Variation in Human Meiotic Recombination

Lynn, Audrey; Ashley, Terry; Hassold, Terry

doi:10.1146/annurev.genom.4.070802.110217

Cited by 154 publications

(149 citation statements)

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“…One focus has to be added for taking into account the obligatory CO on the pseudo-autosomal region of the XY pair. d for additional data on human genetic maps, see also Lynn et al 2004. repair events with the elimination of Rad51/Dmc1 once the strand exchange reactions are complete. Several other proteins have been immunolocalized and found to mark recombination foci.…”

Section: Dsb Repair Events: An Excess Compared To Comentioning

confidence: 99%

“…A recent comparison between both parent strains (C57BL/6 and SPRET) and their F1 hybrid confirmed that the number of MLH1 foci is reduced significantly in the hybrid (Koehler et al 2006). In humans, differences among individuals are well documented, suggesting that genetic factors affect the overall CO rate (Broman et al 1998, Kong et al 2002, Lynn et al 2004, Codina-Pascual et al 2006. Besides these large-scale differences in CO number, the local distribution of CO can also depend on the DNA sequence.…”

Section: Variations In Co Activitymentioning

confidence: 99%

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Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis

2007

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During meiosis the programmed induction of DNA double-stranded breaks (DSB) leads to crossover (CO) and non-crossover products (NCO). One key role of CO is to connect homologs before metaphase I and thus to ensure the proper reductional segregation. This role implies an accurate regulation of CO frequency with the establishment of at least one CO per chromosome arm. Current major challenges are to understand how CO and NCO formation are regulated and what is the role of NCO. We present here the current knowledge about CO and NCO and their regulation in mammals. CO density varies widely along chromosomes and their distribution is not random as they are subject to positive interference. As documented in the mouse and human, a significant excess of DSB are generated relative to the number of CO. In fact, evidence has been obtained for the formation of NCO products, for regulation of the choice of DSB repair towards CO or NCO and for a CO specific pathway. We discuss the roles of Msh4, Msh5 and Sycp1 which affect DSB repair and probably not only the CO pathway. We suggest that, in mammals, the regulation of NCO differs from that described in Saccharomyces cerevisiae.

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Section: Dsb Repair Events: An Excess Compared To Comentioning

confidence: 99%

Section: Variations In Co Activitymentioning

confidence: 99%

Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis

2007

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“…female germ-cell biology and the susceptibility of germ cells to environmental mutagens. The major topics presented were sexual dimorphism, the unique characteristics and susceptibilities of male and female germ-cell stages, differences in the time line for the production and maturation of germ cells in both sexes, sex-specificity of checkpoints during germ-cell maturation, and the sex-and stage-specificity of DNA repair capacity [Inselman et al, 2003;Lynn et al, 2004Lynn et al, ,2005. The major differences in the competence of the various germcell stages, both for checkpoint control of the cell cycle and for DNA repair, are related to the ability of environmental agents to induce mutations in the various germ-cell stages.…”

Section: How Genome Sequence Impacts Germ-cell Mutation and Healthmentioning

confidence: 99%

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

Wyrobek

Mulvihill

Wassom

et al. 2007

Environ and Mol Mutagen

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Birth defects, de novo genetic diseases, and chromosomal abnormality syndromes occur in ~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, multipleendpoint studies. Additional studies could involve the examination of transgenerational effects NIH Public AccessAuthor Manuscript Environ Mol Mutagen. Author manuscript; available in PMC 2007 November 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 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 germcell 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.

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“…Human studies indicate that decreased recombination is associated with diminished spermatogenesis [14,22]. Genes involved in spermatogenesis and spermiogenesis have been altered in animal models, with resulting defects following [5,15].…”

Section: A Brief Overviewmentioning

confidence: 99%