Mature microsatellites: Mechanisms underlying dinucleotide microsatellite mutational biases in human cells

Beverly A. Baptiste, Guruprasad Ananda, Noelle Strubczewski, Andrew Lutzkanin, Su Jen Khoo, Abhinaya Srikanth, Nari Kim, Kateryna D. Makova, Maria M. Krasilnikova, Kristin A. Eckert

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Dinucleotide microsatellites are dynamic DNA sequences that affect genome stability. Here, we focused on mature microsatellites, defined as pure repeats of lengths above the threshold and unlikely to mutate below it in a single mutational event. We investigated the prevalence and mutational behavior of these sequences by using human genome sequence data, human cells in culture, and purified DNA polymerases. Mature dinucleotides (≥10 units)are present within exonic sequences of >350 genes, resulting in vulnerability to cellular genetic integrity. Mature dinucleotide mutagenesis was examined experimentally using ex vivo and in vitro approaches. We observe an expansion bias for dinucleotide microsatellites up to 20 units in length in somatic human cells, in agreement withprevious computational analyses of germline biases. Using purified DNA polymerases and human cell lines deficient for mismatch repair (MMR), we show that the expansion bias is caused by functional MMR and is not due to DNA polymerase error biases. Specifically, we observe that the MutSa and MutLa complexes protect against expansion mutations. Our data support a model wherein different MMR complexes shift the balance of mutations toward deletionor expansion. Finally, we show that replication fork progression is stalled within long dinucleotides, suggesting that mutational mechanisms within long repeats may be distinct from shorter lengths, depending on the biochemistry of fork resolution. Our work combines computational and experimental approaches to explain the complex mutational behavior of dinucleotide microsatellites in humans.

Original languageEnglish (US)
Pages (from-to)451-463
Number of pages13
JournalG3: Genes, Genomes, Genetics
Issue number3
StatePublished - Mar 2013

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Mature microsatellites: Mechanisms underlying dinucleotide microsatellite mutational biases in human cells'. Together they form a unique fingerprint.

Cite this