Pedigree-based estimation of human mobile element retrotransposition rates

Area of Science:

• Genetics and Genomics
• Molecular Biology
• Human Evolution

Background:

• Germline mutation rates in humans are crucial for understanding genetic diversity and disease.
• Previous estimates for retrotransposon activity relied on indirect methods.
• Active retrotransposon families include LINE-1 (L1), Alu, and Short Interspersed Nuclear Element Variable (SVA).

Purpose of the Study:

• To directly measure the germline retrotransposition rate of L1, Alu, and SVA elements in humans.
• To analyze parent-of-origin effects and the timing of mobile element insertions (MEIs).
• To provide an in-depth analysis of human retrotransposition dynamics using whole-genome sequencing (WGS) data.

Main Methods:

• Utilized three distinct computational tools (MELT, RUFUS, TranSurVeyor) for mobile element insertion (MEI) detection.
• Analyzed blood-derived whole-genome sequence (WGS) data from 599 individuals across 33 three-generation CEPH pedigrees.
• Identified 26 de novo MEIs across 437 observed births.

Main Results:

• Estimated Alu retrotransposition rate at one new insertion per 40 births, approximately half of previous phylogenetic estimates.
• Determined L1 retrotransposition rate at one per 63 births, consistent with prior research.
• Found a significantly higher SVA retrotransposition rate at one per 63 births compared to the previous estimate of one per 900 births.
• Observed a statistically significant paternal bias in Alu retrotransposition events.
• Characterized insertion timing during gametogenesis or early embryonic development.

Conclusions:

• This study provides the first direct WGS-based quantification of human germline retrotransposition rates in large pedigrees.
• The findings reveal updated rates for Alu, L1, and SVA elements, with Alu rates being lower and SVA rates higher than previously thought.
• The identified paternal bias in Alu insertions highlights sex-specific differences in retrotransposition dynamics.