The Last Word On Nothing

You probably heard about last week’s Nature study on older dads and autism; it got a lot of attention. The basic findings were fascinating but, in my opinion, far less sensational than what most of the news articles would have us believe.

The researchers, led by Kári Stefánsson of deCODE Genetics in Iceland, showed that the average 20-year-old man passes on about 25 new single-letter DNA mutations to his child. (These kinds of mutations happen spontaneously in sperm cells, so they don’t affect the DNA in the father’s other cells.) With each passing year of age, the man’s sperm acquires two more mutations. This makes sense, biologically. Sperm Primordial sperm cells divide over and over throughout a man’s life. To use an over-used metaphor: Each time the code gets copied, it creates an opportunity for a spelling mistake. Eggs Primordial eggs, in contrast, go through far fewer divisions. Women, no matter what their age, pass on about 14 mutations to each child, the study found.

The researchers also showed, using demographic data of Icelanders going back to 1650, that the average age of fathers has recently shot up, from 27.9 years in 1980 to 33 in 2011. Based on their calculations, that means the average number of mutations passed on to each kid (from mother and father combined) went from 59.7 to 69.9.

Here’s the sensational part. Stefánsson says, given that these mutations have been linked to autism, the increase in older fathers could partially explain why autism rates have risen over approximately the same time period. This is a plausible idea, sure, in theory. But there’s actually not much data to back it up (more on that later). And yet the assertion — reported in the New York Times, Wall Street Journal, Washington Post and more than 250 other outlets (Slate’s XXfactor blog even ran a piece titled, “Dude, Bank Your Sperm. It’ll Get You Laid.”) — was enough to scare some potential fathers. As one of my friends Tweeted, “great, my 34yr-old gonads may be ticking neuro-disorder timebombs.”

It’s an unsettling feeling, I’m sure. I’ve felt a similar panic about being an older mother (though for different reasons). But honestly, men, of all the things to spend time worrying about, this study is not one of them. Here’s why.

1. Mutations are usually harmless.

We all carry these mutations (on average, each of us carries about 60 of them, according to the new study), and the vast majority don’t do any harm. Remember that we have 3 billion pairs of DNA letters in our genome, and a mutation changes only one letter. In order to do harm, the mutation has to land on a letter that, when changed, would prevent a gene from being made into a protein correctly*. Only about 3 percent of our genome codes for protein (it’s called the exome). The math is trickier than I’m making it seem, but still, the odds of any one mutation hitting a vulnerable spot in a vulnerable gene are pretty slim.

Which means the increased risk for older dads is also slim. Think of it like a craps game where, for every mutation in a guy’s sperm, he has to roll the dice once. Each die has a thousand faces, say, and only one combination will lead to his child having an illness. (I’m totally making up the numbers here, the point is the odds are small.) A 20-year-old guy has to roll the dice 25 times. A 30-year-old, 45 times, and a 50-year-old, 85 times. Even the 50-year-old is very unlikely to roll the unlucky combo.

(Even this analogy is probably exaggerating the risk. In the past few years, researchers have discovered that many genetic variants associated with psychiatric disorders have “incomplete penetrance,” meaning that having them doesn’t always mean trouble. Exactly the same genetic lesion can be carried by someone with severe autism, mild autism, or no problems at all.)

2. We have no idea how many cases of autism these mutations might explain.

If mutations are no big deal, then what is the autism link all about? Well, two things. First, several large epidemiological studies have analyzed historical data and found a provocative trend. The risk of an older father having a child with autism is higher than the risk for a younger father. A highly cited study found that fathers older than 50 have 2.2 times the risk of fathers younger than 30. That’s the sort of difference that makes headlines. But for an individual, it’s not that bad: The actual rate for men over 50 was 18.8 per 10,000, compared with 7 per 10,000 for the men under 30. (The reason the rates are so low, compared to today’s autism rate of 113 per 10,000, is because the records were for kids born between 1983 and 1992, before autism prevalence surged.)

Second, four major studies published earlier this year compared the exome sequences of several hundred individuals with autism and their unaffected family members. They showed that participants with autism tend to carry more mutations in this part of the genome than controls do.

The exome studies, though heralded as a breakthrough, also raised lots of questions. Because healthy people carry so many mutations, it’s very difficult, statistically, to figure out which mutations in individuals with autism are causing trouble and which are benign. Nor do we know, of all of the cases of autism in the world, how many are affected by these mutations. Current estimates range from 5 to 20 percent, but it will take a lot more data to pin it down more definitively. Even if you assume the highest estimate, that means lots of individuals with autism (even those with, gasp, older dads!) don’t carry any more mutations than the average Joe.

 3. Being a younger dad isn’t necessarily a good thing.

A fact from the new report that didn’t get mentioned much: Of the 65 participants with either autism or schizophrenia, 12 had fathers 25 years or younger. So it’s not as if being a young dad wipes out the risk of passing on damaging mutations, it just decreases it ever so slightly.

Which leads me to my last and most important point. There are so many legitimate factors to consider when deciding if and when to have a child. A 20-year-old man may not have found the right partner yet, or may not be as emotionally mature or financially stable as his future 30-, 40-, or 50-year-old self. (Poverty and parental neglect, as I’ve ranted about before, can hurt a child’s brain as much as a genetic glitch.) So, under what circumstances — on what planet, really? — would this teeny tiny increased risk of passing on autism-causing mutations be relevant to this decision?

And on a related note, how many times do researchers have to say, “The cause of autism is really complicated” before journalists and the public accept that the disorder can’t be explained by a gene, a brain scan, a father’s age, a gluten-rich diet or risk factor du jour?

—

Update: A mistake has been fixed in the second paragraph, as noted with strike-through text.

*This isn’t strictly true. Undoubtedly there are places in the non-coding part of the genome that, when mutated, could cause trouble. But since nobody knows much of anything about these yet, I’m conveniently ignoring them. Even if you account for them, my basic argument stands. I think.

If you want even more nitty-gritty details of the new study, check out my news piece on SFARI.org.

Photos by paolakosch and Darwin Bell