On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

Look4TRs: A de-novo tool for detecting simple tandem repeats using self-supervised hidden Markov models

Motivation Simple tandem repeats, microsatellites in particular, have regulatory functions, links to several diseases, and applications in biotechnology. There is an immediate need for an accurate tool for detecting microsatellites in newly sequenced genomes. The current available tools are either sensitive or specific but not both; some tools require adjusting parameters manually. Results We propose Look4TRs, the first application of self-supervised hidden Markov models to discovering microsatellites. Look4TRs adapts itself to the input genomes, balancing high sensitivity and low false positive rate. It auto-calibrates itself. We evaluated Look4TRs on 26 eukaryotic genomes. Based on F measure, which combines sensitivity and false positive rate, Look4TRs outperformed TRF and MISA —the most widely-used tools—by 78% and 84%. Look4TRs outperformed the second and the third best tools, MsDetector and Tantan by 17% and 34%. On eight bacterial genomes, Look4TRs outperformed the second and the third best tools by 27% and 137%. Availability https://github.com/TulsaBioinformaticsToolsmith/Look4TRs Supplementary information Supplementary data are available at Bioinformatics online and on https://drive.google.com/open?id=1cIcS7Gvj0wj1B81-rnTU_OAG3IiNH54Y.

Look4TRs: A de-novo tool for detecting simple tandem repeats using self-supervised hidden Markov models

ABSTRACTSimple tandem repeats, microsatellites in particular, have regulatory functions, links to several diseases, and applications in biotechnology. Sequences of thousands of species will be available soon. There is immediate need for an accurate tool for detecting microsatellites in the new genomes. The current available tools have limitations. As a remedy, we proposed Look4TRs, which is the first application of self-supervised hidden Markov models to discovering microsatellites. It adapts itself to the input genomes, balancing high sensitivity and low false positive rate. It auto-calibrates itself, freeing the user from adjusting the parameters manually, leading to consistent results across different studies. We evaluated Look4TRs on eight genomes. Based on F-measure, which combines sensitivity and false positive rate, Look4TRs outperformed TRF and MISA — the most widely-used tools — by 106% and 82%. Look4TRs outperformed the second best tool, MsDetector or Tantan, by 11%. Look4TRs represents technical advances in the annotation of microsatellites.

LENGTH DISTRIBUTIONS OF SIMPLE TANDEM REPEATS IN GENOMES

The length distributions of simple tandem repeats in the genomes of several organisms are evaluated and found to exhibit long-range correlations in A and T nucleotide bases related repeats for most eukaryotes. In particular, the length distributions of the mononucleotide A/T repeat units have longer tails than those of the C/G repeat units. Also, the length distributions of the dinucleotide repeat unit CG show a simple monotonously fast decreasing behavior, while those of repeat units AT, AG and AC have complicated structures at larger repeat lengths, especially for human, mouse and rat chromosomes. These distributive behaviors are due to the CpG deficiency in different genomes with different methylation activities. Especially, methyltransferases in vertebrates appear to methylate specifically the cytosine in CpG dinucleotides, and the methylated cytosines is prone to mutate to thymine by spontaneous deamination. The dinucleotide CpG would gradually decay into TpG and CpA. In addition, there is a peak in the distributions of repeat unit A at repeat-repeat separation 153 nt for humans and chimpanzees. We show that the long-tail behavior of mononucleotide repeat unit A and the peak at repeat separation 153 nt are due to the interspersed repetitive DNA sequences in humans and chimpanzees.