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New Mutations Mount as Fathers Age

27 August 2012. As a man ages, the chance that his children will carry new, spontaneously occurring mutations grows, according to a study published 23 August in Nature. Led by Kari Stefansson of deCODE Genetics in Reykjavik, Iceland, the study sequenced the entire genomes of 78 families consisting mainly of unaffected parents and their children with autism or schizophrenia. The study identified an average of 63 single-nucleotide changes per person that were not inherited from their parents, but arose “de novo,” likely in parental sperm or egg cells. More de novo mutations were found in people with older fathers than with younger fathers, with an effect size of about two mutations per year of a father’s age; a mother’s age did not have an influence.

The study offers an explanation for epidemiological studies that find older fathers are more likely to have children with schizophrenia (see SRF Current Hypothesis) or autism (Croen et al., 2007). Researchers suspect things go wrong at the level of sperm cells, which are made throughout a man’s life, unlike a woman’s egg cells. Each round of DNA replication prior to cell division could introduce copying errors. If these mutations accumulate in sperm cells with age, then the chances of disrupting a gene involved in either disorder would increase. In line with this idea of sperm as crucibles for mutation, a study published July 20 in Cell sequenced the genome within individual sperm cells from a single man, and found 25-36 point mutations in each cell (Wang et al., 2012).

Though previous studies reported a similar effect of a father’s age on de novo mutations in the protein-coding exome of people with autism (see SRF related news story), the extent to which the new findings explain the paternal age epidemiology is unclear. This will depend on how many schizophrenia or autism cases actually result from de novo mutations in the first place—though exome sequencing studies have reported an excess of de novo mutations in schizophrenia (see SRF related news story and SRF news story), these kinds of mutations turn up in healthy people, too. An alternative explanation for the epidemiology hinges on inherited mutations: fathers carrying disease-related mutations may show subclinical signs of schizophrenia, which could delay their married-with-kids stage of life. Last year, a study suggested that a father’s age at the birth of his first child—rather than the birth of the child who eventually develops schizophrenia—matters more (Petersen et al., 2011).

All in the family
First author Augustine Kong and colleagues sequenced the genomes of 44 people with autism, 21 with schizophrenia, 13 without a disorder, and both parents of each. Scanning the entire genome for nucleotide changes present in offspring but not in parents, the researchers identified 4,933 de novo mutations in total, with an average of 63 new mutations in each child in the family. With 2.63 billion base pairs effectively scanned, the researchers pegged the de novo mutation rate at 1.2 x 10-8 per nucleotide per generation, in line with other studies. Though this rate relies largely on data from autism and schizophrenia samples, it may not differ in healthy people.

For five of these families, three generations' worth of data were available because the offspring had children themselves. This allowed the researchers to trace which chromosome—mother’s or father’s—harbored the de novo mutation, thus clarifying where the trouble began. Identifying the de novo mutations that were then inherited by the third generation, the researchers looked for maternal or paternal markers nearby that originated from the first generation. This analysis pointed to the fathers, who contributed an average of 55 mutations to their child, whereas mothers added only 14. The number was substantially more variable in fathers than in mothers, too, leading the researchers to examine age as a factor in this variability.

The father effect
Considering the 4,933 de novo mutations from all the families, the researchers found that the number of mutations increased nearly linearly as the father’s age increased (p = 3.6 x 10-19). For example, children born when their dads were 20 years old carried around 40 mutations, whereas those born when their dads were 40 years old carried about 80. The father’s age could explain up to 97 percent of the variance in de novo mutation number, which seems to limit contributions by other factors, including the mother’s age. Though the mother’s age correlates with the father’s age (r = 0.83), removing the effect of the mother did not change the relationship between the father’s age and de novo mutations. This suggests the mother’s age matters less for point mutations, and more for larger genetic glitches like the extra chromosome found in Down’s syndrome.

The researchers noted some de novo mutations in interesting places. Seventy-three landed in protein-coding parts of genes, and, of interest to schizophrenia, one person with schizophrenia carried a protein-truncating mutation in neurexin. Neurexin is thought to help wire synapses together (see SRF related news story), and several studies have found small deletions within the gene in people with schizophrenia, autism, and other psychiatric disorders (Schaaf et al., 2012; see SRF related news story).

The authors suggest that the influence of a father’s age is so profound that it might not make sense to talk about a stable mutation rate across the genome, but instead to consider it a time-dependent variable. This malleability highlights how societal factors, like shifts in the age when people first become parents, can shape the genome, but whether this influences risk for schizophrenia or autism remains an interesting question.—Michele Solis.

Reference:
Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 22; 488: 471-475. Abstract

 
Comments on News and Primary Papers
Comment by:  Dolores Malaspina
Submitted 27 August 2012 Posted 27 August 2012

The new report by Kong et al. (2012) demonstrates that paternal age is likely to be an important source of mutations that are relevant for schizophrenia, as we earlier hypothesized (Malaspina, 2001). Kong et al. demonstrated that the diversity in human mutation rates for offspring is dominated by the paternal age at conception. Following our initial observation that advancing paternal age was substantially associated with an increasing risk for schizophrenia, explaining a quarter of the population's attributable risk for schizophrenia (Malaspina et al., 2001), many scientists found it difficult to accept that the father’s age could be a risk pathway for schizophrenia. By contrast, the hypothesis that paternal age explained the risk for achondroplastic dwarfism achieved far greater immediate acceptance over 20 years ago (i.e., Thompson et al., 1986). While these new findings will surely advance our understanding of many de novo...  Read more


View all comments by Dolores Malaspina

Comment by:  Patrick Sullivan, SRF Advisor
Submitted 27 August 2012 Posted 27 August 2012

Kong et al. sequenced 78 pedigree clusters (mostly parent-offspring trios) to around 30x coverage. After careful quality control, they identified an average of 63 new mutations per trio. These mutations were “de novo” in that they were absent in the parents but present in an offspring and assumed to have occurred during gametogenesis.

Intriguingly, more of these mutations occurred in older parents. The authors present several lines of evidence to implicate fathers rather than mothers, and estimated that there were about two extra de novo mutations per year of increase in paternal age. This conclusion is consistent with several of the exome sequencing papers published in Nature a few months ago.

Increased paternal age is an epidemiological risk factor for schizophrenia and autism, with relative risks on the order of two and five, respectively. This paper suggests a potential mechanism for the paternal age effect that might eventually prove to be relevant for some fraction of cases.

It is important to note that advanced paternal age is a risk factor, not a...  Read more


View all comments by Patrick Sullivan

Comment by:  John McGrath, SRF Advisor
Submitted 28 August 2012 Posted 28 August 2012
  I recommend the Primary Papers

In 2001, Dolores Malaspina alerted the research community to the link between advanced paternal age and increased risk of schizophrenia—she suggested that this may be due to de novo mutations in the male germ line (Malaspina et al., 2001). The study BY Kong et al. provides compelling evidence in support of this hypothesis (Kong et al., 2012). A related paper in Nature Genetics also demonstrates an association between paternal age and changes in microsatellite properties across generations (Sun et al., 2012).

While the hypothesis that de novo mutations accumulate due to copy error mutations in the production of germ cells in older males is compelling, it is still possible (albeit unlikely) that this association may be due to unmeasured confounding. For example, older men might be exposed to more environmental toxins that accumulate over time and subsequently cause mutations in the offspring of older dads as a byproduct of the...  Read more


View all comments by John McGrath

Comment by:  Georg Winterer (Disclosure)
Submitted 28 August 2012 Posted 28 August 2012
  I recommend the Primary Papers

Just a few thoughts:

One question is whether it is just age per se that produces de novo mutations or an accumulation of environmental effects like drug abuse, alcohol, or other potentially harmful toxic environments, etc. What I also would like to know is whether it is the number of sperm cycles; in that case, men who are sexually more active should have a greater risk to produce more de novo mutations.

View all comments by Georg Winterer


Comment by:  Michael O'Donovan, SRF AdvisorGeorge Kirov
Submitted 31 August 2012 Posted 31 August 2012

In a genomic sequencing study of 78 parent-proband trios (21 probands with schizophrenia, 44 with autism spectrum disorder [ASD]), Kong and colleagues (2012) identify almost 5,000 DNA single base changes that occurred as a result of new mutations. For five of the trios, the proband had a child who was also sequenced, and in this subset with three generations of data, Kong and colleagues were able to determine if the mutations had arisen on the paternal or maternal chromosomes. Although this subsample was small, paternal chromosomes showed much greater variance in the number of mutations than maternal chromosomes, suggesting that paternal variables are more relevant to variance in the overall de novo mutation rate than maternal variables. In the larger sample as a whole, although the parental origin of the mutations could not be determined, the number of new mutations carried by an individual could be almost completely explained by a combination of random variation and paternal age. Models of linear and of exponential increases in the number of mutations by paternal age both...  Read more


View all comments by Michael O'Donovan
View all comments by George Kirov

Comment by:  Bernard Crespi
Submitted 3 September 2012 Posted 5 September 2012
  I recommend the Primary Papers

Kong et al. (2012) is an outstanding paper that provides the first detailed quantification of how human de novo mutations in sperm and eggs vary with parental age. The paper and its aftermath provide a number of important lessons for researchers studying neurodevelopmental disorders and parental age:

1. The work demonstrates directly that CpG dinucleotides contribute the lion's share of new mutations. CpG sites are of particular interest in understanding effects of de novo mutations because they differentially create new transcription factor binding sites (Zemojtel et al., 2011), as well as mediate the effects of methylation and genomic imprinting. Such findings might help to focus efforts at interpreting the functional importance of the myriad de novo variants that pepper each genome.

2. The work generates an apparent paradox: if, as the authors claim, paternal age so strongly predominates over maternal age in its de novo mutational effects, why do so many parental-age studies of autism and schizophrenia show clear...  Read more


View all comments by Bernard Crespi
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