A Census of Tandemly Repeated Polymorphic Loci in Genic Regions Through the Comparative Integration of Human Genome Assemblies

Loredana M. Genovese, Filippo Geraci, Lucia Corrado, Eleonora Mangano, Romina D'Aurizio, Roberta Bordoni, Marco Severgnini, Giovanni Manzini, Gianluca De Bellis, Sandra D'Alfonso, Marco Pellegrini

Polymorphic Tandem Repeat (PTR) is a common form of polymorphism in the human genome. A PTR consists in a variation found in an individual (or in a population) of the number of repeating units of a Tandem Repeat (TR) locus of the genome with respect to the reference genome. Several phenotypic traits and diseases have been discovered to be strongly associated with or caused by specific PTR loci. PTR are further distinguished in two main classes: Short Tandem Repeats (STR) when the repeating unit has size up to 6 base pairs, and Variable Number Tandem Repeats (VNTR) for repeating units of size above 6 base pairs. As larger and larger populations are screened via high throughput sequencing projects, it becomes technically feasible and desirable to explore the association between PTR and a panoply of such traits and conditions. In order to facilitate these studies, we have devised a method for compiling catalogs of PTR from assembled genomes, and we have produced a catalog of PTR for genic regions (exons, introns, UTR and adjacent regions) of the human genome (GRCh38). We applied four different TR discovery software tools to uncover in the first phase 55,223,485 TR (after duplicate removal) in GRCh38, of which 373,173 were determined to be PTR in the second phase by comparison with five assembled human genomes. Of these, 263,266 are not included by state-of-the-art PTR catalogs. The new methodology is mainly based on a hierarchical and systematic application of alignment-based sequence comparisons to identify and measure the polymorphism of TR. While previous catalogs focus on the class of STR of small total size, we remove any size restrictions, aiming at the more general class of PTR, and we also target fuzzy TR by using specific detection tools. Similarly to other previous catalogs of human polymorphic loci, we focus our catalog toward applications in the discovery of disease-associated loci. Validation by cross-referencing with existing catalogs on common clinically-relevant loci shows good concordance. Overall, this proposed census of human PTR in genic regions is a shared resource (web accessible), complementary to existing catalogs, facilitating future genome-wide studies involving PTR.