Written by Poppy Jayne Morgan
A new study published in BMC biology is unravelling the mystery of genome architecture.
Gene transcription, and other essential processes of gene expression, are regulated by the highly ordered 3-dimensional (3D) architecture of the genome. The recent study has identified that the previously mysterious topologically associating domains (TAD) have been evolutionarily conserved across animal species, which may open the doors to new insights on cancer and schizophrenia.
“Efforts have been made to characterize the dynamics of genome architecture between cell types and during normal development and disease. Nonetheless, differences in genome architecture among different species have remained largely undefined,” the authors noted.
From A to Zebrafish
To understand the 3D architecture of the genome better, the researchers performed comparative analyses of high-throughput chromosome conformation capture (Hi-C) in fibroblast cells of 12 vertebrates. Covering humans and livestock, domestic pets and important animal models , the species selected included 10 mammals from four distinct lineages. The study provides a comprehensive comparison of major evolutionary branches and insights into mammalian genome architecture.
The results showed that the genome size and chromosome lengths affect the overall features of 3D genome architecture. For example, the closer the similarity in length between a given pair of chromosomes, the more frequently they interacted with each other, evident in all species examined in the study. In addition, local transcriptional availability of DNA was revealed to be selected through speciation processes.
The findings can guide ongoing investigations of genome evolution by extending our understanding of the mechanisms shaping genome architecture.
Unravelling the mystery of TAD in genome architecture
Topologically associating domains (TAD) range in length from several hundred kilobases to megabases. The functions of TADs are not fully understood and are still a matter of debate.
Disruption of TAD boundaries are found to be associated with wide range of diseases such as cancer, limb malformations, and brain disorders. A recent comparison among bird genomes suggested a strong natural selection pressure on vulnerability of TAD boundaries to DNA double-strand breaks.
Understanding TAD functionality and vulnerabilities could shed light on evolutionary history and offer new ways to approach diseases.
This new study suggested that TADs are evolutionarily conserved gene expression regulatory units. The larger mammalian genomes had more and longer TADs, and a Gene Ontology (GO) enrichment analysis found that genes in the mammalian conserved TAD boundaries are involved in the metabolic process and growth.
In humans, TAD boundaries are associated with the immune system, containing TRIB1, implying a close association to human tumour and cellular immune response. The study also showed a primate gained TAD boundary containing the gene GRM5, a promising target for the treatment of cognitive deficits in schizophrenia.
The authors reported, “this work can serve as a starting point for extended research into 3D genome evolution in vertebrates and provide a rich resource for the genomic evolution research community.”
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