• Weijian Guo1,2 na1,
• Yiting Chen1 na1,
• Huizhong Fan3,
• Xin Huang3,
• Xi Chen4,
• Yousheng Xiao4,
• Chaoming Zhang4,
• Wenliang Zhou1,2 &
• …
• Fuwen Wei1,3,5

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract

Background

Deep-diving cetaceans tolerate acute hypoxia better than their terrestrial ancestors and shallow-diving counterparts. However, our poor understanding of how genetic factors, cellular functions, and physiological characteristics combine to drive hypoxia adaptation in deep-diving cetaceans remains a critical gap.

Results

Here, we studied the genetic basis for this ability by creating a de novo genome assembly for the pygmy sperm whale (Kogia breviceps) and comparatively analyzing genomes from 12 cetacean species, including 2 other deep-diving cetaceans. We also sequenced and compared single-nucleus RNA data from the muscle and heart of the pygmy sperm whale and its terrestrial relative Bos taurus. We found that genetic and cellular changes in the HIF-1 pathway, electron transport chain, glucose and fatty acid catabolism, and heart rate may contribute to hypoxia tolerance in deep-diving cetaceans. Key adaptations include rapid evolution of glycolysis-related genes (PYGM and ENO3), differential expression of HIF-1 pathway genes like ARNT, and accelerated conserved noncoding elements in genes such as ATP5F1E (ATP synthase) and DMD (dystrophin). We found an increase in myocytes and type II cardiomyocytes in the pygmy sperm whale’s muscle and heart tissues, which may support energy metabolism and homeostasis during deep dives.

Conclusions

These findings suggest deep-diving cetaceans have unique genetic and cellular adaptations to cope with hypoxia, offering insights into how mammals handle low oxygen levels at the cellular level.

Data availability

The raw sequencing data for the PacBio HiFi reads and Hi-C linked reads, along with the genome assembly of the pygmy sperm whale, are available in the National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation as accession (GSA: CRA017691 [102] and GWH: GWHEUUE00000000.1 [103]). The single-nucleus RNA-seq data (the muscle and heart from pygmy sperm whale and cattle) have been deposited in the National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation under the accession code (GSA: CRA017691 [102]).

Abbreviations

ACNEG:

Accelerated conserved noncoding element-related gene

ATP:

Adenosine triphosphate

BUSCO:

Benchmarking universal single-copy ortholog

CNE:

Conserved noncoding element

DEG:

Differentially expressed gene

DNA:

Deoxyribonucleic acid

ETC:

Electron transport chain

GO:

Gene Ontology

Hi-C:

Chromosome conformation capture

HIF:

Hypoxia-inducible factor

HIF-1:

Hypoxia-inducible factor-1

HiFi:

High fidelity

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LINE:

Long interspersed nuclear elements

LRT:

Likelihood ratio test

NCBI:

National Center for Biotechnology Information

NR:

Nonredundant protein sequence database

PCA:

Principal component analysis

PDK:

Pyruvate dehydrogenase kinases isoenzyme

PSG:

Positively selected gene

PSS:

Positively selected site

REG:

Rapidly evolving gene

RIN:

Ribonucleic acid integrity numbers

RNA:

Ribonucleic acid

RNA-seq:

Ribonucleic acid sequencing

snRNA:

Single-nucleus ribonucleic acid

tSNE:

T-distributed stochastic neighbor embedding

WEC:

Whale-enriched cell

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