Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy
Thayne Woycinck Kowalski1,2,3,4,5,6, Gabriela Barreto Caldas-Garcia1,7, Julia do Amaral Gomes1,2,3,4
1Post-Graduation Program in Genetics and Molecular Biology, PPGBM, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil.
Frontiers in Genetics
|July 12, 2021
Summary
Species differences in thalidomide embryopathy (TE) were investigated. Researchers found gene variations and co-expression changes linked to TE, suggesting a Cereblon-induced mechanism in mice despite lacking the classic TE phenotype.
Area of Science:
- Developmental Biology
- Toxicology
- Genetics
Background:
- Thalidomide-Cereblon (CRBN) interaction explains thalidomide embryopathy (TE) but species variability persists.
- Understanding genetic differences is key to explaining why some species are unaffected by TE.
Purpose of the Study:
- To identify sequence divergences in TE-affected versus unaffected species.
- To evaluate gene co-expression patterns in a murine model exposed to thalidomide.
Main Methods:
- Comparative analysis of 42 selected genes across 14 species, examining synteny, neighborhood, and protein conservation.
- Differential co-expression analysis using mouse embryonic stem cell (mESC) data (GSE61306) after thalidomide exposure.
- Analysis of protein sequence alignments for key genes.
Main Results:
- Twenty genes upstream of NOS3 showed differences between species developing or not developing TE.
- RECQL4, SALL4, CDH5, KDR, and NOS2 proteins had more variants in unaffected species.
- Cereblon (CRBN) drove co-expression of genes linked to limb reduction defects (LRD), with CRBN and SALL4 showing affected co-expression after thalidomide exposure.
Conclusions:
- Genetic variations and altered gene co-expression contribute to species-specific thalidomide embryopathy.
- A CRBN-induced regulatory mechanism is implicated in mice, potentially affecting LRD-related genes.
- Further functional studies are needed to explore LRD gene interactions with the thalidomide-CRBN pathway.
