A Characterization of the Structural Variation uncovered by Single-Molecule Real-Time Sequencing in the Genome of a Supercentenarian

Genetics is an important factor that determines the cognitive abilities at extreme age. Little of this heritability can be explained by known genomic variation. The repetitive part of the human genome harbours a great number of large variants that are currently underexplored, due to technological complications involved in genotyping this type of variation.

Single-Molecule Real-Time sequencing can be used to produce long reads that enable the characterization of these variants. We use this technology to construct a haplotype-resolved de-novo assembly for the genome of a 115 year-old woman without dementia.

By comparing this assembly to two publicly available SMRT sequencing datasets as well as the GRCh38 reference genome, we detect about thirty thousand large (>50bp) haplotype-resolved variants. We characterize these variants and find that about 70% of these events are attributable to expansions/contractions of highly polymorphic variable number tandem repeats (VNTRs). We also find that the sub-telomeric regions of the genome are strongly enriched with these events. Furthermore, we observe thousands of recent insertions of Alu, L1 and SVA transposable elements and hundreds of inversions and other more complex rearrangements.