A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression

Area of Science:

• Genomics
• Evolutionary Biology
• Molecular Biology

Background:

• Human-specific genomic insertions contribute to unique human traits and diseases.
• The TBC1D8B gene, located on the X chromosome, plays a role in cellular functions.

Purpose of the Study:

• To investigate the origin and function of a human-specific insertion (Insert-446) in the TBC1D8B gene.
• To understand the role of Insert-446 in regulating TBC1D8B expression and its impact on cell behavior and tumorigenesis.

Main Methods:

• Tracing the evolutionary origin of Insert-446 using ancient and comparative genomics.
• Assessing Insert-446's enhancer activity by measuring TBC1D8B gene expression.
• Investigating the functional consequences of TBC1D8B overexpression and knockdown in vitro and in vivo.
• Analyzing the effect of Insert-446 knockout on cell proliferation and migration.

Main Results:

• Insert-446, originating from the EBF1 gene, is present in Neanderthal and Denisovan genomes and fixed in humans post-divergence from chimpanzees.
• Insert-446 functions as an enhancer, significantly increasing human TBC1D8B expression compared to macaques.
• TBC1D8B overexpression promotes cell proliferation and migration via a catalytic mechanism.
• Knockdown of TBC1D8B inhibits tumorigenesis, and knockout of Insert-446 prevents cell proliferation and migration.

Conclusions:

• Human-specific Insert-446 upregulates TBC1D8B, driving cell proliferation and migration.
• This insertion provides insights into the evolutionary impact of genetic elements on human phenotypes and disease susceptibility.