Complete Inactivation of Sebum-Producing Genes Parallels the Loss of Sebaceous Glands in Cetacea

Abstract

Genomes are dynamic biological units, with processes of gene duplication and loss triggering evolutionary novelty. The mammalian skin provides a remarkable case study on the occurrence of adaptive morphological innovations. Skin sebaceous glands (SGs), for instance, emerged in the ancestor of mammals serving pivotal roles, such as lubrication, waterproofing, immunity, and thermoregulation, through the secretion of sebum, a complex mixture of various neutral lipids such as triacylglycerol, free fatty acids, wax esters, cholesterol, and squalene. Remarkably, SGs are absent in a few mammalian lineages, including the iconic Cetacea. We investigated the evolution of the key molecular components responsible for skin sebum production: Dgat2l6, Awat1, Awat2, Elovl3, Mogat3, and Fabp9. We show that all analyzed genes have been rendered nonfunctional in Cetacea species (toothed and baleen whales). Transcriptomic analysis, including a novel skin transcriptome from blue whale, supports gene inactivation. The conserved mutational pattern found in most analyzed genes, indicates that pseudogenization events took place prior to the diversification of modern Cetacea lineages. Genome and skin transcriptome analysis of the common hippopotamus highlighted the convergent loss of a subset of sebum-producing genes, notably Awat1 and Mogat3. Partial loss profiles were also detected in non-Cetacea aquatic mammals, such as the Florida manatee, and in terrestrial mammals displaying specialized skin phenotypes such as the African elephant, white rhinoceros and pig. Our findings reveal a unique landscape of "gene vestiges" in the Cetacea sebum-producing compartment, with limited gene loss observed in other mammalian lineages: suggestive of specific adaptations or specializations of skin lipids.

Keywords: comparative genomics; gene loss; marine mammals; skin lipids.

Fig. 1.

Sebum-producing pathways and phylogenetic distribution of SGs in mammals. (A) Schematic depiction of the HF, SG, and sebum lipid production. (B) Taxonomic distribution of SG degeneration: lineages suggested to lack SGs are highlighted in red, lineages with conflicting reports on the presence of SGs are highlighted in blue.

Fig. 2.

Gene annotation and transcription analysis of sebum-producing genes in Cetacea. Each group of three circles represents a single exon, numbers in the circles indicate number of bases inserted or deleted, whereas nucleotides indicate acceptor or donor splice site mutations. (A) Dgat2l6 and Mogat3; (B) Awat1 and Awat2; (C) Elovl3; (D) Fabp9; and (E) transcriptional analysis of the selected genes in Balaenoptera musculus and Tursiops truncatus skin. Conserved mutations across species are labeled with an arrowhead. Phylogenetic trees were calculated in www.timetree.org ; last accessed March 28, 2019 using species list; values at nodes indicate estimated time of divergence in million years ago.

Fig. 3.

Analysis of coding status of sebum-producing genes in other mammals. (A, B) Gene annotation and transcriptional analysis in Hippopotamus amphibius; (C) gene annotation in Trichechus manatus latirostris; (D) gene annotation in Sus scrofa; (E) gene annotation in Loxodonta africana; and (F) gene annotation in Ceratotherium simum simum. Each group of three circles represents a single exon, numbers in the circles indicate number of bases inserted or deleted, whereas nucleotides indicate acceptor or donor splice site mutations.

Fig. 4.

Schematic representation of ancestral and convergent gene loss events of sebum-producing genes in the analyzed species. Critical/representative ORF-disrupting mutations are indicated. Regarding the Cetacea clade, highlighted mutations are conserved between Odontoceti and Mysticeti.