An international study shows how and when entirely new gene mutations, known as de novo mutations, originate in dogs. A key finding is that higher paternal age increases the number of de novo mutations in puppies. Maternal age also has an effect.

A study completed at the University of Helsinki and the Folkhälsan Research Center analysed 390 parent–offspring trios. Trio denotes a design where the genomes of the puppy and both parents are sequenced. This enables accurately identifying gene mutations that do not occur in either parent’s genome – mutations that have taken place in the sperm, the ovum or soon after conception. While these rare mutations are the basis of evolution, they can also predispose their carriers to hereditary diseases.

“By combining the extended family trees in our biobank with exceptionally comprehensive DNA sequencing, we identified how and where in the genome de novo mutations occur,” says Professor Hannes Lohi from the University of Helsinki and the Folkhälsan Research Center.
The results also show why dogs differ from humans in certain genomic regions and what the findings mean for canine health and breeding.

Parental age affects the number of changes in the genome

The study demonstrated that, on average, only a few dozen entirely new DNA changes occur in puppies per birth, and that the generational mutation rate is surprisingly similar in different breeds, regardless of intense breeding selection.
Parental age is clearly linked to the number of new mutations. Higher paternal age in particular increased the number of new gene mutations in puppies more than previously reported in humans. A separate, albeit less pronounced, maternal effect was observed also.
In terms of size, large breeds appeared to accumulate relatively more early-life mutations, while the number of de novo mutations in small breeds grew faster with age. However, the total number of mutations per generation remained at the same level, regardless of breed.

New insights on the canine genome

A clear emphasis on gene regulatory regions known as CpG islands was seen in the location of these new mutations. In dogs, there was a clear increase in new mutations in these ‘on/off’ regions compared with other parts of the genome – in contrast to humans. A protein called PRDM9 plays a key role in humans and other mammals: it regulates genetic recombination in meiosis, or the production of gametes. This regulator is absent in dogs, which partly explains differences in the location of de novo mutations.

An exceptional case was also observed in the data: one puppy carried many times more mutations than usual, most of which originated in the dam. The case matches the possibility of a temporary disturbance in DNA repair during ovum differentiation. This phenomenon has also been observed in humans.
Applying the results to analyse the evolutionary history of dogs and wolves achieved an increasingly precise estimate of the dog–wolf divergence, indicating it to have taken place 23,000–30,000 years ago.

“Understanding when and where new DNA mutations occur helps to refine breeding decisions, including taking into account parental age,” concludes Lohi.

The results provide a baseline for research on the human genome as well.