Analysis of variable retroduplications in human populations suggests coupling of retrotransposition to cell division

Abstract

In primates and other animals, reverse transcription of mRNA followed by genomic integration creates retroduplications. Expressed retroduplications are either “retrogenes” coding for functioning proteins, or expressed “processed pseudogenes,” which can function as noncoding RNAs. To date, little is known about the variation in retroduplications in terms of their presence or absence across individuals in the human population. We have developed new methodologies that allow us to identify “novel” retroduplications (i.e., those not present in the reference genome), to find their insertion points, and to genotype them. Using these methods, we catalogued and analyzed 174 retroduplication variants in almost one thousand humans, which were sequenced as part of Phase 1 of The 1000 Genomes Project Consortium. The accuracy of our data set was corroborated by (1) multiple lines of sequencing evidence for retroduplication (e.g., depth of coverage in exons vs. introns), (2) experimental validation, and (3) the fact that we can reconstruct a correct phylogenetic tree of human subpopulations based solely on retroduplications. We also show that parent genes of retroduplication variants tend to be expressed at the M-to-G1 transition in the cell cycle and that M-to-G1 expressed genes have more copies of fixed retroduplications than genes expressed at other times. These findings suggest that cell division is coupled to retrotransposition and, perhaps, is even a requirement for it.

Landscape and variation of novel retroduplications in 26 human populations

“…Besides the retroduplication calls shared among callsets, there are also large number of calls unique to our callset, which is likely due to newly enrolled populations in Phase 3 data, and the higher sensitivity of our methods. We resolved 152/503 (30.2%) insertion sites for our predicted retroduplications, a percentage higher than previous studies [5,7]. Functional enrichment analysis for the 503 unique parent genes shows the most enriched functions are related to ribosome/structural molecule activity, intracellular organelle lumen/nucleoplasm, and protein complex assembly.…”

piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals

“…Furthermore, LINE-1-mobilized sequences in cultured cells (Berry et al 2006), tumors Tubio et al 2014), and mice bearing an engineered LINE-1 element are not preferentially targeted to piRNA clusters. Finally, recent processed pseudogene (Abyzov et al 2013) and retrotransposon insertions in human genomes are not enriched within piRNAgenerating loci (Y Zhang and P Gerstein, pers. comm.).…”

The Genomic Impact of Gene Retrocopies: What Have We Learned from Comparative Genomics, Population Genomics, and Transcriptomic Analyses?

“…These studies have also shown that retrotransposition likely occurs during cell division given that many retroCNV cognate genes are expressed during this phase of the cell cycle (Abyzov et al 2013). Importantly, the recent origin of most retroCNVs has led to the identification of molecular signatures specific of either LINEs or LTR retroelements in plants and animals, expanding on the limited perspective offered by studies in mammals wherein L1 elements have been primarily involved in the formation of retrocopies.…”

“…Additionally, retroCNVs appear to form at a lower rate than CNVs generated through DNA duplication in humans (Abyzov et al 2013). …”