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1. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung, Ljungdahl, Alicia, Stenton, Sarah, Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra, Ganesh, Vijay, Ma, Jialan, Ellingford, Jamie, Delage, Erwan, DSouza, Elston, Dong, Shan, Adams, David, Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin, Berger, Seth, Bernstein, Jonathan, Bhatnagar, Ishita, Blair, Ed, Brown, Natasha, Burrage, Lindsay, Chapman, Kimberly, Coman, David, Compton, Alison, Cunningham, Chloe, DSouza, Precilla, Danecek, Petr, Délot, Emmanuèle, Dias, Kerith-Rae, Elias, Ellen, Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie, Gallacher, Lyndon, Genetti, Casie, Goriely, Anne, Grant, Christina, Haack, Tobias, Higgs, Jenny, Hinch, Anjali, Hurles, Matthew, Kuechler, Alma, Lachlan, Katherine, Lalani, Seema, Lecoquierre, François, Leitão, Elsa, Fevre, Anna, Leventer, Richard, Liebelt, Jan, Lindsay, Sarah, Lockhart, Paul, Ma, Alan, Macnamara, Ellen, Mansour, Sahar, Maurer, Taylor, Mendez, Hector, Metcalfe, Kay, Montgomery, Stephen, Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, ODonoghue, Michael, OLeary, Melanie, Palmer, Elizabeth, Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi, Reuter, Chloe, Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill, Sachdev, Rani, Shaw-Smith, Charles, Simons, Cas, Sisodiya, Sanjay, Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen, Tan, Tiong, Tan, Natalie, Temple, Suzanna, Thorburn, David, Tifft, Cynthia, Uebergang, Eloise, VanNoy, Grace, Vasudevan, Pradeep, Vilain, Eric, and Viskochil, David

Subjects
Humans, RNA, Small Nuclear, Neurodevelopmental Disorders, Female, Male, Brain, Heterozygote, Alleles, Syndrome, Spliceosomes, Animals
Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Published
2024

3. SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline

Author

Wood, Katherine A., Tong, R Spencer, Motta, Marialetizia, Cordeddu, Viviana, Scimone, Eleanor R., Bush, Stephen J., Maxwell, Dale W., Giannoulatou, Eleni, Caputo, Viviana, Traversa, Alice, Mancini, Cecilia, Ferrero, Giovanni B., Benedicenti, Francesco, Grammatico, Paola, Melis, Daniela, Steindl, Katharina, Brunetti-Pierri, Nicola, Trevisson, Eva, Wilkie, Andrew OM., Lin, Angela E., Cormier-Daire, Valerie, Twigg, Stephen RF., Tartaglia, Marco, and Goriely, Anne

Published
2024
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4. Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Author

Bernkopf, Marie, Abdullah, Ummi B., Bush, Stephen J., Wood, Katherine A., Ghaffari, Sahar, Giannoulatou, Eleni, Koelling, Nils, Maher, Geoffrey J., Thibaut, Loïc M., Williams, Jonathan, Blair, Edward M., Kelly, Fiona Blanco, Bloss, Angela, Burkitt-Wright, Emma, Canham, Natalie, Deng, Alexander T., Dixit, Abhijit, Eason, Jacqueline, Elmslie, Frances, Gardham, Alice, Hay, Eleanor, Holder, Muriel, Homfray, Tessa, Hurst, Jane A., Johnson, Diana, Jones, Wendy D., Kini, Usha, Kivuva, Emma, Kumar, Ajith, Lees, Melissa M., Leitch, Harry G., Morton, Jenny E. V., Németh, Andrea H., Ramachandrappa, Shwetha, Saunders, Katherine, Shears, Deborah J., Side, Lucy, Splitt, Miranda, Stewart, Alison, Stewart, Helen, Suri, Mohnish, Clouston, Penny, Davies, Robert W., Wilkie, Andrew O. M., and Goriely, Anne

Published
2023
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6. New analysis of atypical spermatocytic tumours reveals extensive heterogeneity and plasticity of germ cell tumours†

Author

Rajpert-De Meyts, Ewa, Goriely, Anne, Almstrup, Kristian, Rajpert-De Meyts, Ewa, Goriely, Anne, and Almstrup, Kristian

Abstract

Testicular germ cell tumours (TGCTs) derived from immature (type I) and pluripotent germ cell neoplasia in situ (GCNIS, type II) are characterised by remarkable phenotypic heterogeneity and plasticity. In contrast, the rare spermatocytic tumour (SpT, type III), derived from mature spermatogonia, is considered a homogenous and benign tumour but may occasionally present as an anaplastic or an aggressive sarcomatoid tumour. While various oncogenic processes had been proposed, the precise mechanism driving malignant progression remained elusive until the molecular characterisation of a series of atypical SpTs described in a recent issue of The Journal of Pathology. The emerging picture suggests the presence of two distinct trajectories for SpTs, involving either RAS/mitogen-activated protein kinase pathway mutations or a ploidy shift with secondary TP53 mutations and/or gain of chromosome 12p, the latter known as pathognomonic for type II GCNIS-derived TGCTs. Here, we discuss the implications of these findings, seen from the perspective of germ cell biology and the unique features of different TGCTs. The evolving phenotype of SpTs, induced by genomic and epigenetic changes, illustrates that the concept of plasticity applies to all germ cell tumours, making them inherently heterogenous and capable of significant transformation during progression. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Published
2024

7. Can the male germline offer insight into mammalian brain size expansion?

Author

Bush, Stephen J. and Goriely, Anne

Subjects
*BIOLOGICAL evolution, *NEURAL stem cells, *SIZE of brain, *STEM cells, *MALE infertility, *SPERMATOGENESIS
Abstract

Recent advances in single‐cell transcriptomic data have greatly expanded our understanding of both spermatogenesis and the molecular mechanisms of male infertility. However, this growing wealth of data could also shed light on a seemingly unrelated biological problem: the genetic basis of mammalian brain size expansion throughout evolution. It is now increasingly recognized that the testis and brain share many cellular and molecular similarities including pivotal roles for the RAS/MAPK and PI3K/AKT/mTOR pathways, mutations in which are known to have a pronounced impact on cell proliferation. Most notably, in the stem cell lineages of both organs, new mutations have been shown to increase cellular output over time. These include ‘selfish’ mutations in spermatogonial stem cells, which disproportionately increase the proportion of mutant sperm, and—to draw a parallel—human‐specific mutations in neural stem cells which, by increasing the number of neurons, have been implicated in neocortical expansion. Here we speculate that the origin for many ‘expansion’‐associated mutations is the male germline and that as such, a deeper understanding of the mechanisms controlling testicular turnover may yield fresh insight into the biology and evolution of the brain. [ABSTRACT FROM AUTHOR]

Published
2024
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10. The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

Author

Stevenson, David A, Schill, Lisa, Schoyer, Lisa, Andresen, Brage S, Bakker, Annette, Bayrak-Toydemir, Pinar, Burkitt-Wright, Emma, Chatfield, Kathryn, Elefteriou, Florent, Elgersma, Ype, Fisher, Michael J, Franz, David, Gelb, Bruce D, Goriely, Anne, Gripp, Karen W, Hardan, Antonio Y, Keppler-Noreuil, Kim M, Kerr, Bronwyn, Korf, Bruce, Leoni, Chiara, McCormick, Frank, Plotkin, Scott R, Rauen, Katherine A, Reilly, Karlyne, Roberts, Amy, Sandler, Abby, Siegel, Dawn, Walsh, Karin, and Widemann, Brigitte C

Subjects
Biological Sciences, Genetics, Congenital Structural Anomalies, Neurosciences, Rare Diseases, Pediatric, Congenital, Capital Financing, Clinical Trials as Topic, Family, Genetic Diseases, Inborn, Humans, Intersectoral Collaboration, Mitogen-Activated Protein Kinases, Signal Transduction, ras Proteins, RASopathy, Ras, MAPK, cancer, rare disorders, clinical trials, experimental models, Ras/MAPK, Clinical Sciences, Clinical sciences
Abstract

The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. © 2016 Wiley Periodicals, Inc.

Published
2016

12. New analysis of atypical spermatocytic tumours reveals extensive heterogeneity and plasticity of germ cell tumours†.

Author

Rajpert‐De Meyts, Ewa, Goriely, Anne, and Almstrup, Kristian

Subjects
GERM cells, CYTOLOGY, TUMORS, PHENOTYPIC plasticity, PROTEIN kinases
Abstract

Testicular germ cell tumours (TGCTs) derived from immature (type I) and pluripotent germ cell neoplasia in situ (GCNIS, type II) are characterised by remarkable phenotypic heterogeneity and plasticity. In contrast, the rare spermatocytic tumour (SpT, type III), derived from mature spermatogonia, is considered a homogenous and benign tumour but may occasionally present as an anaplastic or an aggressive sarcomatoid tumour. While various oncogenic processes had been proposed, the precise mechanism driving malignant progression remained elusive until the molecular characterisation of a series of atypical SpTs described in a recent issue of The Journal of Pathology. The emerging picture suggests the presence of two distinct trajectories for SpTs, involving either RAS/mitogen‐activated protein kinase pathway mutations or a ploidy shift with secondary TP53 mutations and/or gain of chromosome 12p, the latter known as pathognomonic for type II GCNIS‐derived TGCTs. Here, we discuss the implications of these findings, seen from the perspective of germ cell biology and the unique features of different TGCTs. The evolving phenotype of SpTs, induced by genomic and epigenetic changes, illustrates that the concept of plasticity applies to all germ cell tumours, making them inherently heterogenous and capable of significant transformation during progression. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Adult Human, but Not Rodent, Spermatogonial Stem Cells Retain States with a Foetal-like Signature.

Author

Bush, Stephen J., Nikola, Rafail, Han, Seungmin, Suzuki, Shinnosuke, Yoshida, Shosei, Simons, Benjamin D., and Goriely, Anne

Subjects
MACAQUES, STEM cells, GERM cell differentiation, WATER buffalo, PUBERTY, RODENTS, GENE expression profiling, GERM cells
Abstract

Spermatogenesis involves a complex process of cellular differentiation maintained by spermatogonial stem cells (SSCs). Being critical to male reproduction, it is generally assumed that spermatogenesis starts and ends in equivalent transcriptional states in related species. Based on single-cell gene expression profiling, it has been proposed that undifferentiated human spermatogonia can be subclassified into four heterogenous subtypes, termed states 0, 0A, 0B, and 1. To increase the resolution of the undifferentiated compartment and trace the origin of the spermatogenic trajectory, we re-analysed the single-cell (sc) RNA-sequencing libraries of 34 post-pubescent human testes to generate an integrated atlas of germ cell differentiation. We then used this atlas to perform comparative analyses of the putative SSC transcriptome both across human development (using 28 foetal and pre-pubertal scRNA-seq libraries) and across species (including data from sheep, pig, buffalo, rhesus and cynomolgus macaque, rat, and mouse). Alongside its detailed characterisation, we show that the transcriptional heterogeneity of the undifferentiated spermatogonial cell compartment varies not only between species but across development. Our findings associate 'state 0B' with a suppressive transcriptomic programme that, in adult humans, acts to functionally oppose proliferation and maintain cells in a ready-to-react state. Consistent with this conclusion, we show that human foetal germ cells—which are mitotically arrested—can be characterised solely as state 0B. While germ cells with a state 0B signature are also present in foetal mice (and are likely conserved at this stage throughout mammals), they are not maintained into adulthood. We conjecture that in rodents, the foetal-like state 0B differentiates at birth into the renewing SSC population, whereas in humans it is maintained as a reserve population, supporting testicular homeostasis over a longer reproductive lifespan while reducing mutagenic load. Together, these results suggest that SSCs adopt differing evolutionary strategies across species to ensure fertility and genome integrity over vastly differing life histories and reproductive timeframes. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer

Author

Tharmalingam, Melissa D., Matilionyte, Gabriele, Wallace, William H. B., Stukenborg, Jan-Bernd, Jahnukainen, Kirsi, Oliver, Elizabeth, Goriely, Anne, Lane, Sheila, Guo, Jingtao, Cairns, Bradley, Jorgensen, Anne, Allen, Caroline M., Lopes, Federica, Anderson, Richard A., Spears, Norah, and Mitchell, Rod T.

Published
2020
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18. The adult human testis transcriptional cell atlas

Author

Guo, Jingtao, Grow, Edward J., Mlcochova, Hana, Maher, Geoffrey J., Lindskog, Cecilia, Nie, Xichen, Guo, Yixuan, Takei, Yodai, Yun, Jina, Cai, Long, Kim, Robin, Carrell, Douglas T., Goriely, Anne, Hotaling, James M., and Cairns, Bradley R.

Published
2018
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21. De novo variants in the RNU4-2snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2as a syndromic NDD gene. RNU4-2encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2is highly expressed in the developing human brain, in contrast to RNU4-1and other U4 homologues. Using RNA sequencing, we show how 5′ splice-site use is systematically disrupted in individuals with RNU4-2variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Published
2024
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23. The PREGCARE study: Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Author

Bernkopf, Marie, primary, Abdullah, Ummi B., additional, Bush, Stephen J., additional, Wood, Katherine, additional, Ghaffari, Sahar, additional, Giannoulatou, Eleni, additional, Koelling, Nils, additional, Maher, Geoffrey J., additional, Thibault, Loïc M., additional, Williams, Jonathan, additional, Blair, Edward M., additional, Kelly, Fiona Blanco, additional, Bloss, Angela, additional, Burkitt-Wright, Emma, additional, Canham, Natalie, additional, Deng, Alexander T., additional, Dixit, Abhijit, additional, Eason, Jacqueline, additional, Elmslie, Frances, additional, Gardham, Alice, additional, Hay, Eleanor, additional, Holder, Muriel, additional, Homfray, Tessa, additional, Hurst, Jane A., additional, Johnson, Diana, additional, Jones, Wendy D., additional, Kini, Usha, additional, Kivuva, Emma, additional, Kumar, Ajith, additional, Lees, Melissa M., additional, Leitch, Harry G., additional, Morton, Jenny E. V., additional, Németh, Andrea H., additional, Ramachandrappa, Shwetha, additional, Saunders, Katherine, additional, Shears, Deborah J., additional, Side, Lucy, additional, Splitt, Miranda, additional, Stewart, Alison, additional, Stewart, Helen, additional, Suri, Mohnish, additional, Clouston, Penny, additional, Davies, Robert W., additional, Wilkie, Andrew O. M., additional, and Goriely, Anne, additional

Published
2022
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24. GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia

Author

Roberts, Irene, Alford, Kate, Hall, Georgina, Juban, Gaetan, Richmond, Helen, Norton, Alice, Vallance, Grant, Perkins, Kelly, Marchi, Emanuele, McGowan, Simon, Roy, Anindita, Cowan, Gillian, Anthony, Mark, Gupta, Amit, Ho, John, Uthaya, Sabita, Curley, Anna, Rasiah, Shree Vishna, Watts, Timothy, Nicholl, Richard, Bedford-Russell, Alison, Blumberg, Raoul, Thomas, Angela, Gibson, Brenda, Halsey, Chris, Lee, Pek-Wan, Godambe, Sunit, Sweeney, Connor, Bhatnagar, Neha, Goriely, Anne, Campbell, Peter, and Vyas, Paresh

Published
2013
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25. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

Author

Giannoulatou, Eleni, McVean, Gilean, Taylor, Indira B., McGowan, Simon J., Maher, Geoffrey J., Iqbal, Zamin, Pfeifer, Susanne P., Turner, Isaac, Wright, Emma M. M. Burkitt, Shorto, Jennifer, Itani, Aysha, Turner, Karen, Gregory, Lorna, Buck, David, Meyts, Ewa Rajpert-De, Looijenga, Leendert H. J., Kerr, Bronwyn, Wilkie, Andrew O. M., and Goriely, Anne

Published
2013

29. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Author

Ilkovski, Biljana, Pagnamenta, Alistair T., OʼGrady, Gina L., Kinoshita, Taroh, Howard, Malcolm F., Lek, Monkol, Thomas, Brett, Turner, Anne, Christodoulou, John, Sillence, David, Knight, Samantha J.L., Popitsch, Niko, Keays, David A., Anzilotti, Consuelo, Goriely, Anne, Waddell, Leigh B., Brilot, Fabienne, North, Kathryn N., Kanzawa, Noriyuki, Macarthur, Daniel G., Taylor, Jenny C., Kini, Usha, Murakami, Yoshiko, and Clarke, Nigel F.

Published
2015
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31. The Dynamic Transcriptional Cell Atlas of Testis Development during Human Puberty

Author

Guo, Jingtao, Nie, Xichen, Giebler, Maria, Mlcochova, Hana, Wang, Yueqi, Grow, Edward J., Kim, Robin, Tharmalingam, Melissa, Matilionyte, Gabriele, Lindskog, Cecilia, Carrell, Douglas T., Mitchell, Rod T., Goriely, Anne, Hotaling, James M., Cairns, Bradley R., Guo, Jingtao, Nie, Xichen, Giebler, Maria, Mlcochova, Hana, Wang, Yueqi, Grow, Edward J., Kim, Robin, Tharmalingam, Melissa, Matilionyte, Gabriele, Lindskog, Cecilia, Carrell, Douglas T., Mitchell, Rod T., Goriely, Anne, Hotaling, James M., and Cairns, Bradley R.

Abstract

The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To characterize this understudied process, we profiled and analyzed single-cell transcriptomes of similar to 10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty.

Published
2020
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32. The origin of EFNB1 mutations in craniofrontonasal syndrome: Frequent somatic mosaicism and explanation of the paucity of carrier males

Author

Twigg, Stephen R.F., Matsumoto, Kazuya, Kidd, Alexa M.J., Goriely, Anne, Taylor, Indira B., Fisher, Richard B., Hoogeboom, A., Jeannette M., Mathijssen, Irene M.J., Lourenco, M. Teresa, Morton, Jenny E.V., Sweeney, Elizabeth, Wilson, Louise C., Brunner, Han G., Mulliken, John B., Wall, Steven A., and Wilkie, Andrew O.M.

Subjects
Gene mutations -- Research, Mosaicism -- Health aspects, Biological sciences
Abstract

The discovery of causative mutations in the EFNB1 gene is exploited, which encodes ephrin-B1, to survey the molecular alterations in 59 families. Somatic mosaicism was demonstrated in 6 of 53 informative families, and of 17 germline mutations in individuals for whom the parental origin of mutation could be demonstrated, 15 arose from the father.

Published
2006

33. Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Author

Twigg, Stephen R.F., Babbs, Christian, van den Elzen, Marijke E.P., Goriely, Anne, Taylor, Stephen, McGowan, Simon J., Giannoulatou, Eleni, Lonie, Lorne, Ragoussis, Jiannis, Akha, Elham Sadighi, Knight, Samantha J.L., Zechi-Ceide, Roseli M., Hoogeboom, Jeannette A.M., Pober, Barbara R., Toriello, Helga V., Wall, Steven A., Rita Passos-Bueno, M., Brunner, Han G., Mathijssen, Irene M.J., and Wilkie, Andrew O.M.

Published
2013
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38. The Dynamic Transcriptional Cell Atlas of Testis Development during Human Puberty

Author

Guo, Jingtao, primary, Nie, Xichen, additional, Giebler, Maria, additional, Mlcochova, Hana, additional, Wang, Yueqi, additional, Grow, Edward J., additional, Kim, Robin, additional, Tharmalingam, Melissa, additional, Matilionyte, Gabriele, additional, Lindskog, Cecilia, additional, Carrell, Douglas T., additional, Mitchell, Rod T., additional, Goriely, Anne, additional, Hotaling, James M., additional, and Cairns, Bradley R., additional

Published
2020
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44. Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline

Author

Giannoulatou, Eleni, Maher, Geoffrey J., Ding, Zhihao, Gillis, Ad J. M., Dorssers, Lambert C. J., Hoischen, Alexander, Rajpert-De Meyts, Ewa, McVean, Gilean, Wilkie, Andrew O. M., Looijenga, Leendert H. J., Goriely, Anne, and Pathology

Subjects
Male, Cell biology, DNA Copy Number Variations, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biochemistry, Chromosomes, Chromosomal Disorders, Cancer Genomics, Genomic Medicine, Testicular Neoplasms, Animal Cells, Spermatocytes, Basic Cancer Research, Genetics, Medicine and Health Sciences, Biomarkers, Tumor, Point Mutation, Humans, Receptor, Fibroblast Growth Factor, Type 3, Sexual Maturation, Germ-Line Mutation, Clinical Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DNA methylation, Genome, Human, Biology and Life Sciences, High-Throughput Nucleotide Sequencing, DNA, Genomics, Chromatin, Sperm, Spermatogonia, Nucleic acids, Germ Cells, Oncology, Mutation, Somatic Mutation, Epigenetics, Gene expression, Cellular Types, DNA modification, Chromatin modification, Research Article, Chromosome biology
Abstract

Contains fulltext : 174702.pdf (Publisher’s version ) (Open Access) Adult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover, spermatogonia very rarely form tumors, so-called spermatocytic tumors (SpT). In line with the previous identification of FGFR3 and HRAS selfish mutations in a subset of cases, candidate gene screening of 29 SpTs identified an oncogenic NRAS mutation in two cases. To gain insights in the etiology of SpT and into properties of the male germline, we performed whole-genome sequencing of five tumors (4/5 with matched normal tissue). The acquired single nucleotide variant load was extremely low (~0.2 per Mb), with an average of 6 (2-9) non-synonymous variants per tumor, none of which is likely to be oncogenic. The observed mutational signature of SpTs is strikingly similar to that of germline de novo mutations, mostly involving C>T transitions with a significant enrichment in the ACG trinucleotide context. The tumors exhibited extensive aneuploidy (50-99 autosomes/tumor) involving whole-chromosomes, with recurrent gains of chr9 and chr20 and loss of chr7, suggesting that aneuploidy itself represents the initiating oncogenic event. We propose that SpT etiology recapitulates the unique properties of male germ cells; because of evolutionary constraints to maintain low point mutation rate, rare tumorigenic driver events are caused by a combination of gene imbalance mediated via whole-chromosome aneuploidy. Finally, we propose a general framework of male germ cell tumor pathology that accounts for their mutational landscape, timing and cellular origin.

Published
2017
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45. Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes

Author

Maher, Geoffrey J., primary, Ralph, Hannah K., additional, Ding, Zhihao, additional, Koelling, Nils, additional, Mlcochova, Hana, additional, Giannoulatou, Eleni, additional, Dhami, Pawan, additional, Paul, Dirk S., additional, Stricker, Stefan H., additional, Beck, Stephan, additional, McVean, Gilean, additional, Wilkie, Andrew O.M., additional, and Goriely, Anne, additional

Published
2018
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46. Chromatin and Single-Cell RNA- Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development

Author

Guo, Jingtao, Grow, Edward J., Yi, Chongil, Mlcochova, Hana, Maher, Geoffrey J., Lindskog, Cecilia, Murphy, Patrick J., Wike, Candice L., Carrell, Douglas T., Goriely, Anne, Hotaling, James M., Cairns, Bradley R., Guo, Jingtao, Grow, Edward J., Yi, Chongil, Mlcochova, Hana, Maher, Geoffrey J., Lindskog, Cecilia, Murphy, Patrick J., Wike, Candice L., Carrell, Douglas T., Goriely, Anne, Hotaling, James M., and Cairns, Bradley R.

Abstract

Human adult spermatogonial stem cells (hSSCs) must balance self-renewal and differentiation. To understand how this is achieved, we profiled DNA methylation and open chromatin (ATAC-seq) in SSEA4(+) hSSCs, analyzed bulk and single-cell RNA transcriptomes (RNA-seq) in SSEA4+ hSSCs and differentiating c-KIT+ spermatogonia, and performed validation studies via immunofluorescence. First, DNA hypomethylation at embryonic developmental genes supports their epigenetic "poising'' in hSSCs for future/embryonic expression, while core pluripotency genes (OCT4 and NANOG) were transcriptionally and epigenetically repressed. Interestingly, open chromatin in hSSCs was strikingly enriched in binding sites for pioneer factors (NFYA/B, DMRT1, and hormone receptors). Remarkably, single-cell RNA-seq clustering analysis identified four cellular/developmental states during hSSC differentiation, involving major transitions in cell-cycle and transcriptional regulators, splicing and signaling factors, and glucose/mitochondria regulators. Overall, our results outline the dynamic chromatin/transcription landscape operating in hSSCs and identify crucial molecular pathways that accompany the transition from quiescence to proliferation and differentiation.

Published
2017
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47. Chromatin and Single-Cell RNA-Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development

Author

Guo, Jingtao, primary, Grow, Edward J., additional, Yi, Chongil, additional, Mlcochova, Hana, additional, Maher, Geoffrey J., additional, Lindskog, Cecilia, additional, Murphy, Patrick J., additional, Wike, Candice L., additional, Carrell, Douglas T., additional, Goriely, Anne, additional, Hotaling, James M., additional, and Cairns, Bradley R., additional

Published
2017
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48. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

Author

Mirzaa, Ghayda, Timms, Andrew E., Conti, Valerio, Boyle, Evan August, Girisha, Katta M., Martin, Beth, Kircher, Martin, Olds, Carissa, Juusola, Jane, Collins, Sarah, Park, Kaylee, Carter, Melissa, Glass, Ian, Krägeloh-mann, Inge, Chitayat, David, Parikh, Aditi Shah, Bradshaw, Rachael, Torti, Erin, Braddock, Steve, Burke, Leah, Ghedia, Sondhya, Stephan, Mark, Stewart, Fiona, Prasad, Chitra, Napier, Melanie, Saitta, Sulagna, Straussberg, Rachel, Gabbett, Michael, O’Connor, Bridget C., Keegan, Catherine E., Yin, Lim Jiin, Lai, Angeline Hwei Meeng, Martin, Nicole, Mckinnon, Margaret, Addor, Marie-claude, Boccuto, Luigi, Schwartz, Charles E., Lanoel, Agustina, Conway, Robert L., Devriendt, Koenraad, Tatton-Brown, Katrina, Pierpont, Mary Ella, Painter, Michael, Worgan, Lisa, Reggin, James, Hennekam, Raoul, Tsuchiya, Karen, Pritchard, Colin C., Aracena, Mariana, Gripp, Karen W., Cordisco, Maria, Van Esch, Hilde, Garavelli, Livia, Curry, Cynthia, Goriely, Anne, Kayserilli, Hulya, Shendure, Jay, Graham, John, Guerrini, Renzo, Dobyns, William B., Mirzaa, Ghayda, Timms, Andrew E., Conti, Valerio, Boyle, Evan August, Girisha, Katta M., Martin, Beth, Kircher, Martin, Olds, Carissa, Juusola, Jane, Collins, Sarah, Park, Kaylee, Carter, Melissa, Glass, Ian, Krägeloh-mann, Inge, Chitayat, David, Parikh, Aditi Shah, Bradshaw, Rachael, Torti, Erin, Braddock, Steve, Burke, Leah, Ghedia, Sondhya, Stephan, Mark, Stewart, Fiona, Prasad, Chitra, Napier, Melanie, Saitta, Sulagna, Straussberg, Rachel, Gabbett, Michael, O’Connor, Bridget C., Keegan, Catherine E., Yin, Lim Jiin, Lai, Angeline Hwei Meeng, Martin, Nicole, Mckinnon, Margaret, Addor, Marie-claude, Boccuto, Luigi, Schwartz, Charles E., Lanoel, Agustina, Conway, Robert L., Devriendt, Koenraad, Tatton-Brown, Katrina, Pierpont, Mary Ella, Painter, Michael, Worgan, Lisa, Reggin, James, Hennekam, Raoul, Tsuchiya, Karen, Pritchard, Colin C., Aracena, Mariana, Gripp, Karen W., Cordisco, Maria, Van Esch, Hilde, Garavelli, Livia, Curry, Cynthia, Goriely, Anne, Kayserilli, Hulya, Shendure, Jay, Graham, John, Guerrini, Renzo, and Dobyns, William B.

Abstract

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.

Published
2016

50. Mutations in CDC45 , Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis

Author

Fenwick, Aimee L., primary, Kliszczak, Maciej, additional, Cooper, Fay, additional, Murray, Jennie, additional, Sanchez-Pulido, Luis, additional, Twigg, Stephen R.F., additional, Goriely, Anne, additional, McGowan, Simon J., additional, Miller, Kerry A., additional, Taylor, Indira B., additional, Logan, Clare, additional, Bozdogan, Sevcan, additional, Danda, Sumita, additional, Dixon, Joanne, additional, Elsayed, Solaf M., additional, Elsobky, Ezzat, additional, Gardham, Alice, additional, Hoffer, Mariette J.V., additional, Koopmans, Marije, additional, McDonald-McGinn, Donna M., additional, Santen, Gijs W.E., additional, Savarirayan, Ravi, additional, de Silva, Deepthi, additional, Vanakker, Olivier, additional, Wall, Steven A., additional, Wilson, Louise C., additional, Yuregir, Ozge Ozalp, additional, Zackai, Elaine H., additional, Ponting, Chris P., additional, Jackson, Andrew P., additional, Wilkie, Andrew O.M., additional, Niedzwiedz, Wojciech, additional, and Bicknell, Louise S., additional

Published
2016
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