Germline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers

Abstract

Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples are the common mutations at one or a few sites in the genes causing achondroplasia, Noonan syndrome, multiple endocrine neoplasia 2B and Apert syndrome. These mutations are recurrent, provide a gain of function, are paternally derived and are more likely transmitted as the father ages. Recent experiments tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rejects the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load and adaptive evolution.

New insights into the generation and role of de novo mutations in health and disease

“…For instance, gain-of-function mutations in genes in the RAS–MAPK pathway have been shown to cause clonal expansion of mutant spermatogonial stem cells owing to proliferative selective advantage [77, 78]. Computational modeling suggests that this would result from a slightly increased ratio of symmetric versus asymmetric divisions in mutant spermatogonial stem cells, favoring the production of two mutated spermatogonial stem cells compared with a single mutated stem cell and one differentiated spermatogonial stem cell harboring the mutation [79, 80]. Therefore, over time, spermatogonial stem cells carrying these mutations undergo positive selection owing to higher self-renewal than surrounding wild-type cells and expand clonally in the testis [81].…”

Genome evolution is driven by gene expression‐generated biophysical constraints through RNA‐directed genetic variation: A hypothesis

“…As a consequence, male germ cells produce the most complex set of coding and noncoding transcripts and alternative splicing variants [159][160][161][162]. Therefore, male germ cells may experience extensive transcription-mediated genomic instability that could explain the large-scale apoptosis of immature sperm cells [4,163,164]. Another consequence of transcription of genome-wide waves in male germ cells is the expression of a wide variety of retrotransposon-derived RNAs, which results in the activation of the piRNA pathway [159][160][161][162].…”

“…methylation) and structural features (e.g. non B-DNA structures), or chromatin marks and topology [1][2][3][4][5]. This is likely because these genomic factors impact on different mutational processes such as DNA damage or editing, or processes involved in DNA repair [6][7][8][9].…”

Gonadal mosaicism and non‐invasive prenatal diagnosis for ‘reassurance’ in sporadic paternal age effect (PAE) disorders

“…Briefly summarised, these features comprise (1) a very high apparent germ line mutation rate, (2) extreme bias towards a paternal origin of mutations, (3) markedly elevated age of the healthy father (this is the PAE by which these disorders are collectively known) and (4) the causative mutations confer gain‐of‐function to the encoded proteins, which are involved in signalling through the growth factor receptor‐RAS‐mitogen‐activated protein kinase (MAPK) pathway. An alternative collective term is ‘RAMP’ (recurrent, autosomal dominant, male‐biased, PAE) . We have demonstrated that PAE disorders arise in testes by clonal expansion of rare mutations along segments of seminiferous tubules, through a mechanism termed selfish spermatogonial selection .…”

“…An alternative collective term is 'RAMP' (recurrent, autosomal dominant, male-biased, PAE). 6 We have demonstrated that PAE disorders arise in testes by clonal expansion of rare mutations along segments of seminiferous tubules, through a mechanism termed selfish spermatogonial selection. 7,8 This process occurs during adulthood; hence, despite positive selection, the mutations never attain the levels in sperm associated with classical gonadal mosaicism, which arises during early embryonic development.…”