Failure to recombine is a common feature of human oogenesis

Hassold, Terry; Maylor-Hagen, Heather; Wood, Anna; Gruhn, Jennifer R.; Hoffmann, Eva R.; Broman, Karl W.; Hunt, Patricia A.

doi:10.1016/j.ajhg.2020.11.010

Cited by 28 publications

(33 citation statements)

References 32 publications

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“…Specifically, in initial analyses, approximately 5% of chromosomes 21 and 22 were lacking MLH1 foci in human oocytes, and similar MLH1‐less chromosomes 13, 14, 16, and 18 were also observed; in contrast, such exchangeless homologs were almost nonexistent in human spermatocytes. A follow‐up study in which the sample size was expanded to 7000 oocytes from 160 fetal ovarian tissue samples made possible a more accurate determination of the overall level of cells with one or more exchangeless homologs and examined individual variation in the frequency of such cells 32 . The results were striking; over 7% of all oocytes contained at least one exchangeless chromosome, typically involving either chromosome 21 or 22.…”

Section: Mistakes Were Made: Errors At the Onset Of Female Meiosismentioning

confidence: 99%

Missed connections: recombination and human aneuploidy

Hassold

Hunt

2021

Prenatal Diagnosis

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The physical exchange of DNA between homologs, crossing‐over, is essential to orchestrate the unique, reductional first meiotic division (MI). In females, the events of meiotic recombination that serve to tether homologs and facilitate their disjunction at MI occur during fetal development, preceding the MI division by several decades in our species. Data from studies in humans and mice demonstrate that placement of recombination sites during fetal development influences the likelihood of an MI nondisjunction event that results in the production of an aneuploid egg. Here we briefly summarize what we know about the relationship between aneuploidy and meiotic recombination and important considerations for the future of human assisted reproduction.

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Section: Mistakes Were Made: Errors At the Onset Of Female Meiosismentioning

confidence: 99%

Missed connections: recombination and human aneuploidy

Hassold

Hunt

2021

Prenatal Diagnosis

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“…However, if only one or a very few chromosomes lack a chiasma, viable gametes can still form but will be prone to mis-segregation of parental homologs; this can lead to aneuploid embryos. A recent study of recombination in human fetal oocytes revealed that having 10-20% fewer COs (MLH1 foci) overall was associated with such oocytes having 1-2 chromosomes completely lacking a CO 44 .…”

Section: Discussionmentioning

confidence: 99%

MLH1/3variants causing aneuploidy, pregnancy loss, and premature reproductive aging

Singh

Fragoza

Blengini

et al. 2021

Preprint

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Most spontaneous pregnancy losses are a result of embryonic aneuploidy stemming from mis-segregation of chromosomes during meiosis. Proper disjunction of homologous chromosomes is dependent upon precise control of crossing-over, a process requiring the mismatch repair (MMR) genes MLH1 and MLH3. Both are required for fertility and completion of meiosis in mice. People inheriting variants in these genes are often at high risk for colorectal cancer and Lynch syndrome, yet the potential impacts of variants upon reproduction are unclear. To determine if MLH1/3 variants (namely single nucleotide polymorphisms, or SNPs) in human populations can cause reproductive abnormalities, we used a combination of computational predictions, yeast two-hybrid assays, and assays of MMR and recombination in yeast to select nine MLH1 and MLH3 variants for modeling in mice via genome editing. We identified 7 alleles that caused reproductive defects in mice including subfertility in females, male infertility, reduced sperm counts, and increased spermatocyte apoptosis. Remarkably, these alleles in females caused age-dependent decreases in litter size, and increased resorption of embryos during pregnancy. These outcomes were likely a consequence of reduced meiotic chiasmata, in turn causing an increase in misaligned chromosomes and univalents in meiotic metaphase I (MI). Our data indicate that segregating hypomorphic alleles of meiotic recombination genes in populations can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.

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“…For reproductive cells, errors in the segregation of the chromosomes have particularly severe consequences as they give rise to aneuploid embryos that often result in miscarriage or suffer congenital abnormalities (Nagaoka et al, 2012;Greaney et al, 2018;Gruhn et al, 2019;Hassold et al, 2020). Meiosis in human oocytes is especially error prone with aneuploidy rates ranging from 15% in younger women to a staggering 30-70% in oocytes from older women and, by comparison, spermatozoa have an average aneuploidy rate of 1-4% (Nagaoka et al, 2012;Ottolini et al, 2015;Greaney et al, 2018;Gruhn et al, 2019).…”

Section: Protein Health During Reproductive Aging In Womenmentioning

confidence: 99%

“…Meiosis in human oocytes is especially error prone with aneuploidy rates ranging from 15% in younger women to a staggering 30-70% in oocytes from older women and, by comparison, spermatozoa have an average aneuploidy rate of 1-4% (Nagaoka et al, 2012;Ottolini et al, 2015;Greaney et al, 2018;Gruhn et al, 2019). While elegant studies of DNA damage, spindle abnormalities and meiotic errors have provided unique insight into oocyte aging and meiotic failure (Mihajlović and FitzHarris, 2018;Gruhn et al, 2019;Zielinska et al, 2019;Hassold et al, 2020;Mikwar et al, 2020), advances in the application of proteomic and RNA-sequencing technology to oocytes are beginning to reveal an additional layer of complexity to this process whereby declining proteostasis contributes widely to maternal aging processes (Duncan et al, 2017). Our improved understanding of reproductive failure has been marked by the discovery that proteins critical for meiosis, such as those comprising the cohesion complex, are in fact extremely long-lived with no capacity for renewal during oocyte development (Revenkova et al, 2010;Tachibana-Konwalski et al, 2010;Burkhardt et al, 2016;Lee, 2020).…”

Section: Protein Health During Reproductive Aging In Womenmentioning

confidence: 99%

Proteostasis in the Male and Female Germline: A New Outlook on the Maintenance of Reproductive Health

Cafe

Nixon

Ecroyd

et al. 2021

Front. Cell Dev. Biol.

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For fully differentiated, long lived cells the maintenance of protein homeostasis (proteostasis) becomes a crucial determinant of cellular function and viability. Neurons are the most well-known example of this phenomenon where the majority of these cells must survive the entire course of life. However, male and female germ cells are also uniquely dependent on the maintenance of proteostasis to achieve successful fertilization. Oocytes, also long-lived cells, are subjected to prolonged periods of arrest and are largely reliant on the translation of stored mRNAs, accumulated during the growth period, to support meiotic maturation and subsequent embryogenesis. Conversely, sperm cells, while relatively ephemeral, are completely reliant on proteostasis due to the absence of both transcription and translation. Despite these remarkable, cell-specific features there has been little focus on understanding protein homeostasis in reproductive cells and how/whether proteostasis is “reset” during embryogenesis. Here, we seek to capture the momentum of this growing field by highlighting novel findings regarding germline proteostasis and how this knowledge can be used to promote reproductive health. In this review we capture proteostasis in the context of both somatic cell and germline aging and discuss the influence of oxidative stress on protein function. In particular, we highlight the contributions of proteostasis changes to oocyte aging and encourage a focus in this area that may complement the extensive analyses of DNA damage and aneuploidy that have long occupied the oocyte aging field. Moreover, we discuss the influence of common non-enzymatic protein modifications on the stability of proteins in the male germline, how these changes affect sperm function, and how they may be prevented to preserve fertility. Through this review we aim to bring to light a new trajectory for our field and highlight the potential to harness the germ cell’s natural proteostasis mechanisms to improve reproductive health. This manuscript will be of interest to those in the fields of proteostasis, aging, male and female gamete reproductive biology, embryogenesis, and life course health.

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Failure to recombine is a common feature of human oogenesis

Cited by 28 publications

References 32 publications

Missed connections: recombination and human aneuploidy

Missed connections: recombination and human aneuploidy

MLH1/3variants causing aneuploidy, pregnancy loss, and premature reproductive aging

Proteostasis in the Male and Female Germline: A New Outlook on the Maintenance of Reproductive Health

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