Abundance and length of simple repeats in vertebrate genomes are determined by their structural properties

Abstract

Microsatellites are abundant in vertebrate genomes, but their sequence representation and length distributions vary greatly within each family of repeats (e.g., tetranucleotides). Biophysical studies of 82 synthetic single-stranded oligonucleotides comprising all tetra-and trinucleotide repeats revealed an inverse correlation between the stability of folded-back hairpin and quadruplex structures and the sequence representation for repeats Ն30 bp in length in nine vertebrate genomes. Alternatively, the predicted energies of base-stacking interactions correlated directly with the longest length distributions in vertebrate genomes. Genome-wide analyses indicated that unstable sequences, such as CAG:CTG and CCG:CGG, were over-represented in coding regions and that micro/minisatellites were recruited in genes involved in transcription and signaling pathways, particularly in the nervous system. Microsatellite instability (MSI) is a hallmark of cancer, and length polymorphism within genes can confer susceptibility to inherited disease. Sequences that manifest the highest MSI values also displayed the strongest base-stacking interactions; analyses of 62 tri-and tetranucleotide repeat-containing genes associated with human genetic disease revealed enrichments similar to those noted for micro/minisatellite-containing genes. We conclude that DNA structure and base-stacking determined the number and length distributions of microsatellite repeats in vertebrate genomes over evolutionary time and that micro/minisatellites have been recruited to participate in both gene and protein function.

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

“…Moreover, our current data provide a molecular mechanism to explain the hairpin reversal-mediated suppression of TNR instability in human cells. Importantly, in our experiment we used unmodified DNA rather than modified RNA, which has been found to minimize the introduction of mutations at the targeted loci (56). It was reported that unmodified singlestranded oligonucleotides could incorporate into the nascent strand, minimizing checkpoint activation and DNA damage in human cells (26).…”

Environmental stress induces trinucleotide repeat mutagenesis in human cells

“…Finally, different lengths of coding trinucleotide and hexanucleotide repeats, which do not alter the reading frame, have been correlated with skeletal morphology in dogs (8), mating behavior in prairie voles (9), and circadian rhythms in a number of species (2). The mutability of repeats, combined with their incremental effects on protein levels and activity, suggests they could be effective agents for evolutionary plasticity, a hypothesis reinforced by the overrepresentation of trinucleotide repeats (TNRs) in coding regions and their enrichment in genes for transcription factors and other regulatory proteins (10,11).…”

Discovery of the Role of Non-B DNA Structures in Mutagenesis and Human Genomic Disorders

“…Folded DNA Structures and Abundance of Simple Repeats in Chromosomes-During the course of our genomic investigations, A. Bacolla et al (61) recognized that the abundance of certain repeating tetranucleotide sequences was extremely variable in the human genome, ranging from no copies at all to ϳ15,000/genome. Upon examination of the sequence features of the repeating tetranucleotides that were absent, he predicted that the sequences that were most likely to fold into hairpin loop arrangements were the sequences that were absent.…”