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Top 3 Reasons to Stop Fretting About Being an Old Dad

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 TimesWall Street JournalWashington 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

This post was originally published on The Last Word on Nothing

There are 9 Comments. Add Yours.

  1. RAJensen
    August 27, 2012

    Klinefelter Syndrome (KS) along with Down syndrome is one of the most common genetic syndromes affecting between 1 in 500-1,000 boys. KS which affects only males is not inherited and is caused by an extra X chromosome and presents with the KS genotype of XXY in contrast to the typical gender phenotypes of XY (males) and XX (females). The parent of origin is paternal in about half the cases and the parent of origin is maternal in about half the cases. KS is always caused by an XY sperm mutation or an XX egg mutation. The past year has produced increasing evidence that environmental risk factors may be involved in the generation of de novo gene mutations and that there is an age effect (paternal and maternal) operating in the developmental disorders including KS, intellectual disability, autism, ADHD and schizophrenia.

    The pesticides PCB and DDT have been banned in the US however the new classes of pesticides still contain many PCB and DDT congeners. The new classes of pesticides have a long half-life and increasing levels of exposures may build up over time producing increased levels of PCB and DDT congeners in reproductive cells (sperm or egg) and may explain the parental age effect seen in the development disorders.

    The advanced technological achievement of fluorescent in situ hybridization (FISH) has allowed evolutionary biologists to directly examine the locations and frequency of sperm mutations in male donors. The methodology requires examining a minimum of ten thousand individual sperm per donor. McAuliffe and colleagues recently (April 2012) reported that increasing levels of environmental exposure to PCB and DDT congeners measured in blood was associated with increased production of XY sperm in sub fertile males. Lowe’s group examined the sperm of 38 unaffected fathers of Klinefelter boys and found that XY sperm mutations was present in all the fathers and the frequency of XY sperm mutations increased with advancing paternal age.

    The C-BASS (Chinese – Benzene and Sperm Study) group (Nov 2011) examined the frequency of sperm mutations in workers who were benzene exposed in manufacturing plants in China and found increasing levels of workplace benzene exposure produced increased frequency of 1p36 sperm mutations and is a risk factor for 1p36 deletion syndrome. The burning of fossil fuels releases benzene particles into the atmosphere. Benzene is a natural constituent in all fossil fuels, petroleum, natural gas and coal. Benzene because of its high octane number is an additive in the production of refined gasoline and diesel fuels and may explain why living in close proximity to heavily congested polluted freeways in California is associated with an increased risk for autism possibly via sperm or egg mutations.

    http://ghr.nlm.nih.gov/condition/1p36-deletion-syndrome

    http://ghr.nlm.nih.gov/condition/klinefelter-syndrome

    References

    Lowe X, Eskanazi B, Nelson D, Kidd S, Alme A. (2001). Frequency of XY Sperm Increases with Age in Fathers of Boys with Klinefelter Syndrome. Am J Hum Genet. 2001 November; 69(5): 1046–1054. Full text available at:

    http://www.ncbi.nlm.nih.gov/pubmed/11582569

    Marchetti F, Eskanazi B, Weldon RH et al (2011). Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environ Health Perspect
    Doi:10.1289/ehp.1103921. Full text available at:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279447/

    McAuliffe ME, Williams PL, Korrick SA, Altshul LM, Perry MJ. (2012). Environmental Exposure to Polychlorinated Biphenyls and p,p´-DDE and Sperm Sex-Chromosome Disomy. Environ Health Perspect. 2012 April; 120(4): 535–540. Full text available at:

    http://ehp03.niehs.nih.gov/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1289%2Fehp.1104017

    Volk HE, Hertz-Picciotto I et al (2010). Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect 119(6): Full text available at

    http://www.ncbi.nlm.nih.gov/pubmed/21156395

  2. RAJensen
    August 27, 2012

    Virginia;
    You are correct in stating ‘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’.

    Most autism researchers would agree that autism is a strongly genetically influenced disorder and at the same time is a multifactorial disorder. The small genetic glitches seen in de novo mutations, as well as in inherited mutations, most often involves copy number variations (CNV) that deviate from population norms. CNV may be benign however a number of genetic epidemiologists are now beginning to investigate how gene/environment interactions can increase autism risk during fetal development even in the presence of assumed benign CNV.

    The role of CNV, inherited or de novo, in human disease has been found to confer both risk and protective effects. A lesson can be learned from AIDS researchers who have identified common CNV widely distributed throughout the general population. CNV in the gene CCL3L1 which maps to chromosome 17q has been identified in a sub-group of people with and without HIV-1 infection after exposure to HIV-1. Lower CNV are associated with enhanced risk for acquiring HIV-1 infection while higher CNV are associated with reduced risk for acquiring HIV-1 infection. The CCL3L1 CNV appear to be benign and HIV-1 infection is the consequence of a GxE interaction in this sub group.

    CNV in CCL3L1 is also associated with increased risk for Systemic Lupus Erythematosus (SLE). Klinefelter Syndrome boys have an increased risk for SLE and the level of risk is at the same level found in adult women. Lower CNV in CCL3L1 is also associated with increased risk for acquired Hepatitis C. Benign CNV in CCL3L1 is associated with increased risk for autoimmune and infectious disease which in turn are associated with autism risk

    References

    Liu S, Yao L and Zhu H. CCL3L1 copy number variation and susceptibility to HIV-1 infection: a meta-analysis. Plos One. 2010 Dec 30;5(12):e15778.

    http://www.ncbi.nlm.nih.gov/pubmed/21209899

    Mamtani et al (2008). CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus.

    http://www.ncbi.nlm.nih.gov/pubmed/17971457

    Grunehage et al (2010). Lower copy numbers of the chemokine CCL3L1 gene in patients with chronic hepatitis C.

    http://www.ncbi.nlm.nih.gov/pubmed/20044164

  3. Michelle Nijhuis
    August 31, 2012

    Great post, Ginny. And IMHO, that old dad is pretty foxy. (This must mean I’m an old mom … !)

  4. LeAnna
    January 21, 2014

    I love the info

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