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Annotation

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 23 ; 488(7412):471-5. PubMed Abstract

Comments on Paper and Primary News
Primary News: New Mutations Mount as Fathers Age

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

Primary News: New Mutations Mount as Fathers Age

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

Primary News: New Mutations Mount as Fathers Age

Comment by:  John McGrath, SRF Advisor
Submitted 28 August 2012 Posted 28 August 2012
  I recommend this paper

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

Primary News: New Mutations Mount as Fathers Age

Comment by:  Georg Winterer (Disclosure)
Submitted 28 August 2012 Posted 28 August 2012
  I recommend this paper

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


Primary News: New Mutations Mount as Fathers Age

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


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View all comments by George Kirov

Primary News: New Mutations Mount as Fathers Age

Comment by:  Bernard Crespi
Submitted 3 September 2012 Posted 5 September 2012
  I recommend this paper

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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