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Genomic structural variation is associated with hypoxia adaptation in high-altitude zokors

Nature Ecology & Evolution volume 8, pages 339–351 (2024)Cite this article

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Abstract

Zokors, an Asiatic group of subterranean rodents, originated in lowlands and colonized high-elevational zones following the uplift of the Qinghai–Tibet plateau about 3.6 million years ago. Zokors live at high elevation in subterranean burrows and experience hypobaric hypoxia, including both hypoxia (low oxygen concentration) and hypercapnia (elevated partial pressure of CO2). Here we report a genomic analysis of six zokor species (genus Eospalax) with different elevational ranges to identify structural variants (deletions and inversions) that may have contributed to high-elevation adaptation. Based on an assembly of a chromosome-level genome of the high-elevation species, Eospalax baileyi, we identified 18 large inversions that distinguished this species from congeners native to lower elevations. Small-scale structural variants in the introns of EGLN1, HIF1A, HSF1 and SFTPD of E. baileyi were associated with the upregulated expression of those genes. A rearrangement on chromosome 1 was associated with altered chromatin accessibility, leading to modified gene expression profiles of key genes involved in the physiological response to hypoxia. Multigene families that underwent copy-number expansions in E. baileyi were enriched for autophagy, HIF1 signalling and immune response. E. baileyi show a significantly larger lung mass than those of other Eospalax species. These findings highlight the key role of structural variants underlying hypoxia adaptation of high-elevation species in Eospalax.

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Fig. 1: Phylogenetic relationships, elevational distributions and patterns of phenotypic variation among Eospalax.
Fig. 2: Identification and distribution of large inversions (>1 Mb) and SVs (<1 Mb, INS, DEL, INV, TRA and DUP).
Fig. 3: Intronic SVs upregulated gene expression and facilitated hypoxia adaptation.
Fig. 4: Possible functional effects of large inversions (>1 Mb) and rearrangement.

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Data availability

DNA sequence data are available from NCBI SRA under BioProject accession PRJNA947478. The RNA sequence data reported in this paper are deposited in the Genome Sequence Archive in National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (PRJCA019941: CRA012698), which are publicly accessible at https://ngdc.cncb.ac.cn/gsa. The chromosomal level genome assembly and annotation reported in this paper are deposited in the China National GeneBank DataBase (https://db.cngb.org) with BioProject ID CNP0005002 and uploaded in figshare (https://doi.org/10.6084/m9.figshare.24085119). Source data are provided with this paper.

Code availability

The code used for the analyses is available from GitHub (https://github.com/anxuan-web/Structural-variants-in-Eospalax).

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Acknowledgements

We thank members of the Hoekstra laboratory for commenting on the paper. We thank X. Luo from the Kunming Institute of Zoology. This project was supported by the National Natural Science Foundation of China (grants 32271691 and 32071487 to K.L.), the National Key Research and Development Programs (grant 2021YFD1200901 to K.L.), the Fundamental Research Funds for Central Universities, LZU (grants lzujbky-2021-ey17 to K.L. and lzujbky-2022-it01 to Y.W.), the Science Fund for Creative Research Groups of Gansu Province (grant 21JR7RA533 to K.L.), Lanzhou University’s ‘Double First-Class’ Guided Project-Team Building Funding-Research Startup Fee for K. Li, a grant from State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems (Lanzhou University) (grant SKLGAE-202001, -202009 and -202010 to K.L.) and the Key Basic Research Project of Qinghai Provincial Department of Science and Technology (grant 2022-ZJ-733 to Q.X.). We received support for computational work from the Big Data Computing Platform for Western Ecological Environment and Regional Development and Supercomputing Center of Lanzhou University.

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Author notes

  1. These authors contributed equally: Xuan An, Leyan Mao, Yinjia Wang, Qinqin Xu.

Authors and Affiliations

  1. State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China

    Xuan An, Leyan Mao, Yinjia Wang, Xi Liu, Shangzhe Zhang, Bowen Li, Zhuoran Kuang, Na Wan, Xiaolong Liang, Qijiao Duan, Zhilong Feng, Xiaojie Yang, Sanyuan Liu, Jianquan Liu & Kexin Li

  2. Department of Medical Oncology, Qinghai Provincial People’s Hospital, Xining, China

    Qinqin Xu

  3. College of Life Sciences and Technology, Mudanjiang Normal University, Mudanjiang, China

    Zhenglei Qiao & Fang Li

  4. Institute of Evolution, University of Haifa, Haifa, Israel

    Eviatar Nevo

  5. School of Biological Sciences, University of Nebraska, Lincoln, NE, USA

    Jay F. Storz

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Contributions

X.A., X. Liu., Z.Q. and N.W. collected the samples. X.A., L.M., Y.W., Q.X., X. Liu., S.Z., Z.Q., B.L., F.L., Z.K., N.W., X. Liang., Q.D., Z.F., X.Y. and S.L. performed the data analyses. X.A., E.N., J.L., J.F.S. and K.L. wrote the paper. K.L. designed this study. All authors read, revised and approved the final paper.

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Correspondence to Jianquan Liu, Jay F. Storz or Kexin Li.

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Extended data

Extended Data Fig. 1 Genome assembly and annotation of E. baileyi (plateau zokor v3.0).

(a) Full karyotype of a female E. baileyi. (b) Example G-banded chromosome spread with 62 counted chromosomes. (c-d) Genome assembly and annotated genes completeness were evaluated by BUSCO. (e) Heatmap of the E. baileyi chromosome-level genome interaction matrix. (f) MCMCTree was constructed with nine rodent species. Arrows indicate species living underground.

Extended Data Fig. 2 SV (<1 Mb) dataset summary (LR-SV and SR-SV).

(a) The quantity and kinds of SVs were displayed as stacked bar graphs based on short-read sequencing. Bars and dots of various hues denote the type of variation and each species, respectively. (b) Diagram of length distribution for various types of SVs shorter than 10,000 bp. (c) The length distribution of INDELs generated from different sequencing platforms. (d) Annotation of repeat sequences of the LR-SV. (e) The genomic coordinates of LR-SV.

Extended Data Fig. 3 SV (>1 Mb) dataset summary (LR-SV and SR-SV).

The dark blue line at the top of each panel represents the genome of E. fontanierii, while the dark orange line represents the genome of E. baileyi. The orange block in each panel denotes the inversion position. Each panel (a-m) was one of 32 pseudochromosomes.

Extended Data Fig. 4 SV (<1 Mb) dataset summary (LR-SV and SR-SV).

(a) Contigs from de novo genome assemblies (‘query’, y-axis) were aligned to the E. fontanierii reference genome (‘reference’, x-axis). Contigs (blue) and those identifying inversion breakpoints (red) are shown. Predicted inversion boundaries are highlighted (purple box), showing predicted inversion (arrow) above. (b) The Synteny comparison between the genomes of E. fontanierii and E. baileyi showed that part of the contig of E. baileyi was reversed and the other contig was positive.

Extended Data Fig. 5 SV (<1 Mb) dataset summary (LR-SV and SR-SV).

The fixed-SV related differentially expressed genes in the lung (a) liver (b), and heart (c) of E. baileyi. Negative binomial distribution model and generalized linear model were used to identify DEGs, and we multiple-corrected using Benjamini-Hochberg model (padj ≤ 0.05). (d) GO enrichment terms of fixed SV-related genes typically in E. baileyi. (e) Enrichment of genes associated with E. baileyi-specific SVs, E. smithi-specific SVs and the shared SVs between the two species (Hypergeometric test, p < 0.05; Benjamini-Hochberg model, q < 0.05).

Extended Data Fig. 6 SV-related genes were involved in hypoxia adaptation.

(a) The frequency of inversion (2,212 bp) in HIF1A in Eospalax. (b) The nucleotide sequence and amino acid sequence of SFTPD in E. baileyi reveal a loss of one exon and 55 amino acids. De novo prediction of protein structure for E. fontanierii and E. baileyi. (c) A 1,989 bp intronic deletion in UVRAG was validated by coverage of reads. (d) Map and coverage of reads of deletion in XRCC4.

Extended Data Fig. 7 Three-dimensional genomics and divergence time of the rearrangement on chromosome 1.

(a) Compartment A/B, gene density and GC content of chromosome 1 in E. fontanierii and E. baileyi. A/B compartments are determined by the PC1 value, the red bar indicates compartment A and the blue bar indicates compartment B. (b) Topologically associating domains (TAD) insulation score of chromosome 1 in E. fontanierii and E. baileyi. (c) Venn diagram showing species-specific and shared TADs in SV regions and background regions. (d) Two E. baileyi-specific TADs associated hypoxia adaptation. (e) The number of shared/species-specific significant interaction regions between E. fontanierii and E. baileyi in the rearrangement region.

Extended Data Fig. 8 Three-dimensional genomics and divergence time of the rearrangement on chromosome 1.

(a) The overlap of inversions (< 1 Mb) with different types of repeats. Different colors represent different repeat sequence types. The X-axis of each figure represents the percentage of the length of the inverted sequence overlapped with different types of repeats as a percentage of the length of the inverted sequence. The Y-axis represents the number of inversions. (b) The type and proportion of repeated sequences in inversion (< 1 Mb). The x-coordinate represents the ratio of LINE1 to each inversion sequence. (c) Examples of inversions with inverted repeats at both breakpoints on chromosomes 1, 2, 3, 6, 8, 9, 11, 17, 21, 23, 24, 27 and 31. Dotplot depicts the inverted repeats near each inversion breakpoint. Locations of breakpoints are denoted by orange arrows, and only alignments longer than 100 bp and within 1 Mb of the breakpoints are displayed. Inverted repeats located within 1 Mb of both breakpoints are depicted (red) and highlighted (purple box). (d) The pie shows the number of inversions (> 1 Mb) that have at least one pair of inverted repeats at both inversion breakpoints. The histogram shows the length of inverted repeats near breakpoints. (e) Segmental duplication (SD) percentage of randomly selected 1 Mb regions across the genome and inversion (>1 Mb) regions.

Extended Data Table. 1 Genome assembly data
Full size table
Extended Data Table. 2 Dual-luciferase assay of EGLN1, HIF1A, and HSF1
Full size table

Supplementary information

Supplementary Information

Supplementary Figs. 1–3 and Tables 1–14.

Reporting Summary

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Source data

Source Data Extended Data Table 1

FDR value of genefamily analysis (cafe) in E. baileyi.

Source Data Extended Data Table 2

Statistics of RNA-seq data using mashr.

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An, X., Mao, L., Wang, Y. et al. Genomic structural variation is associated with hypoxia adaptation in high-altitude zokors. Nat Ecol Evol 8, 339–351 (2024). https://doi.org/10.1038/s41559-023-02275-7

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