Approved Research

Deciphering the impact of structural variation on human genetic diversity

Lay summary

Any two humans share 99.9% of their DNA sequence. Differences between genomes are due to single nucleotide polymorphisms (SNPs) as well as changes in genome structure. These "structural variants" include duplications, deletions, and inversions of whole blocks of DNA. While a great deal of focus has been placed on analysis of SNPs, structural variants contribute more differences to human genomes than SNPs and are important contributors to human diversity and disease susceptibility.

One region of structural diversity is a large inversion on chromosome 17 referred to as the 17q21.31 inversion locus. This region of the genome has medical relevance and is implicated in disease - including Parkinson's, tau-related dementia, and autism spectrum disorders as well as a very severe spontaneous disease called Koolen-de Vries syndrome. To better understand these diseases, we are looking at the inversion's structure throughout the UK Biobank. The inversion is present in two different forms (called "haplotypes") one of which is present in Europeans at a higher frequency than in other populations. Understanding the history of this locus not only provides a window into human demography but contributes to our understanding of the diseases associated with this region of the genome.

Several regions of the genome exhibit increased susceptibility to disease causing structural variants. Our work proposes to study these regions to identify how these regions evolve and how they might impact human health and disease. Over the next three years, we hope to systematically examine the UK Biobank dataset to analyze this diversity probing inversion loci (such as 17q21.31 ) and to additionally explore other structurally complex loci in the genome.