Pedigree-based estimation of human mobile element retrotransposition rates

• Published in: Genome research Vol. 29; no. 10; pp. 1567 - 1577
• Main Authors: Feusier, Julie, Watkins, W Scott, Thomas, Jainy, Farrell, Andrew, Witherspoon, David J, Baird, Lisa, Ha, Hongseok, Xing, Jinchuan, Jorde, Lynn B
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.10.2019
• Subjects: Alu elements; Alu Elements - genetics; Animals; Births; Blood; Embryogenesis; Female; Gametogenesis; Genomes; Hominidae - blood; Hominidae - genetics; Humans; Interspersed Repetitive Sequences - genetics; Long Interspersed Nucleotide Elements - genetics; Male; Mutation; Mutation rates; Nucleotide sequence; Pedigree; Phylogeny; Polymorphism, Single Nucleotide - genetics; Retroelements - genetics; Retrotransposition; Statistical analysis; Whole Genome Sequencing
• ISSN: 1088-9051; 1549-5469
• DOI: 10.1101/gr.247965.118

Germline mutation rates in humans have been estimated for a variety of mutation types, including single-nucleotide and large structural variants. Here, we directly measure the germline retrotransposition rate for the three active retrotransposon elements: L1, , and SVA. We used three tools for calling mobile element insertions (MEIs) (MELT, RUFUS, and TranSurVeyor) on blood-derived whole-genome sequence (WGS) data from 599 CEPH individuals, comprising 33 three-generation pedigrees. We identified 26 de novo MEIs in 437 births. The retrotransposition rate estimates for elements, one in 40 births, is roughly half the rate estimated using phylogenetic analyses, a difference in magnitude similar to that observed for single-nucleotide variants. The L1 retrotransposition rate is one in 63 births and is within range of previous estimates (1:20-1:200 births). The SVA retrotransposition rate, one in 63 births, is much higher than the previous estimate of one in 900 births. Our large, three-generation pedigrees allowed us to assess parent-of-origin effects and the timing of insertion events in either gametogenesis or early embryonic development. We find a statistically significant paternal bias in retrotransposition. Our study represents the first in-depth analysis of the rate and dynamics of human retrotransposition from WGS data in three-generation human pedigrees.