In search of the adaptive roles of genomic structural variants in the human genome
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Genetic variation comes in different size, ranging from a single nucleotide variation to karyotypic alteration. However, the abundance of the genetic variations in humans with their size larger than a few nucleotides has not been appreciated until this decade. Such genetic variations involving in blocks of sequences are generally termed the genomic structural variants (SVs). SVs, like any other type of genetic variation, potentially lead to phenotypic variation and are targets of natural selection. In the past decade, a plethora of SVs has been detected in a genome-wide manner. The range of mutational mechanisms that underlie SVs include deletions, duplication, multiallelic copy number variants, insertions, inversions, and translocations. One of the emerging goals in the field is to find among them the potential targets of selection. In my dissertation, I developed two approaches to screen for the SVs that likely evolve under non-neutral forces. First, I used the comparative genomics approach to find the exonic deletion variants that are shared between modern humans and Neandertal/Denisovan genomes. Given that most of the deletion variants disrupting coding sequences have been eliminated by negative selection over time, an exonic deletion that remains in the population for an extended period likely evolved under other non-neutral forces. I found fifteen such deletion variants that evolved before the divergence of human and Neandertal/Denisovan. Indeed, further analyses into the adjacent sequence of one of these ancient deletions, the LBC3BC, reveal that this deletion has been maintained under balancing selection. Second, I searched for loci across the human genome where SVs recurrently form. A subset of these “hotspots” of SVs are maintained because the disruption of these sequence by SVs is favored by natural selection, including a series of deletions affecting the genes in the hemoglobin clusters. To reveal the SVs that were not visible in the previous dataset, I conducted a pilot project combining target-specific capturing and PacBio sequencing to detect the variants that were undetectable with the conventional technology. With the success of this method, I discovered SVs previously hidden. Overall, my work demonstrated the adaptive relevance of human SVs and provided new venues for future studies.