PT - JOURNAL ARTICLE AU - Maximilian O. Press AU - Keisha D. Carlson AU - Christine Queitsch TI - The overdue promise of short tandem repeat variation for heritability AID - 10.1101/006387 DP - 2014 Jan 01 TA - bioRxiv PG - 006387 4099 - http://biorxiv.org/content/early/2014/07/28/006387.short 4100 - http://biorxiv.org/content/early/2014/07/28/006387.full AB - Short tandem repeat (STR) variation has been proposed as a major explanatory factor in the heritability of complex traits in humans and model organisms. However, we still struggle to incorporate STR variation into genotype-phenotype maps. Here, we review the promise of STRs in contributing to complex trait heritability, and highlight the challenges that STRs pose due to their repetitive nature. We argue that STR variants are more likely than single nucleotide variants to have epistatic interactions, reiterate the need for targeted assays to accurately genotype STRs, and call for more appropriate statistical methods in detecting STR-phenotype associations. Lastly, somatic STR variation within individuals may serve as a read-out of disease susceptibility, and is thus potentially a valuable covariate for future association studies.Short tandem repeat (STR)a repetitive nucleotide sequence that consists of many copies of a short sequence in tandem (ex. CAGCAGCAGCAG). STRs are frequently called microsatellites.Single nucleotide variant (SNV)Variant that consists of a change at a single nucleotide position. Common SNVs are sometimes called single nucleotide polymorphisms (SNPs).HeritabilityThe fraction of variation in a phenotype across a population that can be attributed to genetic differences.EpistasisNon-reciprocal interactions of non-allelic gene variants, due for instance to functional interdependence between gene products in a protein complex or metabolic pathway.Genome-wide association (GWA)A set of methods by which each of a large number of genetic variants genome-wide is tested for statistical associations with a phenotype. Often referred to in the context of genome-wide association studies (GWAS).Complex disease, complex traitsComplex diseases or traits are phenotypic characters thought to be affected by multiple genetic and environmental factors.Somatic variationGenetic variation across somatic cells or tissues of an organism, which are generally not inherited by offspring (which inherits instead germ-line variation). Generally arises from mutations in specific cell lineages after early development.Microsatellite instability (MSI)Somatic variation of STRs (microsatellites) associated with phenotypic changes such as cancer, often due to mutations in DNA repair genes.Bateson-Dobzhansky-Muller incompatibilityHybrid incompatibilities observed when crossing two close species or divergent strains of a species with one another. Caused by the co-segregation of non-parental allele combinations, resulting in a dysfunctional genetic interaction (negative epistasis).Genetic anticipationA mode of disease inheritance characterized by progressively earlier ages of disease onset as generations progress. Generally caused by the gradual expansion of STRs.