Older Dads’ Kids at Higher Risk for Genetic Disease

High Mutation Rate + Selfish Sperm = Trouble

Over the last few years, it has become apparent that older dads have kids with more genetic diseases than younger dads.  This is clearest for simpler diseases like dwarfism or Apert syndrome.  But newer data is pointing towards an increased risk for more complex diseases like autism and schizophrenia too.

A big reason for this is highlighted in a new study out in Nature that shows that the older the dad, the more mutations he passes down to his kids.  They were able to calculate that for every year older, a dad will pass on an average of two new mutations to his child.  Mom’s age didn’t affect the number of mutations much at all and she contributed fewer mutations to her kids no matter what her age.

Most of the time dad’s extra mutations don’t much matter.  The DNA changes are in parts of our DNA that don’t do a whole lot.  Or the mutation doesn’t muck up anything important.

But sometimes they do matter.  Occasionally a mutation will happen in an important part of the DNA in such a way as to lead to disease.  This is the main reason the children of older dads are at a higher risk for certain genetic diseases --their dad gave them old, battered DNA.

This isn’t enough to explain the increased risk for these diseases though.  While older dads do pass on more mutations, the number isn’t high enough to explain the high incidence of these genetic diseases.  There are too few mutations spread out over way too much DNA.  No, something else must be going on.

In a recent review in The American Journal of Human Genetics, the authors float the idea that certain mutations give advantages to the sperm in its testicular environment.  So the sperm are busy making copies of themselves to be sent out in search of an egg.  Occasionally one gets a mutation that makes it heartier in some way and so it out competes its brethren.  Now it becomes more common.

Unfortunately, what makes a hearty sperm might make for an ill child.  The environment for a single cell in a testicle is obviously very different from a whole person out in the world!  The authors argue that some mutations that lead to disease can be useful for single sperm.

If true, these findings can explain a lot.  And they suggest big changes for human DNA in future generations.

Both men and women are waiting to have children later in life.  That means an increase in the number of mutations being passed down to the next generation.  This might help to explain at least part of the increase in autism in the U.S. and Europe. 

Older dads also means the mutation rate for humans is accelerating.  Humans will more quickly become genetically diverse than they might have in the past.

Now despite the scary sound of the word mutation, this isn’t necessarily a bad thing.  Mutations are where all the genetic diversity in the human race ultimately came from.  And the more diverse humans are, the more likely they are to survive some new biological threat.

But if the selfish sperm hypothesis is true, older dads will also mean a build up of whatever DNA changes are good for making sperm.  Remember, what’s good for the sperm isn’t necessarily good for everyone else.

Any mutations that lead to major disease are not the big problem evolutionarily speaking (although they can obviously be devastating individually).  These mutations do not tend to get passed on. 

Where these mutations become a problem is when they have minor negative effects on people.  Because of the advantage to the sperm, these slightly harmful mutations may get passed on more often and become more common in the population.  Even though their main advantage is to the individual sperm!

Until recently, all the focus was on older moms and their increased chances for having children with big DNA problems.  Now the focus is widening to include older dads.  Even though their changes are smaller, they can still have big effects.

More Information

What got this guy to the egg first may not be good for the resulting child.

 

 

 

 

 

 

 

 

 

 

 

 

The children of older dads are more likley to have dwarfism.  They may also be at a higher risk for autism and schizophrenia.

Continuously Making Sperm Means More Mutations

Men build up more mutations than women because they are constantly churning out new sperm.  Something like 85 million per day on average.  Women on the other hand are born with all the eggs they will ever have.

This matters because one of the big ways to generate mutations is when DNA is copied.  And when men are churning out that much sperm, DNA is getting copied lots and lots of times.

New cells are made when a cell doubles in size, copies its DNA and then splits in two with each new cell getting a copy of the DNA.  Sperm go through an additional step or two at the end where the cells split again without copying the DNA but that doesn’t concern the story here.

What this means is that when a cell divides, it needs to copy all of its six billion A’s, T’s, C’s and G’s, letter for letter.  It would use too much of a cell’s resources to ensure there are no errors in the process.  Cells have to balance error rate against energy cost and that balance means that the occasional mistake will slip through.

This explains why older dads have more mistakes in their sperm DNA.  An older man has had to copy his sperm DNA many more times than a younger man.  And each time a DNA is copied, there is a chance for a mistake to set in.  So there is a bigger chance for additional DNA mistakes.

Recently the cost of looking at DNA has gone down so much that scientists are able to look at lots of people’s DNA in great detail.  In this study, they looked at all of the A’s, G’s, C’s and T’s of thousands of different people. 

To home in on the mutations that came from dad, the researchers focused on the five families they had where they had three generations’ worth of DNA.  By comparing grandparents, parents, and children, they were able to determine from which parent the mutations in the second generation came from.  Here are the results:

 

Dad’s age (years)

Dad’s mutations (number)

Mom’s age (years)

Mom’s mutations (number)

Trio 1

21.8

39

19.3

9

Trio 2

22.7

43

19.8

10

Trio 3

25.0

51

22.1

11

Trio 4

36.2

53

32.2

26

Trio 5

40.0

91

39.1

15

 

As you can see, older dads have more mutations than younger dads.  But what is also obvious is that it can be very difficult to untangle mom and dad’s contributions because they tend to track together in age.  Older dads tend to have children with older moms.

This study is able to show conclusively that as dad ages, he passes down more mutations to his kids.  And that mom’s age doesn’t much matter for these sorts of mutations.  (Her age plays a role in diseases like Down syndrome that involve a different sort of DNA issue.)

They took this further and looked at 63 other families in detail.  From this they were able to calculate the additional 2 mutations/year of dad’s age.

However, even Dad 5 only contributed 91 mutations.  That is 91 out of 6 billion possible mistakes.  The odds of these having a significant impact are slim.  Unless there is some sort of selection for them…

Selfish Sperm

One idea the authors in the second study put forth is that certain mutations allow sperm to thrive in their natural habitat.  The mutated sperm then go on to prosper and become more common.  The DNA in these sperm are then more likely to find their way into the next generation.

This is a nice theory but it isn’t the only possible one.  For example, it could be that certain parts of the DNA are more prone to mutation.  These would then be more common in sperm and get passed down.

The best evidence the authors have is with the diseases dwarfism or Apert syndrome.  These are the easiest to understand because the actual mutations that lead to the diseases are known and the diseases are caused by mutations in a single gene.  This makes analysis and investigation much simpler.

What the authors have found is that these diseases (as well as some other well established paternal age ones) all happen from dominant mutations in growth factor/signaling genes.  Dominant makes sense because they have to happen from a single mutation in a gene.  If it were recessive, there would need to be mutations in both copies of the gene.  This is exceedingly unlikely.

The growth factor part makes sense too.  One way to give a sperm an advantage is to have it grow faster and develop sooner.  Mutations in these types of genes might lead to faster developing sperm especially since many of them are involved in spermatogenesis.

Still, there is a lot more work to be done on this theory.  Whether true or not, one thing for sure is that the trend for older dads means that this generation will pass down more mutations to the next than did our forefathers one hundred years ago.  The rate of genetic change in human DNA is definitely accelerating.

Each time a cell divides, there is a small chance for a mutation.  The more divisions, the greater the number of mutations.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

What's an advantage for the sperm here might not be good news for the child it fathers.