Topologically associating domains and their role in the evolution of genome structure and function inDrosophila

Abstract

Topologically associating domains (TADs) were recently identified as fundamental units of three-dimensional eukaryotic genomic organization, although our knowledge of the influence of TADs on genome evolution remains preliminary. To study the molecular evolution of TADs in Drosophila species, we constructed a new reference-grade genome assembly and accompanying high-resolution TAD map for D. pseudoobscura. Comparison of D. pseudoobscura and D. melanogaster, which are separated by ∼49 million years of divergence, showed that ∼30%-40% of their genomes retain conserved TADs. Comparative genomic analysis of 17 Drosophila species revealed that chromosomal rearrangement breakpoints are enriched at TAD boundaries but depleted within TADs. Additionally, genes within conserved TADs show lower expression divergence than those located in nonconserved TADs. Furthermore, we found that a substantial proportion of long genes (>50 kbp) in D. melanogaster (42%) and D. pseudoobscura (26%) constitute their own TADs, implying transcript structure may be one of the deterministic factors for TAD formation. By using structural variants (SVs) identified from 14 D. melanogaster strains, its three closest sibling species from the D. simulans species complex, and two obscura clade species, we uncovered evidence of selection acting on SVs at TAD boundaries, but with the nature of selection differing between SV types. Deletions are depleted at TAD boundaries in both divergent and polymorphic SVs, suggesting purifying selection, whereas divergent tandem duplications are enriched at TAD boundaries relative to polymorphism, suggesting they are adaptive. Our findings highlight how important TADs are in shaping the acquisition and retention of structural mutations that fundamentally alter genome organization.

Developmental and Evolutionary Comparative Analysis of a Regulatory Landscape in Mammals and Birds

“…TADs which contain pleiotropic genes of key importance for development are frequently conserved across tetrapods and topological changes in their organization often correlate with important modifications in gene expression (Eres et al, 2019; Liao et al, 2021; Torosin et al, 2020; Yakushiji-Kaminatsui et al, 2018). Our results show that despite a considerable divergence in the non-coding elements localized in the mouse and chicken T-DOM, the global pattern of interactions is conserved leading to similar chromatin topologies.…”

“…TADs which contain pleiotropic genes of key importance for development are frequently conserved across tetrapods and topological changes in their organization often correlate with important modifications in gene expression (Eres et al, 2019;Liao et al, 2021;Torosin et al, 2020;Yakushiji-Kaminatsui et al, 2018).…”

Heterochromatin Networks: Topology, Dynamics, and Function (a Working Hypothesis)

“…In mouse embryogenesis, lamina-associated domains (LADs) are settled in the zygote prior to topologically associating domains (TADs) [ 93 ]. The latter are conserved in evolution [ 94 , 95 ]. The link to lamina determines the variable chromatin landscape of mature cells [ 96 ] and the construction of the conventional or inverted (in retina rods of nocturnal animals) structure of cell nuclei [ 21 ].…”

Insulators in Plants: Progress and Open Questions

“…TAD boundaries in Drosophila are also enriched in architectural protein binding sites, and they also function as enhancer blockers in transgenic assays [ 17 , 23 ]. Insulators also show evidence of local sequence constraint [ 24 ], and the level of conservation of insulator sequences positively correlates with their strength as boundaries [ 25 ]. Reporter-based assays show that insulator activity (e.g., “boundary strength”—the ability of an insulator to effectively block interactions between loci located on either of its sides) is positively correlated with the occupancy level of architectural protein binding sites, suggesting co-binding by architectural proteins underlies the functional potential of these loci [ 17 ].…”