An evolutionary driver of interspersed segmental duplications in primates

Abstract

Background: The complex interspersed pattern of segmental duplications in humans is responsible for rearrangements associated with neurodevelopmental disease, including the emergence of novel genes important in human brain evolution. We investigate the evolution of LCR16a, a putative driver of this phenomenon that encodes one of the most rapidly evolving human-ape gene families, nuclear pore interacting protein (NPIP). Results: Comparative analysis shows that LCR16a has independently expanded in five primate lineages over the last 35 million years of primate evolution. The expansions are associated with independent lineage-specific segmental duplications flanking LCR16a leading to the emergence of large interspersed duplication blocks at non-orthologous chromosomal locations in each primate lineage. The intron-exon structure of the NPIP gene family has changed dramatically throughout primate evolution with different branches showing characteristic gene models yet maintaining an open reading frame. In the African ape lineage, we detect signatures of positive selection that occurred after a transition to more ubiquitous expression among great ape tissues when compared to Old World and New World monkeys. Mouse transgenic experiments from baboon and human genomic loci confirm these expression differences and suggest that the broader ape expression pattern arose due to mutational changes that emerged in cis. Conclusions: LCR16a promotes serial interspersed duplications and creates hotspots of genomic instability that appear to be an ancient property of primate genomes. Dramatic changes to NPIP gene structure and altered tissue expression preceded major bouts of positive selection in the African ape lineage, suggestive of a gene undergoing strong adaptive evolution.

Alpha satellite insertion close to an ancestral centromeric region

“…Our structural characterization of the rearrangement provides some insights on the mechanism of alphoid DNA spreading to non-centromeric locations. The coordinated deletion is reminiscent of the mechanism inferred for duplicative transposition and suggests the involvement of double-strand breakage of DNA (Cantsilieris et al 2020), while the absence of active mobile elements adjacent to the insertion or target site duplications argues against retrotransposition (Deininger et al 2003). It may be noteworthy that we also identified an enrichment of LTR elements in the long-range acceptor site.…”

“…Our structural characterization of the rearrangement provides some insights on its mechanism of origin. The coordinated deletion suggests the involvement of double-strand breakage of DNA, as inferred for duplication events 43 . It may be noteworthy that we also identified an enrichment of LTR elements in the long-range acceptor site.…”

“…LTR retrotransposon activity is currently very limited or fully absent in humans (IHGSC 2001) and therefore is unlikely to have directly contributed to this form of structural variation. Such repeat-rich regions have been noted to be deleted as part of the duplicative transposition events associated with the new insertion of large (>100 kbp) blocks of segmental duplication (Johnson et al 2006; Cantsilieris et al 2020). Similarly, such coordinated deletions often (but not always) occur in gene-poor regions of the genome minimizing functional impacts of such massive new insertions and the fitness of the zygote/fetus.…”

Segmental duplications and their variation in a complete human genome

“…These include both biomedically important genes relevant to disease risk (LPA, MUC3A, FCGR2) (33-41) as well as gene families that have been implicated in the expansion of the human brain during human evolution (TBC1D3, NPIP, NPBF) (Fig. 3d, Table S6) (7,(42)(43)(44). In T2T-CHM13, for example, there are additional copies of NPIP, NPBF, and GOLGA that are absent from GRCh38-each of these has been described as core duplicons responsible for the expansion of interspersed duplications in the human genome (24) as well as the emergence of human-specific gene families.…”

Association of structural variation with cardiometabolic traits in Finns

“…These include LCR16a, a core element shared by many SDs on chr16 and a well-known driver of the formation of complex segmental duplication blocks in the genomes of humans and primates. 53,54,55 There are both duplication and deletion alleles of PDPR, and these have indistinguishable breakpoints that correspond to LCR16a duplicons, suggesting these CNVs were caused by recurrent non-allelic homologous recombination. Similar to the ALB deletion described above (and many prior coding associations 26 ), this CNV appears to be enriched in the Finnish population: the duplication allele was identified in 1KG with a frequency of 0.005 in non-Finnish Europeans, 503 less than the 0.025 frequency observed in our Finnish sample, and the deletion allele was not detected in 1KG.…”