (PC) analysis. d Patterns of LD (linkage disequilibrium) decay across the genome in different geographic populations. r2, Pearson’s correlation coefficient. e Significant difference in population nucleotide diversity (π), as evaluated using the Wilcoxon rank-sum test (P < 2.2E−16). The boxplot represents mean value and variance. Maps were generated using DIVA-GIS (http://www.diva-gis.org/). Photographs of locusts were taken by D.D.
Fig. 2
Fig. 2
Selective sweep and expression analysis of hypoxia adaptation. a Distribution of Z-transformed fixation (ZFST) and heterozygosity (ZHP), calculated in 100-kb sliding windows. Genomic region (red point) located at top left of the dash lines (5% of empirical maximum FST and minimum HP) is identified as high-altitude adaptation-associated region in Tibetan locusts. Genes in this region are positively selected genes (PSGs). b KEGG enrichment of PSGs. c Number of differentially expressed genes (DEGs) in response to hypoxia induction through transcriptome sequencing. d KEGG enrichment of DEGs. Only KEGG terms with P < 0.05 are shown (Fisher’s Exact Test). e Expression pattern of DEGs involved in energy metabolism. Heat map signal indicates log2 fold-change values relative to the median expression level within the group. Yellow signal represents higher expression and blue represents lower expression relative to the median level within the group
Fig. 3
Fig. 3
Genetic differentiation of PTPN1. a Principle component analysis plot of geographically different locust populations based on the SNPs of the PTPN1 gene region. Lowland-S and Lowland-N represent South and North China lowland locust populations, respectively. b Multi-species alignment of amino acid sequence of PTP1B encoded by PTPN1. Oedaleus asiaticus and Schistocerca gregaria are two outgroup species closely related to Locusta migratoria (abbreviated as Lm). The missense mutation p.Asn349Ile (N349I) is located at the proline-rich (Pro-Rich) domain of PTP1B. c Mutation frequency of p.Asn349Ile in Tibetan and lowland locusts. The pie chart shows the proportion of p.Asn349Ile allele frequency in each population. Sample size: n ≥ 38. d Allele frequency of mutant loci in PTP1B. I/I, I/N, and N/N represent homozygous wild type, heterozygote mutant, and homozygous mutant for p.Asn349Ile, respectively. Maps were generated using DIVA-GIS (http://www.diva-gis.org/)
Fig. 4
Fig. 4
Effect of PTPN1 mutation on the insulin signaling pathway. a Illustration of the insulin signaling pathway, in which PTP1B is a negative regulator of the pathway through the dephosphorylation of insulin receptor at its tyrosine site. b PTP1B enzyme activity differing between Tibetan and lowland locusts in response to hypoxia induction. Significant differences are denoted by different letters (one-way ANOVA, P < 0.05) (n = 6 replicates). The values of the columns here and below are shown as mean ± standard error (s.e.m.). c The coding mutation altered PTP1B enzyme activity in vitro. The wild-type p.Asn349 (WT) and mutant-type p.Ile349 (Mut) PTP1B were overexpressed in S2 cells and induced by 1% hypoxia for 6 h. PTP1B production level was detected by western blot with anti-V5 tag antibody. *P < 0.05 by Student’s t -test. n = 3 replicates. Supplementary Fig. 15d shows the original image. d Western blot revealed decreased InR and AKT phosphorylation level after hypoxia induction in lowland locusts. P-InR and P-AKT represent phosphorylation of InR and AKT, respectively. The molecular weight markers are shown on the right side of the blot. Supplementary Figs. 15e–h show the original images. e PTP1B knockdown abolished PTP1B mRNA and protein level, repressed PTP1B activity, and increased InR and AKT phosphorylation level under hypoxic condition. The levels were examined 8 days after dsRNA injection. dsPTPN1 represents PTPN1 dsRNA knockdown. dsGFP was used as a negative control. PTP1B knockdown assay was performed with the lowland locusts. **P < 0.01, ***P < 0.001 by Student’s t test. n ≥ 3 replicates. Supplementary Figs. 15i–k show the original images
Fig. 5
Fig. 5
Effect of PTPN1 mutation on energy metabolism alteration. a Trehalose level and glucose concentration in hemolymph and thoracic muscle. The relative ratio is the ratio of the peak area of metabolic intermediate to the peak area of the internal standard (sucrose). (n ≥ 6 replicates, 3 locusts/replicate). b The levels of glycogen, acetyl-CoA, and NADH in the thoracic muscle and lactate in hemolymph. Values in a, b are the mean ± s.e.m. Significant differences are denoted by letters (one-way ANOVA, P < 0.05) (n = 4 replicates, 3 locusts/replicate). c PTP1B knockdown affected hypoxia-induced metabolic regulation by the insulin pathway (n = 5 replicates, three locusts/replicate). *P < 0.05, **P< 0.01 (Student’s t test). N.S. represents no significant difference (Student’s t test). The center line of the boxplots represents median value, the bounds of the box represent 75th and 25th percentile, and the whiskers represent maximum and minimum value

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