Recent advances in sequencing technologies and bioinformatics have created an emerging picture of structurally dynamic human and non-human primate genomes. In addition to single-nucleotide variants, larger structural variants (SVs; e.g., deletions, duplications, and inversions) are prolific within and between species but are more difficult to study. SVs are often too large to reliably identify with short-read (e.g., Illumina) data and frequently coincide with repetitive elements, making these loci historically difficult to assemble, annotate, and functionally investigate. Despite this, SV-associated rearrangements are known to cause morphological and neurodevelopmental abnormalities in humans, and a handful of human-specific duplicated (HSD) genes have been linked to innovative neurological features. The potential functional impact of SVs is enormous, as single mutational events can rearrange genes and regulatory elements throughout the genome. However, while the genes themselves have received growing attention, the regulatory landscape of SVs remains poorly characterized. Gene expression differences are known to contribute to a variety of human diseases, and are thought to be a major contributor to phenotypic divergence between species. SVs thus represent an understudied and likely impactful set of loci to examine in this light. This is particularly intriguing in the case of HSD genes, which show distinct expression patterns despite having nearly identical sequences. This work will use genomic techniques to investigate the effect of evolutionarily recent SVs on gene expression between humans and chimpanzees. This will be accomplished via three approaches: (1) high-throughput assay of human-duplicated regulatory element activity; (2) identification of differences in the promoter-enhancer connectome across SV breakpoints; and (3) testing for causal relationships between candidate regulatory features and gene expression at SV loci of functional significance. The findings of this research will be the first to characterize hundreds of loci in parallel and will offer insight into the mechanistic basis for regulatory changes between primate species.
The results of this study will facilitate understanding of the interplay between genomic structural variation and gene regulation between species on short evolutionary timescales. Structural variants are prolific in humans and other great apes, and they are likely to alter gene expression, which is a prominent contributor to evolution and disease. In humans, many of these loci are associated with neurodevelopmental abnormality and recurrent pathogenic rearrangement, so understanding the epigenetic landscape of these regions will be instrumental in characterizing their etiology.
