DNA polymerase stalling at structured DNA constrains the expansion of short tandem repeats.
Genome Biol
; 21(1): 209, 2020 08 21.
Article
em En
| MEDLINE
| ID: mdl-32819438
ABSTRACT
BACKGROUND:
Short tandem repeats (STRs) contribute significantly to de novo mutagenesis, driving phenotypic diversity and genetic disease. Although highly diverse, their repetitive sequences induce DNA polymerase slippage and stalling, leading to length and sequence variation. However, current studies of DNA synthesis through STRs are restricted to a handful of selected sequences, limiting our broader understanding of their evolutionary behaviour and hampering the characterisation of the determinants of their abundance and stability in eukaryotic genomes.RESULTS:
We perform a comprehensive analysis of DNA synthesis at all STR permutations and interrogate the impact of STR sequence and secondary structure on their genomic representation and mutability. To do this, we developed a high-throughput primer extension assay that allows monitoring of the kinetics and fidelity of DNA synthesis through 20,000 sequences comprising all STR permutations in different lengths. By combining these measurements with population-scale genomic data, we show that the response of a model replicative DNA polymerase to variously structured DNA is sufficient to predict the complex genomic behaviour of STRs, including abundance and mutational constraints. We demonstrate that DNA polymerase stalling at DNA structures induces error-prone DNA synthesis, which constrains STR expansion.CONCLUSIONS:
Our data support a model in which STR length in eukaryotic genomes results from a balance between expansion due to polymerase slippage at repeated DNA sequences and point mutations caused by error-prone DNA synthesis at DNA structures.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
/
Repetições de Microssatélites
/
DNA Polimerase Dirigida por DNA
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Genome Biol
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Reino Unido