Assessing human germ-cell mutagenesis in the Postgenome Era: a celebration of the legacy of William Lawson (Bill) Russell

Abstract

Birth defects, de novo genetic diseases, and chromosomal abnormality syndromes occur in approximately 5% of all live births, and affected children suffer from a broad range of lifelong health consequences. Despite the social and medical impact of these defects, and the 8 decades of research in animal systems that have identified numerous germ-cell mutagens, no human germ-cell mutagen has been confirmed to date. There is now a growing consensus that the inability to detect human germ-cell mutagens is due to technological limitations in the detection of random mutations rather than biological differences between animal and human susceptibility. A multidisciplinary workshop responding to this challenge convened at The Jackson Laboratory in Bar Harbor, Maine. The purpose of the workshop was to assess the applicability of an emerging repertoire of genomic technologies to studies of human germ-cell mutagenesis. Workshop participants recommended large-scale human germ-cell mutation studies be conducted using samples from donors with high-dose exposures, such as cancer survivors. Within this high-risk cohort, parents and children could be evaluated for heritable changes in (a) DNA sequence and chromosomal structure, (b) repeat sequences and minisatellites, and (c) global gene expression profiles and pathways. Participants also advocated the establishment of a bio-bank of human tissue samples from donors with well-characterized exposure, including medical and reproductive histories. This mutational resource could support large-scale, multiple-endpoint studies. Additional studies could involve the examination of transgenerational effects associated with changes in imprinting and methylation patterns, nucleotide repeats, and mitochondrial DNA mutations. The further development of animal models and the integration of these with human studies are necessary to provide molecular insights into the mechanisms of germ-cell mutations and to identify prevention strategies. Furthermore, scientific specialty groups should be convened to review and prioritize the evidence for germ-cell mutagenicity from common environmental, occupational, medical, and lifestyle exposures. Workshop attendees agreed on the need for a full-scale assault to address key fundamental questions in human germ-cell environmental mutagenesis. These include, but are not limited to, the following: Do human germ-cell mutagens exist? What are the risks to future generations? Are some parents at higher risk than others for acquiring and transmitting germ-cell mutations? Obtaining answers to these, and other critical questions, will require strong support from relevant funding agencies, in addition to the engagement of scientists outside the fields of genomics and germ-cell mutagenesis.

Fig. 1

Germ-cell stage-specificity for 28 chemicals tested for heritable mutations and dominant lethality in male and female mice. Gametogenic stages are shown in which positive results have been reported in dominant lethal (top solid bar), heritable translocation (middle /// bar), and specific-locus (bottom \\\ bar) tests. A white bar indicates a mild (<25%) response, a gray bar indicates a moderate (25–50%) response, and a black bar indicates a high (>50%) mutation response. Compiled and adapted from Figures in Witt and Bishop [1996] and Marchetti and Wyrobek [2005].

Fig. 2

Comparison of male and female germ-cell differentiation. The occurrence and duration of various cell cycles (e.g., mitosis/meiosis) and cell types (e.g., spermatocytes, oogonia) in gametogenesis for males (spermatogenesis) and females (oogenesis) during developmental stages (e.g., embryo/fetus) are shown. Adapted from Witt and Bishop [1996].