Modelling segmental duplications in the human genome

Abstract

Background Segmental duplications (SDs) are long DNA sequences that are repeated in a genome and have high sequence identity. In contrast to repetitive elements they are often unique and only sometimes have multiple copies in a genome. There are several well-studied mechanisms responsible for segmental duplications: non-allelic homologous recombination, non-homologous end joining and replication slippage. Such duplications play an important role in evolution, however, we do not have a full understanding of the dynamic properties of the duplication process. Results We study segmental duplications through a graph representation where nodes represent genomic regions and edges represent duplications between them. The resulting network (the SD network) is quite complex and has distinct features which allow us to make inference on the evolution of segmantal duplications. We come up with the network growth model that explains features of the SD network thus giving us insights on dynamics of segmental duplications in the human genome. Based on our analysis of genomes of other species the network growth model seems to be applicable for multiple mammalian genomes. Conclusions Our analysis suggests that duplication rates of genomic loci grow linearly with the number of copies of a duplicated region. Several scenarios explaining such a preferential duplication rates were suggested.

Reconstruction of segmental duplication rates and associated genomic features by network analysis

“…This network approach allows studying segmental duplications as a whole thus revealing some universal biological principles of SDs evolution from the SD network. Earlier we observed that duplication rates grow with the number of copies of a specific duplicated region, which we called preferential duplication rates Abdullaev et al [2021]. This time we further examined the biological characteristics that could affect duplication rates.…”

“…We simulated the PCM network growth and kept information on edges status ("primary" edges representing duplication events or "secondary" ones). All PCM simulations were done with the parameters inferred at (Abdullaev et al [2021]): δ = 5.1 * 10 −4 , f = 0.47. We also considered other centrality measures assigned to nodes of the SD network (Table 2) and estimated an accuracy of each of them when applied to our task.…”

“…For example, pericentromeric and subtelomeric parts of chromosomes are enriched with SDs, especially with interchromosomal ones Linardopoulou et al [2005], She et al [2004], Guy et al [2003]. General principles of segmental duplications propagation in the human genome were suggested when SDs were studied as a graph Abdullaev et al [2021]. A specific SD network where nodes represent genomic loci involved in duplications, while edges correspond to alignments between those loci was constructed and it’s growth was modelled.…”

Low copy repeats in the genome: from neglected to respected

“…Afterwards, these duplicon blocks are copied to other pericentromeric sites, creating a mosaic structure [28]. Interchromosomal duplications are enriched in subtelomeric LCRs via serial translocations (Figure 2C): consecutive events of double-strand breakage and repair in these subtelomeric regions created a mosaic pattern of LCR-containing sequences [28,30]. The largest LCRs in the human genome, are located in interstitial regions and are enriched for intrachromosomal duplications.…”

“…The complex patterns are formed by serial duplication, using the LCRs themselves as homology substrates in consecutive rounds (Figure 2D) [28,30]. Alu repeats are frequently observed at or in the vicinity of the boundaries of LCRs, suggesting involvement of both NAHR and replication-based mechanisms (NHEJ, MMBIR) in the creation of these complex structures [28][29][30][31]. The proportion of LCR sequence varies substantially between the genomes of different species.…”