Landscape and variation of novel retroduplications in 26 human populations

Abstract

Retroduplications come from reverse transcription of mRNAs and their insertion back into the genome. Here, we performed comprehensive discovery and analysis of retroduplications in a large cohort of 2,535 individuals from 26 human populations, as part of 1000 Genomes Phase 3. We developed an integrated approach to discover novel retroduplications combining high-coverage exome and low-coverage whole-genome sequencing data, utilizing information from both exon-exon junctions and discordant paired-end reads. We found 503 parent genes having novel retroduplications absent from the reference genome. Based solely on retroduplication variation, we built phylogenetic trees of human populations; these represent superpopulation structure well and indicate that variable retroduplications are effective population markers. We further identified 43 retroduplication parent genes differentiating superpopulations. This group contains several interesting insertion events, including a SLMO2 retroduplication and insertion into CAV3, which has a potential disease association. We also found retroduplications to be associated with a variety of genomic features: (1) Insertion sites were correlated with regular nucleosome positioning. (2) They, predictably, tend to avoid conserved functional regions, such as exons, but, somewhat surprisingly, also avoid introns. (3) Retroduplications tend to be co-inserted with young L1 elements, indicating recent retrotranspositional activity, and (4) they have a weak tendency to originate from highly expressed parent genes. Our investigation provides insight into the functional impact and association with genomic elements of retroduplications. We anticipate our approach and analytical methodology to have application in a more clinical context, where exome sequencing data is abundant and the discovery of retroduplications can potentially improve the accuracy of SNP calling.

Ultraconserved Elements Occupy Specific Arenas of Three-Dimensional Mammalian Genome Organization

“…The one exception pertains to repetitive elements, where the correlation is significantly negative. Investigating this further, we discovered a negative correlation between UCEs and repetitive elements (p = 1.0 × 10 −130 ; Figure 2C), which is unsurprising, as UCEs are non-repetitive (Bejerano et al, 2004; Chiang et al, 2008; Derti et al, 2006) and avoid insertions of repetitive elements (Zhang et al, 2017). We also uncovered a strong negative correlation between pooled loop anchors and repetitive elements (p = 5.6 × 10 −149 ; Figure 2C), which may again be expected as loop anchors are derived from Hi-C analyses that exclude reads from repetitive regions (Rao et al, 2014).…”

Ultraconserved elements occupy specific arenas of three-dimensional mammalian genome organization

“…The one exception pertains to repetitive elements, where the correlation is significantly negative. Investigating this further, we discovered a negative correlation between UCEs and repetitive elements (P = 1.0×10 -130 ; Figure 2C), which is unsurprising, as UCEs are non-repetitive (1,24,25) and avoid insertions of repetitive elements (96). We also uncovered a strong negative correlation between Pooled loop anchors and repetitive elements (P = 5.6×10 -149 ; Figure 2C).…”

The mutational load in natural populations is significantly affected by high primary rates of retroposition

“…However, the possibility that retroposition events could also be deleterious has been much less considered so far. Deleterious effects could be due to insertions into functional sites, and this has indeed been detected in a retrogene population analysis in humans (12). However, even if they land in non-functional intergenic regions, they could be transcribed and their transcripts could interfere with the function of the parental genes (13)(14)(15).…”