Donnelly researchers report a new mechanistic understanding of the rapid evolutionary change among primate species
When considering regions of genomes that encode proteins, human DNA is approximately 99% identical to that of chimpanzees. But genetic code similarity does not tell the full evolutionary story.
A new study by Donnelly researchers in the Blencowe Lab has illuminated a potentially frequent mechanism that generates evolutionary divergence between primate species.
“We were interested in how alternative splicing undergoes a rapid rate of evolutionary divergence, in contrast to overall species differences in gene expression patterns,” says Ben Blencowe, Donnelly PI, Molecular Genetics professor, and Banbury Chair in Medical Research.
Previous work from the Blencowe Lab has demonstrated that alternative splicing, the process of including or omitting specific instructional segments in a gene, is capable of greatly diversifying information from genes. This diversification generates different RNA transcripts and proteins, affecting more than 95% of human genes.
In a 2012 study, Blencowe’s group compared splicing profiles between the same organs from a broad spectrum of vertebrate species, observing a rapid rate of evolutionary divergence. In the segments of genes known as exons, approximately 50% that undergo alternative splicing are different between humans and chimpanzees.
“In 2012, the mechanisms underlying that remarkable divergence weren’t clear yet,” Blencowe explains. “But we showed evidence that one of the mechanisms was the rapid rearrangement of an RNA sequence code that determined splicing patterns.”
The Blencowe group’s most recent paper investigates how differences in exon splicing patterns arise from RNA structures generated by abundant repetitive sequences scattered across primate genomes, known as Alu elements.
“There's over a million copies of Alu repeats in our genome,” says Blencowe. “During the evolution of hominid primates, insertion of one of these Alu repeat elements resulted in an RNA structure that causes skipping of an exon important for tail development."
The initial direction of the paper started one weekend, when a study connecting tail loss and Alu element insertion caught the attention of Blencowe Lab graduate student Hyunbeen (Jason) Lee and postdoctoral researcher Guillermo Parada González. Knowing the abundance of Alu elements, Parada was interested in performing a systematic analysis of how Alu insertion or loss might impact alternative splicing patterns to potentially contribute to other phenotypic differences between species.
“I called Jason on a Sunday morning, and he patiently listened to my excitement,” says Parada, who is both a co-corresponding author and co-first author with Lee. “We decided to tackle it together.”
“Coming from more of an engineering background, I was in charge of most of the computational work and incorporating results from [our collaborators in] Singapore,” says Lee.
Blencowe’s group collaborated with the labs of Yue Wan (A*STAR Genome Institute of Singapore) and Jernej Ule (The Francis Crick Institute), to map RNA structures generated by Alu elements that link to altered splicing patterns. Their collaboration with the Wan group, including co-first author Xinang Cao led to the surprising observation that most stable RNA structures surrounding skipped exons are derived from Alu elements.
“We now have a clearer understanding of how these repeat sequences have shaped our transcriptome,” says Blencowe. “Our team has provided evidence suggesting that these Alu insertions have contributed to evolutionary divergence.”
“There’s a great complexity present in the transcriptome,” says Parada, who now occupies a postdoctoral position at Blencowe’s UK Satellite Lab in preparation to become an independent researcher. “I’m excited to further explore the rules of RNA structure formation and how it is mediated by other elements.”
The new paper from Blencowe and colleagues was coordinated with a parallel study from Alice Lee’s group at Harvard Medical School, who used a different approach to obtain similar results.
“In a way, this is a community project focusing on the same overall questions,” says Blencowe. “Our effort was in part intended to provide a new resource of splicing changes that others can study in order to understand their potential roles in evolutionary differences between species.”
The paper “Alu-mediated RNA duplexes are associated with widespread exon skipping across primate transcriptomes” is an Open Access article published in Genome Biology.
Read “Alu-mediated RNA duplexes are associated with widespread exon skipping across primate transcriptomes” Here
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