Histocompatibility gene mutation rates in the mouse: a 25-year review

Area of Science:

• Immunogenetics
• Molecular Biology
• Genetics

Background:

• Histocompatibility genes, particularly the H2 complex in mice, are crucial for immune responses and transplantation.
• Previous studies suggested high mutation rates for H2 genes compared to other mammalian genes.
• Understanding mutation rates is vital for genetic integrity monitoring and evolutionary studies.

Purpose of the Study:

• To determine the spontaneous mutation rates of H2 and non-H2 histocompatibility genes in mice over a 25-year period.
• To compare the mutation rates of H2 genes with non-H2 genes and previously reported mammalian gene mutation rates.
• To investigate the specific mutation patterns and rates of the H2-Kb locus.

Main Methods:

• A 25-year monitoring of a mouse colony for genetic integrity, including inbred and hybrid strains.
• Detection of mutations through skin graft rejections.
• Screening of H2 and non-H2 histocompatibility genes for spontaneous mutations.

Main Results:

• Over 80 non-H2 histocompatibility gene mutations and 25 H2 mutations were identified.
• The spontaneous mutation rate for most H2 class I genes was comparable to non-H2 genes and other mouse genes.
• The H2-Kb locus exhibited a significantly higher mutation rate (1-2 x 10(-4) per gene per generation), accounting for over half of all H2 mutations.
• Over half of H2-Kb mutations resulted in a specific "bg" phenotype, indicating recurrent molecular changes.

Conclusions:

• H2 genes, with the exception of H2-Kb, do not mutate at a higher rate than non-H2 genes.
• The H2-Kb gene is an outlier with an exceptionally high spontaneous mutation rate.
• The findings challenge previous assumptions about high H2 gene mutation rates and highlight locus-specific variations.