Accumulation of Deleterious Mutations and Fitness in a Pre-industrial Human Population
Adam D. Hayward1, Virpi Lummaa1,2, Georgii A. Bazykin3,4 1University of Sheffield; 2Wissenschaftskolleg zu Berlin; 3Institute for Information Transmission Problems; 4Moscow State University
Many of the mutations are detrimental to fitness, and each individual carries a burden of deleterious mutations that were accumulated over many generations. In humans, the number of de novo point mutations passed on to an offspring is strongly dependent on the father’s age. Here, we use extensive pedigree data on a pre-industrial Finnish population to get, for each individual, the ages of his or her male ascendants for up to three generations, and use this data as a proxy for the number of acquired mutations. Individuals whose fathers, grandfathers and great-grandfathers fathered their lineage at age of 20 were ~9% more likely to survive to adulthood than those with 40-year-old male ancestors. Among survivors to adulthood, older male ascendants were also associated with a reduced probability of getting married. These observations suggest that the deleterious mutations acquired from recent ancestors may be a substantial burden to fitness in humans.
Greg Cochran has been writing a lot about the accumulation of mutational load due to paternal age.
ReplyDeleteRelated:
ReplyDeleteAm J Psychiatry. 2013 Jun 1;170(6):599-608. doi: 10.1176/appi.ajp.2013.12101352.
"Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders.
Goriely A, McGrath JJ, Hultman CM, Wilkie AO, Malaspina D.
Abstract
There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation through dysregulation of the RAS protein pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare disorders related to paternal age (e.g., Apert syndrome, achondroplasia), this process is known as "selfish spermatogonial selection." This mechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews the mutational profile of sperm as men age, and enriches de novo mutations in the offspring of older fathers that preferentially affect specific cellular signaling pathways. This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. The authors outline hypotheses to test this model. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications.
http://www.ncbi.nlm.nih.gov/pubmed/23639989