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.2019 Oct;29(10):1567-1577.
doi: 10.1101/gr.247965.118.

Pedigree-based estimation of human mobile element retrotransposition rates

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Pedigree-based estimation of human mobile element retrotransposition rates

Julie Feusier et al. Genome Res.2019 Oct.

Abstract

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,Alu, 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 forAlu 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 inAlu 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.

© 2019 Feusier et al.; Published by Cold Spring Harbor Laboratory Press.

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Figures

Figure 1.
Figure 1.
Distribution of de novo MEIs throughout the genome. (A) Genomic map of de novo MEIs using HumanIdiogramLibrary (https://zenodo.org/record/1210245#.XVhePuhKiUk). The numbers to theright of the triangles indicate the ID number of each element listed in Table 1. (B) RepeatMasker (UCSC Genome Browser) context of de novo MEIs (Kent et al. 2002). (C) Genic context of de novo MEIs (UCSC Genome Browser) (Kent et al. 2002). The genomic context inB andC was determined using the TSD region of each locus.
Figure 2.
Figure 2.
Three source L1 elements identified by 3′ transductions. (A) Circlize plot of L1 elements to identified offspring elements in the CEPH data set (Gu et al. 2014). Source elements are highlighted with a star. (B) Minor allele frequency (MAF) of the three source elements in the Simons Genome Diversity Project (Mallick et al. 2016). Genotypes were manually typed from IGV screenshots (Supplemental Table S4).
Figure 3.
Figure 3.
Tracking de novo retrotransposition in multigenerational pedigrees. The maternal grandfather's haplotype is shown in light blue, and the maternal grandmother's haplotype is shown in light red. An individual with the de novo MEI is in black.
Figure 4.
Figure 4.
Estimated retrotransposition rates. Estimated retrotransposition rates for previous studies are listed (Deininger and Batzer 1999; Cordaux et al. 2006; Xing et al. 2009b; Ewing and Kazazian 2010; Huang et al. 2010). Confidence intervals are shown if available from the study. Rates and binomial 95% CI were determined for Werling et al. (2018) and this study.Alu element rates are shown in red, L1 in green, and SVA in blue.
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