Dynamic Evolution of the Cthrc1 Genes, a Newly Defined Collagen-Like Family

Area of Science:

• Evolutionary biology
• Genomics
• Biochemistry

Background:

• Collagen triple helix repeat containing protein 1 (Cthrc1) is a secreted glycoprotein involved in collagen deposition and linked to TGF-β/BMP and Wnt/PCP pathways.
• Cthrc1 is upregulated after arterial injury and highly expressed in various human cancers.
• Previous studies focused on Cthrc1 in vertebrates, leaving its broader evolutionary history unexplored.

Purpose of the Study:

• To investigate the phylogenetic and evolutionary trends of the metazoan Cthrc1 gene family.
• To identify Cthrc1 orthologs in non-vertebrate species and analyze gene duplication and loss events.
• To characterize the structural features of the Cthrc1 protein, particularly its C-terminal domain.

Main Methods:

• Phylogenetic analysis of Cthrc1 orthologs across diverse metazoan clades.
• Identification of Cthrc1 genes in cnidarian species (Nematostella vectensis, Clytia hemisphaerica).
• Sequence evolutionary rate analysis and structural modeling of the Cthrc1 C-terminal domain.

Main Results:

• Cthrc1 orthologs were identified in cnidarians, with multiple copies found in Nematostella vectensis and Clytia hemisphaerica.
• Clade-specific diversification of Cthrc1 occurred multiple times in cnidarians and other metazoan groups; gene loss was observed in arthropods and nematodes.
• Vertebrates possess a single conserved Cthrc1 gene, with a significantly reduced evolutionary rate in gnathostomes, coinciding with the conserved FZD6 gene.
• Structural modeling revealed the Cthrc1 C-terminal domain is similar to the C1q superfamily domain.

Conclusions:

• Cthrc1 represents a collagen-like gene family with a variable collagen triple helix domain and a conserved C-terminal domain structurally related to the C1q family.
• The evolutionary history of Cthrc1 is characterized by significant diversification and gene loss in various metazoan lineages.
• The reduced evolutionary rate in vertebrates may be linked to the co-evolution with its neighboring gene Frizzled 6 (FZD6).