A naturally occurring variant of MBD4 causes maternal germline hypermutation in primates

Area of Science:

• Genetics
• Genomics
• Molecular Biology

Background:

• The methyl-CpG binding domain 4, DNA glycosylase (MBD4) gene is crucial for repairing C>T deamination mutations at CpG sites.
• MBD4 dysfunction is implicated in human somatic hypermutation and cancer predisposition.

Purpose of the Study:

• To investigate the impact of a germline MBD4 frameshift mutation on de novo mutation rates in rhesus macaque offspring.
• To explore the role of MBD4 in germline mutation repair beyond CpG dinucleotides.

Main Methods:

• Genome sequencing of a rhesus macaque family with a homozygous MBD4 frameshift mutation.
• Analysis of de novo mutation burden and types in MBD4-null offspring.

Main Results:

• Offspring of the MBD4-null dam exhibited a fourfold to sixfold increase in de novo mutation burden.
• The excess mutations were predominantly C>T at CpG sites, consistent with MBD4 loss of function.
• A significant excess of C>T mutations at CpA sites was observed, suggesting an unappreciated role for MBD4 in these contexts.

Conclusions:

• This study provides the first evidence of a genetic factor causing germline hypermutation in a mammal.
• MBD4 plays a significant role in repairing DNA deamination at both CpG and CpA sites in the maternal germline.
• Naturally occurring variants modulating germline mutation rates are rare and MBD4 loss of function is a notable example.