Extensive gene conversion at the PMS2 DNA mismatch repair locus

Area of Science:

• Genetics
• Molecular Biology
• Genomic Instability

Background:

• Mutations in the PMS2 DNA repair gene are linked to various cancers, presenting in childhood or adulthood.
• Accurate detection of PMS2 mutations is hindered by homologous pseudogenes, particularly PMS2CL, located on chromosome 7.
• The PMS2CL pseudogene resides within a large inverted duplication (inv dup) on chromosome 7p22, complicating genetic analysis.

Purpose of the Study:

• To investigate the reliability of reference genomic sequences in distinguishing between the PMS2 gene and its pseudogene, PMS2CL.
• To understand the evolutionary history and ongoing sequence homogenization within the 7p22 inverted duplication.
• To identify the impact of sequence diversity and exchange on PMS2 mutation screening.

Main Methods:

• Comparative genomic analysis of PMS2 and PMS2CL loci.
• Examination of sequence homology and exchange within the 7p22 inverted duplication.
• Assessment of sequence diversity and its implications for mutation detection assays.

Main Results:

• Reference genomic sequences are insufficient for reliably differentiating PMS2 from PMS2CL due to sequence transfer.
• The 7p22 inverted duplication is ancient, predating ape species divergence, and has undergone significant sequence homogenization.
• Ongoing sequence exchange between PMS2 and PMS2CL generates allelic diversity, leading to potential false-positive and false-negative mutation detection results.

Conclusions:

• The sequence similarity and exchange between PMS2 and PMS2CL pose significant challenges for accurate mutation screening.
• Careful consideration of sequence diversity and the use of specialized methods are crucial for reliable PMS2 mutation analysis.
• Further research is needed to develop robust strategies for PMS2 mutation detection in clinical diagnostics.