Paternal age is a risk factor of interest in psychiatry: offspring of fathers 40 years of age and older are at two- to three-fold increased risk for schizophrenia (SCZ) and for autism-spectrum disorders (ASD), a heterogeneous group of disorders which now affects as many 1 in 88 children born in the United States. Although paternal age is known to be positively associated with mutation rate at certain Mendelian disease genes, paternal age has not yet been demonstrated to increase mutation rate genome-wide. Meanwhile a rapidly-growing body of literature links spontaneous changes in gene copy number (de novo copy-number variants, CNVs) to both ASD and SCZ. Furthermore, paternal age has recently been shown to be associated with altered epigenetic marks at key genes expressed in brain tissue. Taken together, these observations hold out the enticing possibility that advancing paternal age, by increasing germline mutation and epi-mutation rate, may explain some portion of the contemporary increase in ASD incidence in the industrialized West. Studying the effect of paternal age in human populations is quite difficult, but laboratory mice provide an ideal system in which to estimate both the magnitude and inter-individual variability of the effects of age on the fidelity of genetic transmission through males. The objective of this Kirschstein-NRSA individual (F30) fellowship proposal is to quantify the paternal-age effect (PAE) on genome stability in the germline of male mice, thus providing insight both on fundamental biological processes and an important and timely question in psychiatry. Using a mouse model, we will characterize the PAE at three levels: whole chromosomes, DNA sequence, and chromatin modifications.
The specific aims of this proposal are as follows: (1) Characterize the effect of age on the rate and distribution of meiotic recombination - the process by which many CNVs arise - in the male germline. (2) Use next-generation sequencing to precisely quantify the PAE on mutation rate for one specific class of mutations, CNVs, known to be associated with neuropsychiatric disorders. (3) Characterize the PAE on the landscape of one specific class of epigenetic marks, methylation. These studies will shed light on the mechanisms by which the stability of the genome is maintained with age in male germ cells, as well as advance understanding of the etiology of a group of common neuropsychiatric disorders.
Children of older fathers (age >40 years) are at increased risk for psychiatric and neurological disorders including autism and schizophrenia. This risk could be explained by an accumulation of new DNA mutations in sperm as men age. However, a rigorous test of this hypothesis in humans is difficult, and it remains to be shown that advanced paternal age leads to a net increase in the number of new mutations passed on to children. Instead, we propose to use laboratory mice to examine the relationship between paternal age and genetic abnormalities. As the proportion of children conceived by older men grows, this question has increasing relevance for public health and for our understanding of the epidemiology of mental illness.