Alu-Sc-mediated exonization generated a mitochondrial LKB1 gene variant found only in higher order primates

Area of Science:

• Evolutionary biology
• Molecular biology
• Genetics

Background:

• The tumor suppressor LKB1/STK11 is crucial for cellular metabolism and stress responses, with mutations linked to cancers.
• A novel exon 1b in LKB1/STK11 generates an alternative isoform that targets mitochondria and regulates oxidative stress.

Purpose of the Study:

• To investigate the evolutionary origin and emergence of the novel LKB1/STK11 exon 1b.
• To determine the functional significance and evolutionary distribution of this exon in primates.

Main Methods:

• Comparative genomic analysis of LKB1/STK11 sequences across primate species.
• Identification and characterization of retrotransposable elements, specifically Alu-Sc, involved in exonization.
• Analysis of splice sites and translation start signals to assess exon functionality.

Main Results:

• The exonization of LKB1/STK11 exon 1b was mediated by the Alu-Sc retrotransposable element.
• Recognizable exon 1b sequences are present from New World Monkeys onward.
• Functional LKB1/STK11 exon 1b, with essential regulatory sites, is found exclusively in humans and great apes.

Conclusions:

• The novel LKB1/STK11 exon 1b is a recent evolutionary acquisition in the great ape lineage.
• Its presence correlates with increased body mass and longevity in humans and great apes, suggesting a role in these traits.