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

As part of an ongoing genome sequencing project at the Oregon National Primate Research Center, we identified a rhesus macaque with a rare homozygous frameshift mutation in the gene methyl-CpG binding domain 4, DNA glycosylase ( MBD4 ). MBD4 is responsible for the repair of C>T deamination mutations at CpG dinucleotides and has been linked to somatic hypermutation and cancer predisposition in humans. We show here that MBD4-associated hypermutation also affects the germline: the 6 offspring of the MBD4 -null dam have a 4-6-fold increase in de novo mutation burden. This excess burden was predominantly C>T mutations at CpG dinucleotides consistent with MBD4 loss-of-function in the dam. There was also a significant excess of C>T at CpA sites, indicating an important, unappreciated role for MBD4 to repair deamination in CpA contexts. The MBD4 -null dam developed sustained eosinophilia later in life, but we saw no other signs of neoplastic processes associated with MBD4 loss-of-function in humans, nor any obvious disease in the hypermutated offspring. This work provides the first evidence for a genetic factor causing hypermutation in the maternal germline of a mammal, and adds to the very small list of naturally occurring variants known to modulate germline mutation rates in mammals.