The how, when and where of human genetic mutation is a complex and (to me, anyway) fascinating topic:
How: There are diverse and only partially understood molecular mechanisms by which DNA strands are altered, from a single base change up to complex rearrangements of entire chromosomes.
When: Mutations can occur at any time in life, from meiotic defects prior to fertilization all the way up to acquired mutations late in life.
Where: Mutations can be constitutional (in all your cells) or somatic (in just some of your cells). Constitutional changes are usually inherited from your parents, whilst somatic mutations are really the domain of cancer.
But you can also be mosaic for a mutation too, meaning that you have developed such that some of your cells contain a mutation while others do not. So some of your tissues may be “mutant” while others will be “normal”, although what effect this has on phenotype is really all over the map. Or, you can be a germline mosaic, which is a special situation where the mutation is generally confined to your germ cells (that make eggs/sperm). For example, a mother has multiple sons with muscular dystrophy but testing her shows that she isn’t a carrier for the mutation. Possibly her ovaries do carry the mutation, but her blood that was tested does not. In practice, germline mosaicism is difficult to detect and it often keeps clinical geneticists from feeling certain about inherited disease.
All this is a very long-winded introduction to this recent paper on recurrent mutations in Noonan Syndrome. Noonan Syndrome is an inherited disorder that affects about 1 in 2500 children worldwide – individuals have short stature, heart defects and characteristic physical features.
Mutations in genes of the RAS-MAPK pathway have been identified as the cause of this disorder. In particular, a specific mutation in the gene PTPN11 has been seen in many affected individuals, and an association has been made between this mutation and increased paternal age. In other words, the fathers of children who carry this mutation tend to be older. But why is that? The authors of this paper present data supporting a perhaps unexpected answer. This particular mutation gives a selective growth advantage to their spermatocytes (sperm producing cells). Natural selection. In your pants. It’s happening right now, guys.
Unlike women, as men age their germ cells continue to divide and during this time they can acquire new mutations resulting from errors during DNA replication. If you’re 40 years old then your germ cells have gone through about 800 cell divisions (versus 23 for a woman), and each division carries the chance of creating a new mutation. But since all spermatocytes have a roughly equal chance of producing the sperm that results in an offspring these mutations are generally diluted. However, in the case of the PTPN11 mutation c.922A>G, the spermatocytes that acquire this mutation grow much better than the others and so they can out-produce their rivals. This greatly increases the frequency of sperm carrying this same mutation, thus increasing the chances that offspring will inherit the change. And while the mutation makes the spermatocytes grow better it causes Noonan Syndrome when carried as a constitutional mutation.
There is a whole lot more to the paper than this, but if nothing else it’s a great example of a neat when and where of human mutation. Plus, it’s a reminder that selective growth advantage is important in biology in ways we often don’t appreciate.
Here’s the publication: https://www.sciencedirect.com/science/article/pii/S0002929713002140?np=y
Figure below shows the spatial distribution of mutation c.922A>G in the dissected testicles of healthy males. (I think – I stopped reading the methods right around that point.)
