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1. Genome diversity and instability in human germ cells and preimplantation embryos

Author

Miya Kudo Høffding, Eva Hoffmann, and Vallari Shukla

Subjects
0301 basic medicine, Genome instability, Infertility, Rearrangements, DNA repair, DNA damage, Embryonic Development, Aneuploidy, Biology, DNA damage response, Genome, Article, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Genome editing, medicine, Humans, Human oocytes and embryos, CNVs, Genetics, Genomic disorders, Cell Biology, medicine.disease, Germ Cells, 030104 developmental biology, Homologous recombination, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Genome diversity is essential for evolution and is of fundamental importance to human health. Generating genome diversity requires phases of DNA damage and repair that can cause genome instability. Humans have a high incidence of de novo congenital disorders compared to other organisms. Recent access to eggs, sperm and preimplantation embryos is revealing unprecedented rates of genome instability that may result in infertility and de novo mutations that cause genomic imbalance in at least 70% of conceptions. The error type and incidence of de novo mutations differ during developmental stages and are influenced by differences in male and female meiosis. In females, DNA repair is a critical factor that determines fertility and reproductive lifespan. In males, aberrant meiotic recombination causes infertility, embryonic failure and pregnancy loss. Evidence suggest germ cells are remarkably diverse in the type of genome instability that they display and the DNA damage responses they deploy. Additionally, the initial embryonic cell cycles are characterized by a high degree of genome instability that cause congenital disorders and may limit the use of CRISPR-Cas9 for heritable genome editing.

Published
2021

2. Preconception genome medicine: current state and future perspectives to improve infertility diagnosis and reproductive and health outcomes based on individual genomic data

Author

Vallari Shukla, Eva Hoffmann, Csilla Krausz, Antoni Riera-Escamilla, Carlos Simón, Miya Kudo Høffding, Antonio Capalbo, and Maurizio Poli

Subjects
Male, Infertility, medicine.medical_specialty, Population, Reproductive medicine, Genome-wide association study, Bioinformatics, polygenic medicine, genetic diagnosis, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, reproductive genetics, Outcome Assessment, Health Care, medicine, Genetic predisposition, Humans, whole-exome sequencing, Prospective Studies, education, IVF/ICSI outcomes, Exome sequencing, 030304 developmental biology, Reproductive health, Genetic testing, 0303 health sciences, education.field_of_study, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, oocyte and embryo genetic defects, business.industry, Obstetrics and Gynecology, Genomics, medicine.disease, 3. Good health, Reproductive Medicine, whole-genome sequencing, genomic sequencing, preconception carrier screening, Female, infertility, business, Genome-Wide Association Study
Abstract

BACKGROUND Our genetic code is now readable, writable and hackable. The recent escalation of genome-wide sequencing (GS) applications in population diagnostics will not only enable the assessment of risks of transmitting well-defined monogenic disorders at preconceptional stages (i.e. carrier screening), but also facilitate identification of multifactorial genetic predispositions to sub-lethal pathologies, including those affecting reproductive fitness. Through GS, the acquisition and curation of reproductive-related findings will warrant the expansion of genetic assessment to new areas of genomic prediction of reproductive phenotypes, pharmacogenomics and molecular embryology, further boosting our knowledge and therapeutic tools for treating infertility and improving women’s health. OBJECTIVE AND RATIONALE In this article, we review current knowledge and potential development of preconception genome analysis aimed at detecting reproductive and individual health risks (recessive genetic disease and medically actionable secondary findings) as well as anticipating specific reproductive outcomes, particularly in the context of IVF. The extension of reproductive genetic risk assessment to the general population and IVF couples will lead to the identification of couples who carry recessive mutations, as well as sub-lethal conditions prior to conception. This approach will provide increased reproductive autonomy to couples, particularly in those cases where preimplantation genetic testing is an available option to avoid the transmission of undesirable conditions. In addition, GS on prospective infertility patients will enable genome-wide association studies specific for infertility phenotypes such as predisposition to premature ovarian failure, increased risk of aneuploidies, complete oocyte immaturity or blastocyst development failure, thus empowering the development of true reproductive precision medicine. SEARCH METHODS Searches of the literature on PubMed Central included combinations of the following MeSH terms: human, genetics, genomics, variants, male, female, fertility, next generation sequencing, genome exome sequencing, expanded carrier screening, secondary findings, pharmacogenomics, controlled ovarian stimulation, preconception, genetics, genome-wide association studies, GWAS. OUTCOMES Through PubMed Central queries, we identified a total of 1409 articles. The full list of articles was assessed for date of publication, limiting the search to studies published within the last 15 years (2004 onwards due to escalating research output of next-generation sequencing studies from that date). The remaining articles’ titles were assessed for pertinence to the topic, leaving a total of 644 articles. The use of preconception GS has the potential to identify inheritable genetic conditions concealed in the genome of around 4% of couples looking to conceive. Genomic information during reproductive age will also be useful to anticipate late-onset medically actionable conditions with strong genetic background in around 2–4% of all individuals. Genetic variants correlated with differential response to pharmaceutical treatment in IVF, and clear genotype–phenotype associations are found for aberrant sperm types, oocyte maturation, fertilization or pre- and post-implantation embryonic development. All currently known capabilities of GS at the preconception stage are reviewed along with persisting and forthcoming barriers for the implementation of precise reproductive medicine. WIDER IMPLICATIONS The expansion of sequencing analysis to additional monogenic and polygenic traits may enable the development of cost-effective preconception tests capable of identifying underlying genetic causes of infertility, which have been defined as ‘unexplained’ until now, thus leading to the development of a true personalized genomic medicine framework in reproductive health.

Published
2020

3. Genetic insights into biological mechanisms governing human ovarian ageing

Author

Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases

Subjects
Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Published
2021

4. Genetic insights into the biological mechanisms governing human ovarian ageing

Author

Unnur Styrkarsdottir, Daniel I. Chasman, Rehannah Borup, Anne B. Newman, Kristina W. Olsen, Lude Franke, Stefania Bandinelli, Nora Franceschini, Celine M. Vachon, Nicholas J. Timpson, James F. Wilson, Micaella Joaquim, Christa Meisinger, Felix R. Day, Charles Kooperberg, Qin Wang, Pascal Timshel, Dennis O. Mook-Kanamori, Luigi Ferrucci, Jennifer A. Smith, Miriam Dwek, Pascal Guénel, Claus Yding Andersen, Peter A. Fasching, Sven Bergmann, Thomas Meitinger, Nicholas Bowker, Jane L. Tarry-Adkins, Jeremy A. Daniel, Katharina E. Schraut, Mikael Eriksson, Amruta Shrikhande, Jacques E. Rossouw, Amber N. Wilcox, Simon S. Cross, Stasa Stankovic, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Annette Peters, David Schlessinger, Sheila Ulivi, Mònica Ferrer-Roda, Immaculata De Vivo, Michela Traglia, Jessica Tyrrell, Paul R. H. J. Timmers, Rico Rueedi, Ko Willems van Dijk, N. Charlotte Onland-Moret, Doris Stöckl, Anthony J. Swerdlow, Paul M. Ridker, Zoltán Kutalik, Patrick Deelen, Gerardo Heiss, Marie Louise Grøndahl, Alison M. Dunning, Dale R. Nyholt, Nicholas J. Wareham, Reedik Mägi, Stephen J. Chanock, Martina La Bianca, Ozren Polasek, Daniel F. Gudbjartsson, Rebecca D. Jackson, Alison D. Murray, Lynda M. Rose, Hironori Abe, Joanne M. Murabito, Henry Völzke, Daniela Ruggiero, Dorret I. Boomsma, Harald Grallert, Stefania Benonisdottir, Javier Martin Gonzalez, Esther M. John, Natalia Perjakova, Georgia Chenevix-Trench, John R. B. Perry, Jenny Chang-Claude, Archie Campbell, Teresa Nutile, Ellen W. Demerath, Robin N Beaumont, Jouke J. Hottenga, Albert V. Smith, David Karasik, Linda Broer, Raymond Noordam, Wei He, Niclas Håkansson, Catherine E. Aiken, Robert Karlsson, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Sharon L.R. Kardia, Nicholas G. Martin, Jodie N. Painter, Peter K. Joshi, Gonneke Willemsen, Lenore J. Launer, Alicja Wolk, Konstantin Strauch, Stig E. Bojesen, Manjeet K. Bolla, Allison W. Kurian, Renée de Mutsert, Joop S.E. Laven, Antonella Mulas, Igor Rudan, Vallari Shukla, Kathyrn L Lunetta, Susan E. Ozanne, Loic Le Marchand, Jenny A. Visser, Gad Rennert, Jennifer A. Brody, Paul D.P. Pharoah, Tune H. Pers, Sara Lindström, Ignasi Roig, Angela Cox, Unnur Þorsteinsdottir, Graham G. Giles, Toshiko Tanaka, Eva Hoffmann, Melissa A. Troester, Claudia Langenberg, Serena Sanna, Julie E. Buring, Anna Pujol, Mike A. Nalls, Kamila Czene, Tõnu Esko, Jian'an Luan, Lili Milani, Iffat Rahman, Sarah E. Medland, Caterina Barbieri, Emil Peter Trane Hertz, Behrooz Z. Alizadeh, David G. Hunter, Sandra Turon, Antonietta Robino, Marina Ciullo, Barbara McKnight, Chunyan He, Bruce H. R. Wolffenbuttel, David R. Weir, Daniela Toniolo, Ulrike Peters, George Davey-Smith, Saleh Shekari, Caroline Hayward, Elinor J. Sawyer, Patrick Sulem, Simin Liu, Tanguy Corre, Susan M. Ring, Peter Kraft, Alexander Teumer, Marjanka K. Schmidt, André G. Uitterlinden, Arto Mannermaa, Kristan J. Aronson, Heiko Becher, John L. Hopper, Alpa V. Patel, Joyce B. J. van Meurs, kConFab Investigators, Hamdi Mbarek, Frits R. Rosendaal, Minouk J. Schoemaker, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Nancy L. Pedersen, Jessica D. Faul, Patrik K. E. Magnusson, Jingmei Li, Christopher G. Scott, Joe Dennis, Genevieve Lachance, Ajuna Azad, Yongmei Liu, Elnaz Naderi, Andrew R. Wood, Yan Huang, Anna Murray, Annique Claringbould, Stephen Burgess, Jose E. Castelao, Brumat Marco, Eco J. C. de Geus, Veronique Vitart, Ken K. Ong, Kari Stefansson, Blair H. Smith, Francesco Cucca, Grant W. Montgomery, Emmanouil Saloustros, Andrés J. López-Contreras, Jonathan Marten, Håkan Olsson, Dale P. Sandler, Alice M. Arnold, Ana Martínez-Marchal, Tim D. Spector, Chloé Sarnowski, John J. Spinelli, Vilmundur Gudnason, Frank B. Hu, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Eric Boerwinkle, Matthias W. Beckmann, Jazib Hussain, Uwe Völker, Peter Vollenweider, Douglas F. Easton, Irene L. Andrulis, Harry Campbell, Manuela Gago-Dominguez, Cari M. Kitahara, Yvonne T. van der Schouw, Eleonora Porcu, Annika Lindblom, Martha S. Linet, Meir J. Stampfer, Eulalia Catamo, Roger L. Milne, Ivana Kolcic, Annelie Augustinsson, Cinzia Sala, Debbie A Lawlor, Cristina Menni, Timothy M. Frayling, Lauren R. Teras, Marek Zygmunt, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Per Hall, Rossella Sorice, Wei Zhao, Andres Metspalu, Katherine S. Ruth, Andrew F. Olshan, Massimo Mezzavilla, Murielle Bochud, and Christian Gieger

Subjects
media_common.quotation_subject, Genetic predisposition, Longevity, Fertility, Disease, Biology, Premature ovarian insufficiency, Bioinformatics, Ovarian reserve, FMR1, Human genetics, media_common
Abstract

Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenicFMR1premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Published
2021

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