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Mlh1 heterozygosity and promoter methylation associates with microsatellite instability in mouse sperm

Kul S Shrestha1,2, Minna M Tuominen1, Liisa Kauppi1,3

  • 1Systems Oncology (ONCOSYS) Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8 (PO Box 63), FI-00014 Helsinki, Finland.

Mutagenesis
|March 19, 2021
PubMed

Insights

Mlh1 heterozygosity in mice causes microsatellite instability in sperm, a key DNA repair pathway. Promoter methylation in sperm correlated with increased instability, unlike in somatic cells.

Area of Science:

  • Genetics
  • Molecular Biology
  • Reproductive Biology

Background:

  • DNA mismatch repair (MMR) proteins are crucial for genome stability in germline and somatic cells.
  • MLH1 is a central MMR protein; its loss causes infertility and microsatellite instability (MSI) in spermatocytes.
  • The impact of Mlh1 heterozygosity on germline genome stability and MSI remains largely unknown.

Purpose of the Study:

  • To investigate the effect of Mlh1 heterozygosity on MSI in mature sperm.
  • To explore the relationship between Mlh1 promoter methylation and MSI in Mlh1+/- sperm.
  • To compare MSI levels in germline cells versus non-proliferating somatic cells.

Main Methods:

  • Utilized mouse genetics to create Mlh1+/- mice.
  • Employed single-molecule PCR to detect allelic changes at unstable microsatellites in sperm.
  • Analyzed Mlh1 promoter methylation in sperm DNA.

Main Results:

  • Observed 4.5% and 5.9% MSI in sperm of 4- and 12-month-old Mlh1+/- mice, respectively.
  • Found a correlation between Mlh1 promoter methylation and increased MSI in Mlh1+/- sperm.
  • Detected no elevated MSI in non-proliferating somatic cells of Mlh1+/- mice.
  • Demonstrated differing dynamics of deletions versus insertions at mononucleotide repeat microsatellites in sperm.

Conclusions:

  • Mlh1 heterozygosity compromises genome stability in mature sperm, leading to MSI.
  • Mlh1 promoter methylation is associated with increased germline MSI.
  • Germline cells exhibit distinct responses to Mlh1 heterozygosity compared to somatic cells regarding MSI.

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