Comprehensive Analysis of Human Subtelomeres by Whole Genome Mapping

Author summary The ends of human chromosomes have caps called telomeres that are essential. These telomeres are influenced by the portions of DNA next to them, a region known as the subtelomere. We need to better understand the subtelomeric region to understand how it impacts the telomeres. This subtelomeric region is not well described in the current references. This is due to large variations in this region and portions that are repeated many times, making current sequencing technologies struggle to capture these regions. Many of these variations are evolutionary recent. Here we use 154 different samples from the 26 geographic regions of the world to gain a better understanding of the variation in these regions. We found many new haplotypes and clarified the haplotypes existing in the current reference. We then examined population and chromosome specific trends. Detailed comprehensive knowledge of the structures of individual long-range telomere-terminal haplotypes are needed to understand their impact on telomere function, and to delineate the population structure and evolution of subtelomere regions. However, the abundance of large evolutionarily recent segmental duplications and high levels of large structural variations have complicated both the mapping and sequence characterization of human subtelomere regions. Here, we use high throughput optical mapping of large single DNA molecules in nanochannel arrays for 154 human genomes from 26 populations to present a comprehensive look at human subtelomere structure and variation. The results catalog many novel long-range subtelomere haplotypes and determine the frequencies and contexts of specific subtelomeric duplicons on each chromosome arm, helping to clarify the currently ambiguous nature of many specific subtelomere structures as represented in the current reference sequence (HG38). The organization and content of some duplicons in subtelomeres appear to show both chromosome arm and population-specific trends. Based upon these trends we estimate a timeline for the spread of these duplication blocks.