The Experts below are selected from a list of 4332 Experts worldwide ranked by ideXlab platform
Norman Arnheim - One of the best experts on this subject based on the ideXlab platform.
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frequency of human disease mutations and spermatogonial stem cell function
2017Co-Authors: Norman Arnheim, Peter CalabreseAbstract:Some human disease mutations enter the human population each generation as a result of de novo germline base substitutions that immediately affect children born to normal parents. In some cases the frequency of these mutations exceeds the well-documented germline mutation rate 100–1000 fold. Recent technologies have made it possible to estimate the frequency of single base disease mutations in both sperm and testes from normal men. The evidence confirms that, although unaffected, the men have high enough frequencies of these mutations in semen and testis to explain the high sporadic disease incidence. The explanation for the high frequency initially was ascribed to the idea that the affected nucleotide site was a mutation hot spot with a mutation rate per cell division at that site far greater than the rate at other sites. Recent evidence rules out this hot spot model. An alternative model suggests that any of these types of rare disease mutations can confer upon a single testis stem cell a selective advantAge. Over time, a disproportionate increase of mutant stem cells over the wild-type stem cells occurs that increases the disease mutation frequency in sperm. The evidence against the hot spot model and for the selection model is reviewed and the functional consequences of these disease mutations on testis stem cell proliferation is also summarized. Finally, the consequence of these mutations is considered within the context of the Paternal Age Effect and the human genetic load.
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germline stem cell competition mutation hot spots genetic disorders and older fathers
Annual Review of Genomics and Human Genetics, 2016Co-Authors: Norman Arnheim, Peter CalabreseAbstract:Some de novo human mutations arise at frequencies far exceeding the genome averAge mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are Paternally derived, and are more likely to be transmitted as the father Ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantAge of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the Paternal Age Effect, the human mutational load, and adaptive evolution.
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new evidence for positive selection helps explain the Paternal Age Effect observed in achondroplasia
Human Molecular Genetics, 2013Co-Authors: Deepali N Shinde, Norman Arnheim, Peter Calabrese, Dominik P Elmer, Jerome Boulanger, Irene TiemannboegeAbstract:There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome averAge. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the Paternal Age Effect (PAE). The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single-nucleotide substitution (c.1138G>A) in FGFR3. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80-year-old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2.7 × 10(-6). We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead, we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantAge over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism.
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positive selection for new disease mutations in the human germline evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2b
PLOS Genetics, 2012Co-Authors: Sookyung Choi, Peter Calabrese, Songro Yoon, Norman ArnheimAbstract:Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100–200 times greater than would be expected based on the genome averAge mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot) or a selective advantAge conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors Aged 36–68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors Aged 19–23 mutations were almost non-existent, demonstrating that clusters in middle-Aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men Aged 75–80 were heterogeneous with some like middle-Aged and others like younger testes. Incorporating data on Age-dependent death of spermatogonial stem cells explains the results from all Age groups. Germline selection also explains MEN2B's male mutation bias and Paternal Age Effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantAge by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.
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the ups and downs of mutation frequencies during aging can account for the apert syndrome Paternal Age Effect
PLOS Genetics, 2009Co-Authors: Songro Yoon, Norman Arnheim, Ethylin Wang Jabs, Rivka L Glaser, Jian Qin, Nancy S Wexler, Rebecca Z Sokol, Peter CalabreseAbstract:Apert syndrome is almost always caused by a spontaneous mutation of Paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the Age of the father (Paternal Age Effect), and this increase is greater than what would be expected based on the greater number of germ-line divisions in older men. We use a highly sensitive PCR assay to measure the frequencies of the two causal mutations in the sperm of over 300 normal donors with a wide range of Ages. The mutation frequencies increase with the Age of the sperm donors, and this increase is consistent with the increase in the incidence rate. In both the sperm data and the birth data, the increase is non-monotonic. Further, after normalizing for Age, the two Apert syndrome mutation frequencies are correlated within individual sperm donors. We consider a mathematical model for germ-line mutation which reproduces many of the attributes of the data. This model, with other evidence, suggests that part of the increase in both the sperm data and the birth data is due to selection for mutated premeiotic cells. It is likely that a number of other genetic diseases have similar features.
Andrew O.m. Wilkie - One of the best experts on this subject based on the ideXlab platform.
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Selfish Spermatogonial Selection: Evidence from an Immunohistochemical Screen in Testes of Elderly Men
2016Co-Authors: Jasmine Lim. ¤a, Anne Goriely, Geoffrey J Maher, Ewa Rajpertde Meyts, Gareth D. H. Turner¤b, Stephen Taylor, Andrew O.m. WilkieAbstract:The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia–caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively–represent classical examples of Paternal Age-Effect mutation, a class that arises at particularly high frequencies in the sperm of older men. Previous analyses of DNA from randomly selected cadaveric testes showed that the levels of the corresponding FGFR2, FGFR3 and RET mutations exhibit very uneven spatial distributions, with localised hotspots surrounded by large mutation-negative areas. These studies imply that normal testes are mosaic for clusters of mutant cells: these clusters are predicted to have altered growth and signalling properties leading to their clonal expansion (selfish spermatogonial selection), but DNA extraction eliminates the possibility to study such processes at a tissue level. Using a panel of antibodies optimised for the detection of spermatocytic seminoma, a rare tumour of spermatogonial origin, we demonstrate that putative clonal events are frequent within normal testes of elderly men (mean Age: 73.3 yrs) and can be classed into two broad categories. We found numerous small (less than 200 cells) cellular aggregations with distinct immunohistochemical characteristics, localised to a portion of the seminiferous tubule, which are of uncertain significance. However more infrequently we identified additional regions where entire seminiferous tubules had a circumferentially altered immunohistochemical appearance that extended through multiple serial sections that were physically contiguous (up to 1 mm in length), and exhibited enhanced staining fo
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Paternal Age Effect mutations and selfish spermatogonial selection causes and consequences for human disease
American Journal of Human Genetics, 2012Co-Authors: Anne Goriely, Andrew O.m. WilkieAbstract:Advanced Paternal Age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this Effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term “Paternal Age Effect” (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the Paternal Age Effect lies in the dysregulation of spermatogonial cell behavior, an Effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time—explaining the observed Paternal Age Effect associated with these disorders—and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.
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germline and somatic mosaicism for fgfr2 mutation in the mother of a child with crouzon syndrome implications for genetic testing in Paternal Age Effect syndromes
American Journal of Medical Genetics Part A, 2010Co-Authors: Anne Goriely, Andrew O.m. Wilkie, Helen Lord, Jasmine Lim, David Johnson, Tracy Lester, Helen V FirthAbstract:Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive Paternal origin of mutation and elevated Paternal Age ("Paternal Age Effect"). However, even if this is the major mode of origin of mutations in Paternal Age-Effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other Paternal Age-Effect syndromes.
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Missing heritability: Paternal Age Effect mutations and selfish spermatogonia.
Nature reviews. Genetics, 2010Co-Authors: Anne Goriely, Andrew O.m. WilkieAbstract:In a recent Viewpoint on missing heritability (Missing heritability and strategies for finding the underlying causes of complex disease. Nature Rev. Genet. 11, 446–450 (2010))1, several commentators mentioned the expected importance of rare variants. Except for copy number polymorphisms (CNPs), contemporary technologies do not enable the systematic identification of rare variants that, given moderate Effect size, could contribute significantly to missing heritability2. However strategies to identify such sequence changes will soon become available3.
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activating mutations in fgfr3 and hras reveal a shared genetic origin for congenital disorders and testicular tumors
Nature Genetics, 2009Co-Authors: Anne Goriely, Ruth M S Hansen, Indira B Taylor, Inge A Olesen, G K Jacobsen, Simon J Mcgowan, Susanne P Pfeifer, Gilean Mcvean, Ewa Rajpertde Meyts, Andrew O.m. WilkieAbstract:Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis1,2, but the causative germline and somatic mutations occur in separate cells at different times of an organism’s life. Here we unify these processes for mutations arising in male germ cells that show a Paternal Age Effect3. Screening of 30 spermatocytic seminomas4,5 for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G encoding K650E, which causes thanatophoric dysplasia in the germline)6 and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that the FGFR3 mutation increases with Paternal Age, with a similar mutation spectrum at the K650 codon to that in bladder cancer7,8. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that Paternal Age Effect mutations activate a common “selfish” pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer.
Peter Calabrese - One of the best experts on this subject based on the ideXlab platform.
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frequency of human disease mutations and spermatogonial stem cell function
2017Co-Authors: Norman Arnheim, Peter CalabreseAbstract:Some human disease mutations enter the human population each generation as a result of de novo germline base substitutions that immediately affect children born to normal parents. In some cases the frequency of these mutations exceeds the well-documented germline mutation rate 100–1000 fold. Recent technologies have made it possible to estimate the frequency of single base disease mutations in both sperm and testes from normal men. The evidence confirms that, although unaffected, the men have high enough frequencies of these mutations in semen and testis to explain the high sporadic disease incidence. The explanation for the high frequency initially was ascribed to the idea that the affected nucleotide site was a mutation hot spot with a mutation rate per cell division at that site far greater than the rate at other sites. Recent evidence rules out this hot spot model. An alternative model suggests that any of these types of rare disease mutations can confer upon a single testis stem cell a selective advantAge. Over time, a disproportionate increase of mutant stem cells over the wild-type stem cells occurs that increases the disease mutation frequency in sperm. The evidence against the hot spot model and for the selection model is reviewed and the functional consequences of these disease mutations on testis stem cell proliferation is also summarized. Finally, the consequence of these mutations is considered within the context of the Paternal Age Effect and the human genetic load.
-
germline stem cell competition mutation hot spots genetic disorders and older fathers
Annual Review of Genomics and Human Genetics, 2016Co-Authors: Norman Arnheim, Peter CalabreseAbstract:Some de novo human mutations arise at frequencies far exceeding the genome averAge mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are Paternally derived, and are more likely to be transmitted as the father Ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantAge of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the Paternal Age Effect, the human mutational load, and adaptive evolution.
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new evidence for positive selection helps explain the Paternal Age Effect observed in achondroplasia
Human Molecular Genetics, 2013Co-Authors: Deepali N Shinde, Norman Arnheim, Peter Calabrese, Dominik P Elmer, Jerome Boulanger, Irene TiemannboegeAbstract:There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome averAge. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the Paternal Age Effect (PAE). The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single-nucleotide substitution (c.1138G>A) in FGFR3. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80-year-old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2.7 × 10(-6). We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead, we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantAge over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism.
-
positive selection for new disease mutations in the human germline evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2b
PLOS Genetics, 2012Co-Authors: Sookyung Choi, Peter Calabrese, Songro Yoon, Norman ArnheimAbstract:Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100–200 times greater than would be expected based on the genome averAge mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot) or a selective advantAge conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors Aged 36–68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors Aged 19–23 mutations were almost non-existent, demonstrating that clusters in middle-Aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men Aged 75–80 were heterogeneous with some like middle-Aged and others like younger testes. Incorporating data on Age-dependent death of spermatogonial stem cells explains the results from all Age groups. Germline selection also explains MEN2B's male mutation bias and Paternal Age Effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantAge by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.
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the ups and downs of mutation frequencies during aging can account for the apert syndrome Paternal Age Effect
PLOS Genetics, 2009Co-Authors: Songro Yoon, Norman Arnheim, Ethylin Wang Jabs, Rivka L Glaser, Jian Qin, Nancy S Wexler, Rebecca Z Sokol, Peter CalabreseAbstract:Apert syndrome is almost always caused by a spontaneous mutation of Paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the Age of the father (Paternal Age Effect), and this increase is greater than what would be expected based on the greater number of germ-line divisions in older men. We use a highly sensitive PCR assay to measure the frequencies of the two causal mutations in the sperm of over 300 normal donors with a wide range of Ages. The mutation frequencies increase with the Age of the sperm donors, and this increase is consistent with the increase in the incidence rate. In both the sperm data and the birth data, the increase is non-monotonic. Further, after normalizing for Age, the two Apert syndrome mutation frequencies are correlated within individual sperm donors. We consider a mathematical model for germ-line mutation which reproduces many of the attributes of the data. This model, with other evidence, suggests that part of the increase in both the sperm data and the birth data is due to selection for mutated premeiotic cells. It is likely that a number of other genetic diseases have similar features.
Anne Goriely - One of the best experts on this subject based on the ideXlab platform.
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Selfish Spermatogonial Selection: Evidence from an Immunohistochemical Screen in Testes of Elderly Men
2016Co-Authors: Jasmine Lim. ¤a, Anne Goriely, Geoffrey J Maher, Ewa Rajpertde Meyts, Gareth D. H. Turner¤b, Stephen Taylor, Andrew O.m. WilkieAbstract:The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia–caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively–represent classical examples of Paternal Age-Effect mutation, a class that arises at particularly high frequencies in the sperm of older men. Previous analyses of DNA from randomly selected cadaveric testes showed that the levels of the corresponding FGFR2, FGFR3 and RET mutations exhibit very uneven spatial distributions, with localised hotspots surrounded by large mutation-negative areas. These studies imply that normal testes are mosaic for clusters of mutant cells: these clusters are predicted to have altered growth and signalling properties leading to their clonal expansion (selfish spermatogonial selection), but DNA extraction eliminates the possibility to study such processes at a tissue level. Using a panel of antibodies optimised for the detection of spermatocytic seminoma, a rare tumour of spermatogonial origin, we demonstrate that putative clonal events are frequent within normal testes of elderly men (mean Age: 73.3 yrs) and can be classed into two broad categories. We found numerous small (less than 200 cells) cellular aggregations with distinct immunohistochemical characteristics, localised to a portion of the seminiferous tubule, which are of uncertain significance. However more infrequently we identified additional regions where entire seminiferous tubules had a circumferentially altered immunohistochemical appearance that extended through multiple serial sections that were physically contiguous (up to 1 mm in length), and exhibited enhanced staining fo
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Paternal Age Effect mutations and selfish spermatogonial selection causes and consequences for human disease
American Journal of Human Genetics, 2012Co-Authors: Anne Goriely, Andrew O.m. WilkieAbstract:Advanced Paternal Age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this Effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term “Paternal Age Effect” (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the Paternal Age Effect lies in the dysregulation of spermatogonial cell behavior, an Effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time—explaining the observed Paternal Age Effect associated with these disorders—and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.
-
germline and somatic mosaicism for fgfr2 mutation in the mother of a child with crouzon syndrome implications for genetic testing in Paternal Age Effect syndromes
American Journal of Medical Genetics Part A, 2010Co-Authors: Anne Goriely, Andrew O.m. Wilkie, Helen Lord, Jasmine Lim, David Johnson, Tracy Lester, Helen V FirthAbstract:Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive Paternal origin of mutation and elevated Paternal Age ("Paternal Age Effect"). However, even if this is the major mode of origin of mutations in Paternal Age-Effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other Paternal Age-Effect syndromes.
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Missing heritability: Paternal Age Effect mutations and selfish spermatogonia.
Nature reviews. Genetics, 2010Co-Authors: Anne Goriely, Andrew O.m. WilkieAbstract:In a recent Viewpoint on missing heritability (Missing heritability and strategies for finding the underlying causes of complex disease. Nature Rev. Genet. 11, 446–450 (2010))1, several commentators mentioned the expected importance of rare variants. Except for copy number polymorphisms (CNPs), contemporary technologies do not enable the systematic identification of rare variants that, given moderate Effect size, could contribute significantly to missing heritability2. However strategies to identify such sequence changes will soon become available3.
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activating mutations in fgfr3 and hras reveal a shared genetic origin for congenital disorders and testicular tumors
Nature Genetics, 2009Co-Authors: Anne Goriely, Ruth M S Hansen, Indira B Taylor, Inge A Olesen, G K Jacobsen, Simon J Mcgowan, Susanne P Pfeifer, Gilean Mcvean, Ewa Rajpertde Meyts, Andrew O.m. WilkieAbstract:Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis1,2, but the causative germline and somatic mutations occur in separate cells at different times of an organism’s life. Here we unify these processes for mutations arising in male germ cells that show a Paternal Age Effect3. Screening of 30 spermatocytic seminomas4,5 for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G encoding K650E, which causes thanatophoric dysplasia in the germline)6 and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that the FGFR3 mutation increases with Paternal Age, with a similar mutation spectrum at the K650 codon to that in bladder cancer7,8. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that Paternal Age Effect mutations activate a common “selfish” pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer.
Jürgen Kohlhase - One of the best experts on this subject based on the ideXlab platform.
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SALL1 mutations in sporadic Townes-Brocks syndrome are of predominantly Paternal origin without obvious Paternal Age Effect.
American journal of medical genetics. Part A, 2006Co-Authors: Johann Böhm, Susanne Munk-schulenburg, Stephanie Felscher, Jürgen KohlhaseAbstract:Autosomal dominant Townes–Brocks syndrome (TBS) is characterized by imperforate anus, triphalangeal and supernumerary thumbs, dysplastic ears and sensorineural hearing loss, and may also involve other organ systems. Strong inter- and intrafamiliar variability is known. Approximately 50% of TBS cases are sporadic and due to de novo mutations in the SALL1 gene. SALL1 encodes a zinc finger protein operating as a transcriptional repressor and localizing to pericentromeric heterochromatin. We traced the parental origin of SALL1 mutations in sporadic TBS by analysis of linkAge between SALL1 mutations and exonic or intronic polymorphisms in 16 families with 10 different mutations. Mutations were of Paternal origin in 14 of 16 cases (87.5%). Paternal origin was independent of the mutation type. The mean Paternal Age at conception was 29.9 and the mean maternal Age 26.5 years. We conclude that de novo mutations in SALL1 mostly occur on the Paternally derived chromosome 16 without an obvious Age Effect. © 2006 Wiley-Liss, Inc.
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sall1 mutations in sporadic townes brocks syndrome are of predominantly Paternal origin without obvious Paternal Age Effect
American Journal of Medical Genetics Part A, 2006Co-Authors: Johann Böhm, Stephanie Felscher, Susanne Munkschulenburg, Jürgen KohlhaseAbstract:Autosomal dominant Townes-Brocks syndrome (TBS) is characterized by imperforate anus, triphalangeal and supernumerary thumbs, dysplastic ears and sensorineural hearing loss, and may also involve other organ systems. Strong inter- and intrafamiliar variability is known. Approximately 50% of TBS cases are sporadic and due to de novo mutations in the SALL1 gene. SALL1 encodes a zinc finger protein operating as a transcriptional repressor and localizing to pericentromeric heterochromatin. We traced the parental origin of SALL1 mutations in sporadic TBS by analysis of linkAge between SALL1 mutations and exonic or intronic polymorphisms in 16 families with 10 different mutations. Mutations were of Paternal origin in 14 of 16 cases (87.5%). Paternal origin was independent of the mutation type. The mean Paternal Age at conception was 29.9 and the mean maternal Age 26.5 years. We conclude that de novo mutations in SALL1 mostly occur on the Paternally derived chromosome 16 without an obvious Age Effect.