The evolution of two transmissible leukaemias colonizing the coasts of Europe

Abstract

Transmissible cancers are malignant cell clones that spread among individuals through transfer of living cancer cells. Several such cancers, collectively known as bivalve transmissible neoplasia (BTN), are known to infect and cause leukaemia in marine bivalve molluscs. This is the case of BTN clones affecting the common cockle, Cerastoderma edule, which inhabits the Atlantic coasts of Europe and north-west Africa. To investigate the origin and evolution of contagious cancers in common cockles, we collected 6,854 C. edule specimens and diagnosed 390 cases of BTN. We then generated a reference genome for the species and assessed genomic variation in the genomes of 61 BTN tumours. Analysis of tumour-specific variants confirmed the existence of two cockle BTN lineages with independent clonal origins, and gene expression patterns supported their status as haemocyte-derived marine leukaemias. Examination of mitochondrial DNA sequences revealed several mitochondrial capture events in BTN, as well as co-infection of cockles by different tumour lineages. Mutational analyses identified two lineage-specific mutational signatures, one of which resembles a signature associated with DNA alkylation. Karyotypic and copy number analyses uncovered genomes marked by pervasive instability and polyploidy. Whole-genome duplication, amplification of oncogenes CCND3 and MDM2, and deletion of the DNA alkylation repair gene MGMT, are likely drivers of BTN evolution. Characterization of satellite DNA identified elements with vast expansions in the cockle germ line, yet absent from BTN tumours, suggesting ancient clonal origins. Our study illuminates the evolution of contagious cancers under the sea, and reveals long-term tolerance of extreme instability in neoplastic genomes.

Genetic markers associated with divergent selection against the parasite Marteilia cochillia in common cockle (Cerastoderma edule) using transcriptomics and population genomics data

“…Genomic resources of common cockle have recently increased in the framework of the COCKLES Interreg (EAPA_458/2016) and the Scuba Cancers (ERC-2016-STG) projects, which ensured a robust genetic baseline for that purpose. A population genomics approach using 2b-RADseq along with the chromosome-level genome assembly of the species (Bruzos et al, 2022) was applied to disentangle the demographic and environmental factors underlying the common cockle structure in the Northeast Atlantic (Vera et al, 2022). Furthermore, RNAseq was applied to identify differentially expressed genes (DEG) in the digestive gland across the different infection stages.…”

Transcriptome characterization of the common cockle (Cerastoderma edule) after exposure to aMarteilia cochilliaoutbreak

“…After filtering, 1991 million total reads were retained, 1609 million from the digestive gland and 381 million from whole meat. Among the 33 million pair-end filtered reads per sample, 28.8 million were consistently aligned to the chromosome-level assembled cockle genome (Bruzos et al, 2022) by retaining only the single best hit when more than one position matched.…”

“…Specifically, i) residual Illumina-specific adaptors were clipped from the reads; ii) the read removed, if a sliding window average Phred score over five bases was < 20; and iii) only reads where both pair-ends were longer than 50 bp post-filtering were retained. Filtered reads were aligned against the cockle genome (Bruzos et al, 2022) using a custom script with SAMtools v1.9 (Li et al, 2009) and STAR v2.7.0e (Dobin et al, 2013). Bam files from aligned reads were merged with SAMtools and a cockle transcriptome draft was finally obtained.…”

“…After filtering, 1991 million total reads were retained, 1609 million from the digestive gland and 381 million from whole meat. Among the 33 million pair-end filtered reads per sample, 28.8 million were consistently aligned to the chromosome-level assembled cockle genome (Bruzos et al, 2022) by retaining only the single best hit when more than one position matched. The common cockle transcriptome, particularly enriched on the digestive gland, was constructed taking as reference the cockle genome assembly and using a conservative bioinformatic pipeline (Fig.…”

Centuries of genome instability and evolution in soft-shell clam transmissible cancer

“…Our analysis of the MarBTN genome is presented alongside an independent analysis of two lineages in the common cockle ( Cerastoderma edule ), or CedBTN, in a companion paper ( 51 ). The CedBTN genomes display signatures of ongoing instability similar to what we observe in MarBTN, supporting the hypothesis that genome instability is a common feature of BTN evolution and confirming that long-term survival of a cancer lineage can be maintained despite remarkably widespread and continued genome rearrangement.…”