186 results on '"Veitia, RA"'
Search Results
2. Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans
- Author
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Laissue P, Lakhal B, Vatin M, Batista F, Burgio G, Mercier E, Santos ED, Buffat C, Sierra-Diaz DC, Renault G, Montagutelli X, Salmon J, Monget P, Veitia RA, Méhats C, Fellous M, Gris JC, Cocquet J, Vaiman D.
- Abstract
Recurrent spontaneous abortion (RSA) is a common cause of infertility, but previous attempts at identifying RSA causative genes have been relatively unsuccessful. Such failure to describe RSA aetiological genes might be explained by the fact that reproductive phenotypes should be considered as quantitative traits resulting from the intricate interaction of numerous genetic, epigenetic and environmental factors. Here, we studied an interspecific recombinant congenic strain (IRCS) of Mus musculus from the C57BL6/J strain of mice harbouring an approximate 5 Mb DNA fragment from chromosome 13 from Mus spretus mice (66H-MMU13 strain), with a high rate of embryonic resorption (ER). Transcriptome analyses of endometrial and placental tissues from these mice showed a deregulation of many genes associated with the coagulation and inflammatory response pathways. Bioinformatics approaches led us to select Foxd1 as a candidate gene potentially related to ER and RSA. Sequencing analysis of Foxd1 in the 66H-MMU13 strain, and in 556 women affected by RSA and 271 controls revealed non-synonymous sequence variants. In vitro assays revealed that some led to perturbations in FOXD1 transactivation properties on promoters of genes having key roles during implantation/placentation, suggesting a role of this gene in mammalian implantation processes.
- Published
- 2016
3. Allelic reduction of Dlx5 and Dlx6 results in earlyfollicular depletion: a new mouse model of primary ovarian insufficiency
- Author
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Bouhali, K, Dipietromaria, A, Fontaine, A, Caburet, S, Barbieri, Ottavia, Bellessort, B, Fellous, M, Veitia, Ra, and Levi, G.
- Published
- 2011
4. Genome-Wide ENU Mutagenesis in Combination with High Density SNP Analysis and Exome Sequencing Provides Rapid Identification of Novel Mouse Models of Developmental Disease
- Author
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Veitia, RA, Caruana, G, Farlie, PG, Hart, AH, Bagheri-Fam, S, Wallace, MJ, Dobbie, MS, Gordon, CT, Miller, KA, Whittle, B, Abud, HE, Arkell, RM, Cole, TJ, Harley, VR, Smyth, IM, Bertram, JF, Veitia, RA, Caruana, G, Farlie, PG, Hart, AH, Bagheri-Fam, S, Wallace, MJ, Dobbie, MS, Gordon, CT, Miller, KA, Whittle, B, Abud, HE, Arkell, RM, Cole, TJ, Harley, VR, Smyth, IM, and Bertram, JF
- Abstract
BACKGROUND: Mice harbouring gene mutations that cause phenotypic abnormalities during organogenesis are invaluable tools for linking gene function to normal development and human disorders. To generate mouse models harbouring novel alleles that are involved in organogenesis we conducted a phenotype-driven, genome-wide mutagenesis screen in mice using the mutagen N-ethyl-N-nitrosourea (ENU). METHODOLOGY/PRINCIPAL FINDINGS: ENU was injected into male C57BL/6 mice and the mutations transmitted through the germ-line. ENU-induced mutations were bred to homozygosity and G3 embryos screened at embryonic day (E) 13.5 and E18.5 for abnormalities in limb and craniofacial structures, skin, blood, vasculature, lungs, gut, kidneys, ureters and gonads. From 52 pedigrees screened 15 were detected with anomalies in one or more of the structures/organs screened. Using single nucleotide polymorphism (SNP)-based linkage analysis in conjunction with candidate gene or next-generation sequencing (NGS) we identified novel recessive alleles for Fras1, Ift140 and Lig1. CONCLUSIONS/SIGNIFICANCE: In this study we have generated mouse models in which the anomalies closely mimic those seen in human disorders. The association between novel mutant alleles and phenotypes will lead to a better understanding of gene function in normal development and establish how their dysfunction causes human anomalies and disease.
- Published
- 2013
5. Coexpression of nuclear receptors and histone methylation modifying genes in the testis: implications for endocrine disruptor modes of action.
- Author
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Veitia, RA, Anderson, AM, Carter, KW, Anderson, D, Wise, MJ, Veitia, RA, Anderson, AM, Carter, KW, Anderson, D, and Wise, MJ
- Abstract
BACKGROUND: Endocrine disruptor chemicals elicit adverse health effects by perturbing nuclear receptor signalling systems. It has been speculated that these compounds may also perturb epigenetic mechanisms and thus contribute to the early origin of adult onset disease. We hypothesised that histone methylation may be a component of the epigenome that is susceptible to perturbation. We used coexpression analysis of publicly available data to investigate the combinatorial actions of nuclear receptors and genes involved in histone methylation in normal testis and when faced with endocrine disruptor compounds. METHODOLOGY/PRINCIPAL FINDINGS: The expression patterns of a set of genes were profiled across testis tissue in human, rat and mouse, plus control and exposed samples from four toxicity experiments in the rat. Our results indicate that histone methylation events are a more general component of nuclear receptor mediated transcriptional regulation in the testis than previously appreciated. Coexpression patterns support the role of a gatekeeper mechanism involving the histone methylation modifiers Kdm1, Prdm2, and Ehmt1 and indicate that this mechanism is a common determinant of transcriptional integrity for genes critical to diverse physiological endpoints relevant to endocrine disruption. Coexpression patterns following exposure to vinclozolin and dibutyl phthalate suggest that coactivity of the demethylase Kdm1 in particular warrants further investigation in relation to endocrine disruptor mode of action. CONCLUSIONS/SIGNIFICANCE: This study provides proof of concept that a bioinformatics approach that profiles genes related to a specific hypothesis across multiple biological settings can provide powerful insight into coregulatory activity that would be difficult to discern at an individual experiment level or by traditional differential expression analysis methods.
- Published
- 2012
6. The Transcription Factor Encyclopedia
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Yusuf, D, Butland, SL, Swanson, MI, Bolotin, E, Ticoll, A, Cheung, WA, Zhang, XYC, Dickman, CTD, Fulton, DL, Lim, JS, Schnabl, JM, Ramos, OHP, Vasseur-Cognet, M, de Leeuw, CN, Simpson, EM, Ryffel, GU, Lam, EW-F, Kist, R, Wilson, MSC, Marco-Ferreres, R, Brosens, JJ, Beccari, LL, Bovolenta, P, Benayoun, BA, Monteiro, LJ, Schwenen, HDC, Grontved, L, Wederell, E, Mandrup, S, Veitia, RA, Chakravarthy, H, Hoodless, PA, Mancarelli, MM, Torbett, BE, Banham, AH, Reddy, SP, Cullum, RL, Liedtke, M, Tschan, MP, Vaz, M, Rizzino, A, Zannini, M, Frietze, S, Farnham, PJ, Eijkelenboom, A, Brown, PJ, Laperriere, D, Leprince, D, de Cristofaro, T, Prince, KL, Putker, M, del Peso, L, Camenisch, G, Wenger, RH, Mikula, M, Rozendaal, M, Mader, S, Ostrowski, J, Rhodes, SJ, Van Rechem, C, Boulay, G, Olechnowicz, SWZ, Breslin, MB, Lan, MS, Nanan, KK, Wegner, M, Hou, J, Mullen, RD, Colvin, SC, Noy, PJ, Webb, CF, Witek, ME, Ferrell, S, Daniel, JM, Park, J, Waldman, SA, Peet, DJ, Taggart, M, Jayaraman, P-S, Karrich, JJ, Blom, B, Vesuna, F, O'Geen, H, Sun, Y, Gronostajski, RM, Woodcroft, MW, Hough, MR, Chen, E, Europe-Finner, GN, Karolczak-Bayatti, M, Bailey, J, Hankinson, O, Raman, V, LeBrun, DP, Biswal, S, Harvey, CJ, DeBruyne, JP, Hogenesch, JB, Hevner, RF, Heligon, C, Luo, XM, Blank, MC, Millen, KJ, Sharlin, DS, Forrest, D, Dahlman-Wright, K, Zhao, C, Mishima, Y, Sinha, S, Chakrabarti, R, Portales-Casamar, E, Sladek, FM, Bradley, PH, Wasserman, WW, Yusuf, D, Butland, SL, Swanson, MI, Bolotin, E, Ticoll, A, Cheung, WA, Zhang, XYC, Dickman, CTD, Fulton, DL, Lim, JS, Schnabl, JM, Ramos, OHP, Vasseur-Cognet, M, de Leeuw, CN, Simpson, EM, Ryffel, GU, Lam, EW-F, Kist, R, Wilson, MSC, Marco-Ferreres, R, Brosens, JJ, Beccari, LL, Bovolenta, P, Benayoun, BA, Monteiro, LJ, Schwenen, HDC, Grontved, L, Wederell, E, Mandrup, S, Veitia, RA, Chakravarthy, H, Hoodless, PA, Mancarelli, MM, Torbett, BE, Banham, AH, Reddy, SP, Cullum, RL, Liedtke, M, Tschan, MP, Vaz, M, Rizzino, A, Zannini, M, Frietze, S, Farnham, PJ, Eijkelenboom, A, Brown, PJ, Laperriere, D, Leprince, D, de Cristofaro, T, Prince, KL, Putker, M, del Peso, L, Camenisch, G, Wenger, RH, Mikula, M, Rozendaal, M, Mader, S, Ostrowski, J, Rhodes, SJ, Van Rechem, C, Boulay, G, Olechnowicz, SWZ, Breslin, MB, Lan, MS, Nanan, KK, Wegner, M, Hou, J, Mullen, RD, Colvin, SC, Noy, PJ, Webb, CF, Witek, ME, Ferrell, S, Daniel, JM, Park, J, Waldman, SA, Peet, DJ, Taggart, M, Jayaraman, P-S, Karrich, JJ, Blom, B, Vesuna, F, O'Geen, H, Sun, Y, Gronostajski, RM, Woodcroft, MW, Hough, MR, Chen, E, Europe-Finner, GN, Karolczak-Bayatti, M, Bailey, J, Hankinson, O, Raman, V, LeBrun, DP, Biswal, S, Harvey, CJ, DeBruyne, JP, Hogenesch, JB, Hevner, RF, Heligon, C, Luo, XM, Blank, MC, Millen, KJ, Sharlin, DS, Forrest, D, Dahlman-Wright, K, Zhao, C, Mishima, Y, Sinha, S, Chakrabarti, R, Portales-Casamar, E, Sladek, FM, Bradley, PH, and Wasserman, WW
- Abstract
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
- Published
- 2012
7. Cytogenetic analyses of premature ovarian failure using karyotyping and interphase fluorescence in situ hybridization (FISH) in a group of 1000 patients
- Author
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Lakhal, B, primary, Braham, R, additional, Berguigua, R, additional, Bouali, N, additional, Zaouali, M, additional, Chaieb, M, additional, Veitia, RA, additional, Saad, A, additional, and Elghezal, H, additional
- Published
- 2009
- Full Text
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8. FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD)
- Author
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Hersmus, R, primary, Kalfa, N, additional, de Leeuw, B, additional, Stoop, H, additional, Oosterhuis, JW, additional, de Krijger, R, additional, Wolffenbuttel, KP, additional, Drop, SLS, additional, Veitia, RA, additional, Fellous, M, additional, Jaubert, F, additional, and Looijenga, LHJ, additional
- Published
- 2008
- Full Text
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9. A cellular model provides insights into the pathogenicity of the oncogenic FOXL2 somatic variant p.Cys134Trp.
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Herman L, Amo A, Legois B, Di Carlo C, Veitia RA, and Todeschini AL
- Subjects
- Humans, Female, Cell Line, Tumor, Cell Movement genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Ovarian Neoplasms metabolism, Smad3 Protein genetics, Smad3 Protein metabolism, CRISPR-Cas Systems, Gene Expression Regulation, Neoplastic, Forkhead Box Protein L2 genetics, Forkhead Box Protein L2 metabolism, Granulosa Cell Tumor genetics, Granulosa Cell Tumor pathology
- Abstract
Background: FOXL2 is a transcription factor expressed in ovarian granulosa cells. A somatic variant of FOXL2 (c.402 C > G, p.Cys134Trp) is the hallmark of adult-type granulosa cell tumours., Methods: We generated KGN cell clones either heterozygous for this variant (MUT) or homozygous for the wild-type (WT) allele by CRISPR/Cas9 editing. They underwent RNA-Seq and bioinformatics analyses to uncover pathways impacted by deregulated genes. Cell morphology and migration were studied., Results: The differentially expressed genes (DEGs) between WT/MUT and WT/WT KGN cells (DEGs-
WT/MUT ), pointed to several dysregulated pathways, like TGF-beta pathway, cell adhesion and migration. Consistently, WT/MUT cells were rounder than WT/WT cells and displayed a different distribution of stress fibres and paxillin staining. A comparison of the DEGs-WT/MUT with those found when FOXL2 was knocked down (KD) in WT/WT KGN cells showed that most DEGs-WT/MUT cells were not so in the KD experiment, supporting a gain-of-function (GOF) scenario. MUT-FOXL2 also displayed a stronger interaction with SMAD3., Conclusions: Our work, aiming at better understanding the GOF scenario, shows that the dysregulated genes and pathways are consistent with this idea. Besides, we propose that GOF might result from an enhanced interaction with SMAD3 that could underlie an ectopic capacity of mutated FOXL2 to bind SMAD4., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
- Full Text
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10. The forkhead DNA-binding domain binds specific G2-rich RNA sequences.
- Author
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Zutterling C, Todeschini AL, Fourmy D, Busso D, Veaute X, Ducongé F, and Veitia RA
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- Animals, Base Sequence, Protein Domains, Binding Sites genetics, Mammals genetics, Forkhead Transcription Factors metabolism, DNA genetics
- Abstract
Transcription factors contain a DNA-binding domain ensuring specific recognition of DNA target sequences. The family of forkhead (FOX) transcription factors is composed of dozens of paralogs in mammals. The forkhead domain (FHD) is a segment of about 100 amino acids that binds an A-rich DNA sequence. Using DNA and RNA PCR-SELEX, we show that recombinant FOXL2 proteins, either wild-type or carrying the oncogenic variant C134W, recognize similar DNA-binding sites. This suggests that the oncogenic variant does not alter the intrinsic sequence-specificity of FOXL2. Most importantly, we show that FOXL2 binds G2-rich RNA sequences whereas it virtually fails to bind similar sequences in DNA chemistry. Interestingly, a statistically significant subset of genes responding to the knock-down of FOXL2/Foxl2 harbor such G2-rich sequences and are involved in crucial signaling pathways and cellular processes. In addition, we show that FOXA1, FOXO3a and chimeric FOXL2 proteins containing the FHD of the former are also able to interact with some of the preferred FOXL2-binding sequences. Our results point to an unexpected and novel characteristic of the forkhead domain, the biological relevance of which remains to be explored., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2023
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11. Dominant negative variants and cotranslational assembly of macromolecular complexes.
- Author
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Veitia RA
- Abstract
Pathogenic variants occurring in protein-coding regions underlie human genetic disease through various mechanisms. They can lead to a loss of function (LOF) such as in recessive conditions or in dominant conditions due to haploinsufficiency. Dominant-negative (DN) effects, counteracting the activity of the normal gene-product, and gain of function (GOF) are also mechanisms driving dominance. Here, I discuss a few papers on these specific mechanisms. In short, there is accumulating evidence pointing to differences between LOF versus non-LOF variants (DN and GOF). The latter are thought to have milder effects on protein structure and, as expected, DN variants are enriched at protein interfaces. This tendency to cluster in 3D space can help improve the ability of computational tools to predict the pathogenicity of DN variants, which is currently a challenging issue. More recent results support the hypothesis whereby cotranslational assembly of macromolecular complexes can buffer deleterious consequences of variants that would otherwise lead to DN effects (DNEs). Indeed, subunits the variants of which are responsible for DNEs tend to elude cotranslational assembly, thus poisoning complexes involving wild-type subunits. The constraints explaining why the buffering of DNEs is not universal require further investigation., (© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.)
- Published
- 2023
- Full Text
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12. Recurrent missense variants in clonal hematopoiesis-related genes present in the general population.
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Ariste O, de la Grange P, and Veitia RA
- Subjects
- Humans, Aged, Mutation, Hematopoietic Stem Cells, Germ-Line Mutation, Clonal Hematopoiesis, Hematopoiesis genetics
- Abstract
Clonal hematopoiesis (CH) consists in an abnormal expansion of a hematopoietic stem cell bearing an advantageous somatic variant. A survey of known recurrent somatic missense variants in DNMT3A, SF3B1, SRSF2, and TP53, some of the most prominent genes underlying CH of indeterminate potential (CHIP), in gnomAD noncancer database shows the presence of 73 variants. Many of them reach frequencies higher than 0.01% in various populations and, in many cases, are enriched in specific populations. Consistent with a potential involvement in CHIP, we found that the age distribution of the carriers is shifted towards old ages. Moreover, the variant allele frequencies are on average lower than 50%, expected for germline heterozygous variants. The pervasive presence of some of such variants in blood DNA from elder individuals is compatible with CHIP of somatic origin. On practical grounds, CHIP can lead to misclassification of somatic variants in cancer-predisposition genes as inherited, which bear consequences for the affected individuals and their families., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
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13. The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors.
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Llano E, Todeschini AL, Felipe-Medina N, Corte-Torres MD, Condezo YB, Sanchez-Martin M, López-Tamargo S, Astudillo A, Puente XS, Pendas AM, and Veitia RA
- Subjects
- Adult, Female, Humans, Animals, Mice, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Mutation, Forkhead Box Protein L2 genetics, Granulosa Cell Tumor genetics, Granulosa Cell Tumor metabolism, Skin Abnormalities, Ovarian Neoplasms genetics
- Abstract
Adult-type granulosa cell tumors (AGCT) are the most common type of malignant ovarian sex cord-stromal tumors. Most AGCTs carry the somatic variant c.402C>G (p.C134W) affecting the transcription factor FOXL2. Germline dominant variants in FOXL2 are responsible for blepharophimosis syndrome, which is characterized by underdevelopment of the eyelid. In this work, we generated a mouse model harboring the C134W variant of FOXL2 to evaluate in vivo the poorly understood oncogenic role of FOXL2. The mutation was dominant regarding eyelid hypoplasia, reminiscent of blepharophimosis syndrome. Interestingly, Foxl2+/C134W female mice had reduced fertility and developed AGCTs through a progression from abnormal ovaries with aberrant granulosa cells to ovaries with stromal hyperplasia and atypia and on to tumors in adut mice. The genes dysregulated in mouse AGCTs exhibited the hallmarks of cancer and were consistent with a gain-of-function of the mutated allele affecting TGFβ signaling. A comparison of these data with previous results on human AGCTs indicated similar deregulated pathways. Finally, a mutational analysis of mouse AGCT transcriptomic data suggested the absence of additional driver mutations apart from FOXL2-C134W. These results provide a clear in vivo example in which a single mutational hit triggers tumor development associated with profound transcriptomic alterations., Significance: A newly generated mouse model carrying a FOXL2 mutation characteristic of adult-type granulosa cell tumors shows that FOXL2 C134W shifts the transcriptome towards a signature of granulosa cell cancer and drives tumorigenesis., (©2022 American Association for Cancer Research.)
- Published
- 2023
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14. A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions.
- Author
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Franca MM, Condezo YB, Elzaiat M, Felipe-Medina N, Sánchez-Sáez F, Muñoz S, Sainz-Urruela R, Martín-Hervás MR, García-Valiente R, Sánchez-Martín MA, Astudillo A, Mendez J, Llano E, Veitia RA, Mendonca BB, and Pendás AM
- Subjects
- Animals, Female, Humans, Mice, Chromosome Aberrations, DNA Repair genetics, Fibroblasts metabolism, Meiosis, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Primary Ovarian Insufficiency genetics, Primary Ovarian Insufficiency metabolism
- Abstract
Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POI cases remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B -(c.92delT) in two sisters with POI. In vitro studies revealed that this variant leads to translation reinitiation at methionine 64. Here, we show that this is a pathogenic hypomorphic variant in a mouse model. Rad51b
c.92delT/c.92delT mice exhibited meiotic DNA repair defects due to RAD51 and HSF2BP/BMRE1 accumulation in the chromosome axes leading to a reduction in the number of crossovers. Interestingly, the interaction of RAD51B-c.92delT with RAD51C and with its newly identified interactors RAD51 and HELQ was abrogated or diminished. Repair of mitomycin-C-induced chromosomal aberrations was impaired in RAD51B/Rad51b-c.92delT human and mouse somatic cells in vitro and in explanted mouse bone marrow cells. Accordingly, Rad51b-c.92delT variant reduced replication fork progression of patient-derived lymphoblastoid cell lines and pluripotent reprogramming efficiency of primary mouse embryonic fibroblasts. Finally, Rad51bc.92delT/c.92delT mice displayed increased incidence of pituitary gland hyperplasia. These results provide new mechanistic insights into the role of RAD51B not only in meiosis but in the maintenance of somatic genome stability., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)- Published
- 2022
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15. Who ever thought genetic mutations were random?
- Author
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Veitia RA
- Subjects
- Mutation genetics, Arabidopsis genetics
- Abstract
In a recent study of de novo mutations in arabidopsis (Arabidopsis thaliana), Monroe et al. found a lower mutation frequency inside gene bodies and certain essential genes, shattering the long-standing idea that mutations are entirely random across the genome. Here I highlight the molecular nonrandomness of mutations and the type of gene affected., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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16. Pathogenic "germline" variants associated with myeloproliferative disorders in apparently normal individuals: Inherited or acquired genetic alterations?
- Author
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Veitia RA and Innan H
- Subjects
- Calreticulin genetics, Germ Cells, Humans, Mutation, Receptors, Thrombopoietin genetics, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders genetics, Primary Myelofibrosis diagnosis, Primary Myelofibrosis genetics
- Abstract
Myeloproliferative syndromes (MPS) are hematologic malignancies due to the expansion of an abnormal hematopoietic stem cell. They include chronic myeloid leukemia (CML) and non-CML MPS such as polycythemia vera, essential thrombocythemia and primary myelofibrosis. The latter are distinguished by somatic pathogenic variants affecting JAK2, CALR, or MPL genes. Apparent germline pathogenic variants have been reported in the general population. Here, we found that two gnomAD data-sets report more homozygotes than expected for the JAK2 c.1849G > T(Val617Phe) variant. We propose that somatic gene conversion can explain the presence of those unexpected homozygotes in normal populations. Consistently, homozygous individuals are older than 65 years. We also found a lower-than-expected frequency of the JAK2 variant in younger individuals suggesting that somatic mutation can underlie its presence in (at least some) heterozygotes. Regarding pathogenic variants in MPL and CALR, they are also present in the gnomAD data-sets explored. However, we cannot conclude that such seemingly germline variants are in fact somatic alterations. These results suggest that apparently normal individuals bearing MPS-related variants can be subclinical/undiagnosed MPS cases of somatic origin. It would be interesting to assess the hematologic phenotype of such individuals and the presence of the relevant variants in other tissues., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
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17. Gene-dosage issues: a recurrent theme in whole genome duplication events.
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Veitia RA and Birchler JA
- Subjects
- Evolution, Molecular, Gene Dosage, Genome, Plant genetics, Plants genetics, Arabidopsis genetics, Gene Duplication
- Abstract
Two recent studies have addressed the long-term consequences of whole genome duplications (WGD). Specifically, they analyzed transcriptomes of the plant Arabidopsis thaliana and of four salmonids to assess the impact of WGD on gene expression. These studies point to commonalities in gene expression adjustments after polyploidization that we outline and discuss below., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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18. FOXL2 in adult-type granulosa cell tumour of the ovary: oncogene or tumour suppressor gene?
- Author
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Pilsworth JA, Todeschini AL, Neilson SJ, Cochrane DR, Lai D, Anttonen M, Heikinheimo M, Huntsman DG, and Veitia RA
- Subjects
- Female, Humans, Mutation, Forkhead Box Protein L2 genetics, Granulosa Cell Tumor genetics, Oncogenes genetics
- Abstract
A recurrent mutation in FOXL2 (c.402C>G; p.C134W) is present in over 95% of adult-type granulosa cell tumours (AGCTs). In contrast, various loss-of-function mutations in FOXL2 lead to the development of blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). BPES is characterised by an eyelid malformation often accompanied with primary ovarian insufficiency. Two recent studies suggest that FOXL2 C402G is a gain- or change-of-function mutation with altered DNA-binding specificity. Another study proposes that FOXL2 C402G is selectively targeted for degradation, inducing somatic haploinsufficiency, suggesting its role as a tumour suppressor. The latter study relies on data indicative of an FOXL2 allelic imbalance in AGCTs. Here we present RNA-seq data as genetic evidence that no real allelic imbalance is observed at the transcriptomic level in AGCTs. Additionally, there is no loss of protein expression in tumours harbouring the mutated allele. These data and other features of this mutation compared to other oncogenes and tumour suppressor genes argue strongly against FOXL2 being a tumour suppressor in this context. Given the likelihood that FOXL2 C402G is oncogenic, targeting the variant protein or its downstream consequences is the most viable path forward to identifying an effective treatment for this cancer. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2021
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19. A reply to: Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals.
- Author
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Veitia RA
- Subjects
- Blood Cells, Humans, Male, Aging genetics, Chromosomes, Human, Y genetics
- Published
- 2021
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20. Reply to "An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2".
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Veitia RA, Pilsworth J, Todeschini AL, and Huntsman D
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- Forkhead Box Protein L2 genetics, Humans, Mutation, Open Reading Frames, Neoplasms genetics
- Published
- 2021
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21. Genes Encoding Teleost Orthologs of Human Haploinsufficient and Monoallelically Expressed Genes Remain in Duplicate More Frequently Than the Whole Genome.
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Picolo F, Grandchamp A, Piégu B, Rolland AD, Veitia RA, and Monget P
- Abstract
Gene dosage is an important issue both in cell and evolutionary biology. Most genes are present in two copies or alleles in diploid eukariotic cells. The most outstanding exception is monoallelic gene expression (MA) that concerns genes localized on the X chromosome or in regions undergoing parental imprinting in eutherians, and many other genes scattered throughout the genome. In diploids, haploinsufficiency (HI) implies that a single functional copy of a gene in a diploid organism is insufficient to ensure a normal biological function. One of the most important mechanisms ensuring functional innovation during evolution is whole genome duplication (WGD). In addition to the two WGDs that have occurred in vertebrate genomes, the teleost genomes underwent an additional WGD, after their divergence from tetrapods. In the present work, we have studied on 57 teleost species whether the orthologs of human MA or HI genes remain more frequently in duplicates or returned more frequently in singleton than the rest of the genome. Our results show that the teleost orthologs of HI human genes remained more frequently in duplicate than the rest of the genome in all of the teleost species studied. No signal was observed for the orthologs of genes mapping to the human X chromosome or subjected to parental imprinting. Surprisingly, the teleost orthologs of the other human MA genes remained in duplicate more frequently than the rest of the genome for most teleost species. These results suggest that the teleost orthologs of MA and HI human genes also undergo selective pressures either related to absolute protein amounts and/or of dosage balance issues. However, these constraints seem to be different for MA genes in teleost in comparison with human genomes., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Floriane Picolo et al.)
- Published
- 2021
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22. Insights into the pathogenicity of missense variants in the forkhead domain of FOX proteins underlying Mendelian disorders.
- Author
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Bermúdez-Guzmán L and Veitia RA
- Subjects
- Computational Biology methods, Databases, Genetic, Genetic Predisposition to Disease genetics, Humans, Forkhead Transcription Factors genetics, Genetic Diseases, Inborn genetics, Mutation, Missense genetics
- Abstract
Forkhead box (FOX) proteins are members of a conserved family of transcription factors. Pathogenic variants in FOX genes have been shown to be responsible for several human genetic diseases. Here, we have studied the molecular and structural features of germline pathogenic variants in seven FOX proteins involved in Mendelian disorders and compared them with those of variants present in the general population (gnomAD). Our study shows that the DNA-binding domain of FOX proteins is particularly sensitive to damaging variation, although some family members show greater mutational tolerance than others. Next, we set to demonstrate that this tolerance depends on the inheritance mode of FOX-linked disorders. Accordingly, genes whose variants underlie recessive conditions are supposed to have a greater tolerance to variation. This is what we found. As expected, variants responsible for disorders with a dominant inheritance pattern show a higher degree of pathogenicity compared to those segregating in the general population. Moreover, we show that pathogenic and likely pathogenic variants tend to affect mutually exclusive sites with respect to those reported in gnomAD. The former also tend to affect sites with lower solvent exposure and a higher degree of conservation. Our results show the value of using publicly available databases and bioinformatics to gain insights into the molecular and structural bases of disease-causing genetic variation.
- Published
- 2021
- Full Text
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23. Predictable increase in female reproductive window: A simple model connecting age of reproduction, menopause, and longevity.
- Author
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Innan H, Vaiman D, and Veitia RA
- Subjects
- Alleles, Female, Humans, Menopause, Reproduction, Infertility, Longevity genetics
- Abstract
With the ever-increasing lifespan along with societal changes, women can marry and procreate later than in previous centuries. However, pathogenic genetic variants segregating in the population can lead to female subfertility or infertility well before the average age of normal menopause, leading to counter-selection of such deleterious alleles. In reviewing this field, we speculate that a logical consequence would be the later occurrence of menopause and the extension of women's reproductive lifespan. We illustrate this point with a simple model that applies to other variants that contribute to female infertility, including epigenetic variation. We also consider the effect of medical interventions and lifestyle., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
24. Forkhead Transcription Factors in Health and Disease.
- Author
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Herman L, Todeschini AL, and Veitia RA
- Subjects
- Aging physiology, Animals, Forkhead Transcription Factors chemistry, Forkhead Transcription Factors genetics, Gene Expression Regulation, Genetic Diseases, Inborn genetics, Humans, Mice, Multigene Family, Evolution, Molecular, Forkhead Transcription Factors metabolism, Neoplasms genetics
- Abstract
Forkhead box (FOX) proteins belong to an evolutionarily conserved family of transcription factors that has evolved by gene/genome duplication. FOX family members have undergone sequence and regulatory diversification. However, they have retained some degree of functional redundancy, in addition to playing specific roles, both during development and in the adult. Genetic alterations or misregulation of FOX genes underlie human genetic diseases, cancer, and/or aging. In this review, we provide an updated overview of the main characteristics of the members of this family, in terms of breadth of expression, protein domain composition, evolution, and function., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
25. Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion.
- Author
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Herman L, Legois B, Todeschini AL, and Veitia RA
- Subjects
- Animals, Cell Adhesion, Cell Line, Tumor, Cell Movement, Estrogen Receptor beta genetics, Female, Forkhead Box Protein L2 genetics, Gene Editing, Mice, Estrogen Receptor beta metabolism, Forkhead Box Protein L2 metabolism, Granulosa Cells physiology
- Abstract
FOXL2 and ESR2 are key transcriptional regulators in ovarian granulosa cells. To explore their transcriptional roles and their interplay, we have depleted Foxl2 and Esr2 in mouse primary granulosa cells to assess their ability to bind their targets and/or to modulate gene expression and cellular functions. We show that FOXL2 is involved in a large number of regulatory actions essential for the maintenance of granulosa cell fate. A parallel ChIP-seq analysis showed that FOXL2 mainly binds to sites located in intergenic regions quite far from its targets. A bioinformatic analysis demonstrated that FOXL2-activated genes were enriched in peaks associated with the H3K27ac mark, whereas FOXL2-repressed genes were not, suggesting that FOXL2 can activate transcription through binding to enhancer sites. We also identified about 500 deregulated genes upon Esr2 silencing, of which one third are also targets of FOXL2. We provide evidence showing that both factors modulate, through a coherent feed-forward loop, a number of common targets. Many of the FOXL2/ESR2 targets are involved in cell motility and, consistently, granulosa cells depleted for either Foxl2 or Esr2 exhibit decreased migration, invasion and adhesion. This effect is paralleled by the depletion of their target Phactr1, involved in actin cytoskeleton dynamics. Our analysis expands the number of direct and indirect transcriptional targets of both FOXL2 and ESR2, which deserve investigation in the context of adult-type granulosa cell tumors whose molecular diagnostic hallmark is the presence of the C134W FOXL2 pathogenic variant., (© 2021 Federation of American Societies for Experimental Biology.)
- Published
- 2021
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- View/download PDF
26. Clinical Genetics paving the way to the future.
- Author
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Veitia RA
- Subjects
- Editorial Policies, Forecasting, Humans, Genetics, Medical trends, Periodicals as Topic
- Published
- 2021
- Full Text
- View/download PDF
27. One Hundred Years of Gene Balance: How Stoichiometric Issues Affect Gene Expression, Genome Evolution, and Quantitative Traits.
- Author
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Birchler JA and Veitia RA
- Subjects
- Animals, Datura stramonium genetics, Dosage Compensation, Genetic, Drosophila melanogaster genetics, Genetic Speciation, Humans, Sex Chromosomes genetics, Aneuploidy, Evolution, Molecular, Gene Expression Regulation, Genome genetics, Quantitative Trait, Heritable
- Abstract
A century ago experiments with the flowering plant Datura stramonium and the fruit fly Drosophila melanogaster revealed that adding an extra chromosome to a karyotype was much more detrimental than adding a whole set of chromosomes. This phenomenon was referred to as gene balance and has been recapitulated across eukaryotic species. Here, we retrace some developments in this field. Molecular studies suggest that the basis of balance involves stoichiometric relationships of multi-component interactions. This concept has implication for the mechanisms controlling gene expression, genome evolution, sex chromosome evolution/dosage compensation, speciation mechanisms, and the underlying genetics of quantitative traits., (© 2021 S. Karger AG, Basel.)
- Published
- 2021
- Full Text
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28. DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation.
- Author
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Elzaiat M, Flatters D, Sierra-Díaz DC, Legois B, Laissue P, and Veitia RA
- Subjects
- Cell Line, Tumor, Female, HeLa Cells, Humans, Male, Molecular Dynamics Simulation, Protein Conformation, Proteolysis, Genetic Predisposition to Disease genetics, Gonadal Dysgenesis, 46,XY genetics, Hedgehog Proteins genetics, Mutation genetics
- Abstract
In humans, pathogenic variants in the DHH gene underlie cases of 46,XY gonadal dysgenesis. DHH is part of the Hedgehog family of proteins, which require extensive processing, including self-cleavage of the precursor for efficient signalling. In our work, we have assessed the effect of several human DHH pathogenic variants involved in recessive complete or partial gonadal dysgenesis, on protein processing and sub-cellular localization. We found that a subset of variants was unable to perform self-cleavage, which correlated albeit not perfectly with an altered subcellular localization of the resulting proteins. For the processing-proficient variants, we used structural modelling tools and molecular dynamic (MD) simulations to predict the potential impact of the variants on protein conformation and/or interaction with partners. Our study contributes to a better understanding of the molecular mechanisms involved in DHH dysfunction leading to 46,XY disorders of sex development.
- Published
- 2020
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29. An exome-wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes.
- Author
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Alvarez-Mora MI, Todeschini AL, Caburet S, Perets LP, Mila M, Younis JS, Shalev S, and Veitia RA
- Subjects
- Adolescent, Adult, Alleles, Exome genetics, Female, Genetic Predisposition to Disease, Humans, Primary Ovarian Insufficiency pathology, Risk Factors, Exome Sequencing, Young Adult, Inhibins genetics, Minichromosome Maintenance Proteins genetics, Primary Ovarian Insufficiency genetics, Steroidogenic Factor 1 genetics
- Abstract
Primary ovarian insufficiency (POI) implies the cessation of menstruation for several months in women before the age of 40 years and is a major cause of infertility. The study of the contribution of genetic factors to POI has been fueled by the use of whole exome sequencing (WES). Here, to uncover novel causative pathogenic variants and risk alleles, WES has been performed in 12 patients with familial POI (eight unrelated index cases and two pairs of sisters) and six women with early menopause and family history of POI (four index cases and one pair of sisters). Likely causative variants in NR5A1 and MCM9 genes were identified as well as a variant in INHA that requires further investigation. Moreover, we have identified more than one candidate variant in 3 out of 15 familial cases. Taken together, our results highlight the genetic heterogeneity of POI and early menopause and support the hypothesis of an oligogenic inheritance of such conditions, in addition to monogenic inheritance., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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30. A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1.
- Author
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Felipe-Medina N, Caburet S, Sánchez-Sáez F, Condezo YB, de Rooij DG, Gómez-H L, Garcia-Valiente R, Todeschini AL, Duque P, Sánchez-Martin MA, Shalev SA, Llano E, Veitia RA, and Pendás AM
- Subjects
- Animals, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Female, Mice, Mice, Knockout, Rad51 Recombinase genetics, Rad51 Recombinase metabolism, Exome Sequencing, Carrier Proteins genetics, Carrier Proteins metabolism, Heat-Shock Proteins genetics, Heat-Shock Proteins metabolism, Meiosis genetics, Mutation, Missense genetics, Primary Ovarian Insufficiency genetics, Recombination, Genetic genetics
- Abstract
Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP , an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bp
S167L/S167L females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility., Competing Interests: NF, SC, FS, YC, Dd, LG, RG, AT, PD, MS, SS, EL, RV, AP No competing interests declared, (© 2020, Felipe-Medina et al.)- Published
- 2020
- Full Text
- View/download PDF
31. The Muller's Ratchet and Aging.
- Author
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Govindaraju DR, Innan H, and Veitia RA
- Subjects
- Computer Simulation, Evolution, Molecular, Humans, Aging genetics, Epigenesis, Genetic, Genetics, Population, Models, Genetic, Mutation, Selection, Genetic
- Abstract
Aging entails an irreversible deceleration of physiological processes, altered metabolic activities, and a decline of the integrity of tissues, organs, and organ systems. The accumulation of alterations in the genetic and epigenetic spaces has been proposed as an explanation for aging. They result, at least in part, from DNA replication and chromosome segregation errors due to cell division during development, growth, renewal, and repair. Such deleterious alterations, including epigenetic drift, irreversibly accumulate in a stepwise, ratchet-like manner and reduce cellular fitness, similar to the process known as Muller's ratchet. Here, we revisit the Muller's ratchet principle applied to the aging of somatic cell populations and discuss the implications for understanding the origins of senescence, frailty, and morbidity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
32. Primary ovarian insufficiency, meiosis and DNA repair.
- Author
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Veitia RA
- Subjects
- Female, Follicular Atresia genetics, High-Throughput Nucleotide Sequencing methods, Humans, Mutation genetics, DNA Repair genetics, Meiosis genetics, Primary Ovarian Insufficiency genetics
- Abstract
Premature ovarian insufficiency (POI) is a major cause of female infertility. It is a heterogeneous disease that affects about 1% of women under 40 years of age. POI may be due to abnormal follicle stock formation, increased follicular atresia, impaired recruitment of dominant follicles, blocked follicular maturation or rapid depletion of the follicular stock. It remains idiopathic in most cases but the existence of familial cases shows that it can have a genetic origin. Next generation sequencing (NGS) strategies have allowed the identification of new genes involved in the etiology of POI. Here, I briefly describe some studies demonstrating that pathogenic variants in 'DNA repair and meiotic genes' underlie POI. Some of the examples show the power of the combination of classical genetics and NGS in the discovery of novel 'POI genes'., Competing Interests: Conflicts of Interest The author has no conflict of interest to declare., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
33. Insights into the loss of the Y chromosome with age in control individuals and in patients with age-related macular degeneration using genotyping microarray data.
- Author
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Grassmann F, Weber BHF, and Veitia RA
- Subjects
- Aneuploidy, Chromosome Deletion, Genotype, Humans, Leukocytes physiology, Male, Aging genetics, Chromosomes, Human, Y genetics, Macular Degeneration genetics
- Abstract
The extent of aneuploidy of the sex chromosomes increases with age in human leukocytes. Here, we re-explore the dynamics of normal loss of the Y chromosome (LOY) with age based on microarray data using two exponential models and two different ways to estimate the fraction of LOY. This analysis shows the existence of a significant correlation between the fraction of LOY estimated from molecular cytogenetics and genotyping microarray data. Although the specific estimates of the parameters for the two exponential models are different from those derived from cytogenetics data, the present analysis in an independent dataset of normal individuals confirms that X0 cells have a selective advantage over XY cells. Moreover, patients with age-related macular degeneration display higher fraction of LOY values and seem to have a predisposition to lose their Y chromosome even at young ages compared to control individuals. As there are no data available for the same individuals at different time points, the parameters reported here are average values drawn from population analyses.
- Published
- 2020
- Full Text
- View/download PDF
34. Special issue on "Molecular genetics of aging and longevity": a critical time in the field of geroscience.
- Author
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Benayoun BA and Veitia RA
- Subjects
- Humans, Molecular Biology methods, Aging genetics, Longevity genetics
- Published
- 2020
- Full Text
- View/download PDF
35. Conventional and unconventional interactions of the transcription factor FOXL2 uncovered by a proteome-wide analysis.
- Author
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Penrad-Mobayed M, Perrin C, Herman L, Todeschini AL, Nigon F, Cosson B, Caburet S, and Veitia RA
- Subjects
- Animals, Cells, Cultured, Female, Granulosa Cells cytology, Mice, Pituitary Gland cytology, Proteome analysis, Forkhead Box Protein L2 metabolism, Granulosa Cells metabolism, Pituitary Gland metabolism, Protein Interaction Maps, Proteome metabolism
- Abstract
Beyond the study of its transcriptional target genes, the identification of the various interactors of a transcription factor (TF) is crucial to understand its diverse cellular roles. We focused on FOXL2, a winged-helix forkhead TF important for ovarian development and maintenance. FOXL2 has been implicated in diverse cellular processes, including apoptosis, the control of cell cycle or the regulation of steroid hormone synthesis. To reliably identify partners of endogenous FOXL2, we performed a proteome-wide analysis using co-immunoprecipitation in the murine granulosa cell-derived AT29c and the pituitary-derived alpha-T3 cell lines, using three antibodies targeting different parts of the protein. Following a stringent selection of mass spectrometry data on the basis of identification reliability and protein enrichment, we identified a core set of 255 partners common to both cell lines. Their analysis showed that we could co-precipitate several complexes involved in mRNA processing, chromatin remodeling and DNA replication and repair. We further validated (direct and/or indirect) interactions with selected partners, suggesting an unexpected role for FOXL2 in those processes. Overall, this comprehensive analysis of the endogenous FOXL2 interactome sheds light on its numerous and diverse interactors and unconventional cellular roles., (© 2019 Federation of American Societies for Experimental Biology.)
- Published
- 2020
- Full Text
- View/download PDF
36. The Gene Balance Hypothesis: Epigenetics and Dosage Effects in Plants.
- Author
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Shi X, Chen C, Yang H, Hou J, Ji T, Cheng J, Veitia RA, and Birchler JA
- Subjects
- Aneuploidy, Chromosomes, Plant genetics, Epigenomics methods, Gene Expression genetics, Gene Expression Regulation genetics, Gene Frequency genetics, Genome, Plant genetics, Phenotype, Polyploidy, Quantitative Trait, Heritable, Epigenesis, Genetic genetics, Gene Dosage genetics, Plants genetics
- Abstract
Dosage effects in plants are caused by changes in the copy number of chromosomes, segments of chromosomes, or multiples of individual genes. Genes often exhibit a dosage effect in which the amount of product is closely correlated with the number of copies present. However, when larger segments of chromosomes are varied, there are trans-acting effects across the genome that are unleashed that modulate gene expression in cascading effects. These appear to be mediated by the stoichiometric relationship of gene regulatory machineries. There are both positive and negative modulations of target gene expression, but the latter is the plurality effect. When this inverse effect is combined with a dosage effect, compensation for a gene can occur in which its expression is similar to the normal diploid regardless of the change in chromosomal dosage. In contrast, changing the whole genome in a polyploidy series has fewer relative effects as the stoichiometric relationship is not disrupted. Together, these observations suggest that the stoichiometry of gene regulation is important as a reflection of the mode of assembly of the individual subunits involved in the effective regulatory macromolecular complexes. This principle has implications for gene expression mechanisms, quantitative trait genetics, and the evolution of genes depending on the mode of duplication, either segmentally or via whole-genome duplication.
- Published
- 2020
- Full Text
- View/download PDF
37. MIRAGE Syndrome: Phenotypic Rescue by Somatic Mutation and Selection.
- Author
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Veitia RA
- Subjects
- Humans, Mutation, Phenotype, Adrenal Insufficiency genetics, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics, Intracellular Signaling Peptides and Proteins genetics
- Abstract
MIRAGE syndrome, a multisystem disorder, results from heterozygous gain-of-function mutations in SAMD9, which encodes a growth suppressor, located on chromosome 7. Somatic changes involving loss-of-function mutations of the altered SAMD9 allele or loss of chromosome 7 act as phenotypic modifiers, providing a typical example of somatic mutation and selection process., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
38. Causes and effects of haploinsufficiency.
- Author
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Johnson AF, Nguyen HT, and Veitia RA
- Subjects
- Chromosome Disorders genetics, Gene Dosage, Gene Expression, Genes, Tumor Suppressor, Haploinsufficiency genetics, Humans, Mutation, Neoplasms genetics, Stochastic Processes, Haploinsufficiency physiology
- Abstract
Haploinsufficiency is a form of genetic dominance and is the underlying mechanism of numerous human inherited conditions in which the causal genes are sensitive to altered dosage. This review examines the poorly understood relationships between haploinsufficiency, dosage sensitivity and genetic dominance, whose common theme is the existence of nonlinear relationships between genotype and phenotype. We present an up-to-date account of the bases of haploinsufficiency from the perspective of theoretical and experimental models. We also discuss human conditions caused by haploinsufficiency, including developmental syndromes and cancer. Connections between the understanding of these conditions' genetic mechanisms and advances in treatments are also described., (© 2019 Cambridge Philosophical Society.)
- Published
- 2019
- Full Text
- View/download PDF
39. AFF3: a new player in maintaining XIST monoallelic expression.
- Author
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Veitia RA
- Subjects
- Alleles, Cell Differentiation, DNA Methylation
- Published
- 2019
- Full Text
- View/download PDF
40. Darwinian selection within an individual or somatic selection: facts and models.
- Author
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Veitia RA
- Subjects
- Animals, Cell Division genetics, Cell Division physiology, Female, Humans, Leukocytes metabolism, Mitochondria genetics, Mitochondria metabolism, Models, Genetic, Sex Chromosomes metabolism, Models, Theoretical, Selection, Genetic genetics
- Published
- 2019
- Full Text
- View/download PDF
41. DNA Content, Cell Size, and Cell Senescence.
- Author
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Veitia RA
- Subjects
- Aging, Animals, Cell Size, Cytoplasm, DNA, Cellular Senescence, Proteomics
- Abstract
A recent study assessed the impact of cell size on various cell properties. Oversized yeast cells display slow cell division, cytoplasmic dilution, and transcriptomic and proteomic alterations. It highlights commonalities between aging yeast and mammalian cells, suggesting the existence of a range of DNA content: cell volume ratio ensuring optimal function., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
42. High-throughput Exploration of the Network Dependent on AKT1 in Mouse Ovarian Granulosa Cells.
- Author
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Elzaiat M, Herman L, Legois B, Léger T, Todeschini AL, and Veitia RA
- Subjects
- Animals, Cell Line, Cell Movement, Female, Gene Expression Regulation, Genome, Mice, Peptides metabolism, Phosphorylation, Protein Processing, Post-Translational, RNA, Messenger genetics, RNA, Messenger metabolism, Transcription Factors metabolism, Granulosa Cells metabolism, Proto-Oncogene Proteins c-akt metabolism
- Abstract
The PI3K/AKT signaling pathway is known to regulate a broad range of cellular processes, and it is often altered in several types of cancers. Recently, somatic AKT1 mutations leading to a strong activation of this kinase have been reported in juvenile granulosa cell tumors. However, the molecular role of AKT1 in the supporting cell lineage of the ovary is still poorly understood. To get insights into its function in such cells, we depleted Akt1 in murine primary granulosa cells and assessed the molecular consequences at both the transcript and protein levels. We were able to corroborate the involvement of AKT1 in the regulation of metabolism, apoptosis, cell cycle, or cytoskeleton dynamics in this ovarian cell type. Consistently, we showed in established granulosa cells that depletion of Akt1 provoked altered directional persistent migration and increased its velocity. This study also allowed us to put forward new direct and indirect targets of the kinase. Indeed, a series of proteins involved in intracellular transport and mitochondrial physiology were significantly affected by Akt1 depletion. Using in silico analyses, we also propose a set of kinases and transcription factors that can mediate the action of AKT1 on the deregulated transcripts and proteins. Taken altogether, our results provide a resource of direct and indirect AKT1 targets in granulosa cells and may help understand its roles in this ovarian cell type., (© 2019 Elzaiat et al.)
- Published
- 2019
- Full Text
- View/download PDF
43. Further quantitative insights into the decrease of heteroplasmy of m.3243A>G with age in leukocytes.
- Author
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Veitia RA
- Subjects
- Disease Susceptibility, Genetic Association Studies, Humans, Mutation, Alleles, Genes, Mitochondrial, Genotype, Leukocytes metabolism, Mitochondrial Diseases diagnosis, Mitochondrial Diseases genetics
- Published
- 2019
- Full Text
- View/download PDF
44. A truncating MEIOB mutation responsible for familial primary ovarian insufficiency abolishes its interaction with its partner SPATA22 and their recruitment to DNA double-strand breaks.
- Author
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Caburet S, Todeschini AL, Petrillo C, Martini E, Farran ND, Legois B, Livera G, Younis JS, Shalev S, and Veitia RA
- Subjects
- Adolescent, Adult, Animals, Biomarkers, Cell Line, Consanguinity, Female, Gene Expression, Humans, Informatics methods, Mice, Pedigree, Primary Ovarian Insufficiency diagnosis, Protein Binding, Exome Sequencing, Young Adult, Cell Cycle Proteins metabolism, DNA Breaks, Double-Stranded, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Mutation, Primary Ovarian Insufficiency etiology, Primary Ovarian Insufficiency metabolism
- Abstract
Background: Primary Ovarian Insufficiency (POI), a major cause of infertility, affects about 1-3% of women under forty years of age. Although there is a growing list of causal genetic alterations, POI remains mostly idiopathic., Methods: We performed exome sequencing (WES) of two sisters affected with POI, one unaffected sister and their mother from a consanguineous family. We assessed the impact of the identified MEIOB variant with a minigene assay and by sequencing illegitimate transcripts from the proband's leukocytes. We studied its functional impact on the interaction between MEIOB with its partner SPATA22 and their localization to DNA double-strand breaks (DSB)., Findings: We identified a homozygous variant in the last base of exon 12 of MEIOB, which encodes a factor essential for meiotic recombination. This variant was predicted to strongly affect MEIOB pre-mRNA splicing. Consistently, a minigene assay showed that the variant induced exon 12 skipping, which was confirmed in vivo in the proband's leukocytes. Aberrant splicing leads to the production of a C-terminally truncated protein that cannot interact with SPATA22, abolishing their recruitment to DSBs., Interpretation: This truncating MEIOB variant is expected to provoke meiotic defects and a depleted follicular stock, as in Meiob
-/- mice. This is the first molecular defect reported in a meiosis-specific single-stranded DNA-binding protein (SSB) responsible for POI. We hypothesise that alterations in other SSB proteins could explain cases of syndromic or isolated ovarian insufficiency. FUND: Université Paris Diderot, Fondation pour la Recherche Médicale, Fondation ARC contre le cancer, Commissariat à l'Energie Atomique and Institut Universitaire de France., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
45. Genomic Balance and Speciation.
- Author
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Birchler JA and Veitia RA
- Abstract
The role of genomic balance in accumulating species hybrid incompatibilities is discussed. Aneuploidy has been shown to produce more global modulations than polyploidy with the responsible genes being transcription factors and signaling components involved in molecular complexes, illustrating a stoichiometric component to gene expression. Genomic imbalance is usually detrimental to the organism and in many cases results in lethality. Here, it is proposed that once gene flow is prevented between or within populations by various speciation initiating processes, the stoichiometric relationship of members of macromolecular complexes can change via compensatory drift with the eventual result of newly established functional balances. However, when these new relationships are brought together in interspecific hybrids, detrimental consequences will occur. We suggest that these detrimental interactions contribute to hybrid incompatibilities., Competing Interests: Declaration Of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2019
- Full Text
- View/download PDF
46. Three-dimensional genome architecture in health and disease.
- Author
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Ouimette JF, Rougeulle C, and Veitia RA
- Subjects
- Chromosomes, Human, Gene Expression Regulation, Genetic Association Studies methods, Gonads embryology, Gonads metabolism, Humans, Muscle Development genetics, Genetic Predisposition to Disease, Genome, Human, Genomics methods, Health
- Abstract
More than a decade of massive DNA sequencing efforts have generated a large body of genomic, transcriptomic and epigenomic information that has provided a more and more detailed view of the functional elements and transactions within the human genome. Considerable efforts have also focused on linking these elements with one another by mapping their interactions and by establishing 3-dimensional (3D) genomic landscapes in various cell and tissue types. In parallel, multiple studies have associated genomic deletions, duplications and other rearrangements with human pathologies. In this review, we explore recent progresses that have allowed connecting disease-causing alterations with perturbations of the 3D genome organization., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
47. On the loss of human sex chromosomes in lymphocytes with age: a quantitative treatment.
- Author
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Veitia RA
- Subjects
- Female, Humans, Lymphocytes cytology, Male, Aging genetics, Chromosome Deletion, Models, Genetic, Sex Chromosomes genetics
- Abstract
Increasing levels of aneuploidy of the sex chromosomes in human lymphocytes with age have been noted for several decades. The percentage of chromosome Y loss can reach up to 1.5% or even more, whereas the levels of X0 cells in females can increase up to 5% with age. Here, I propose simple mathematical models of the dynamics of 'normal' sex chromosome loss with age. These exponential models provide more mechanistic insights than linear regressions. They account for the lower incidence of sex chromosome loss in young individuals and its increase with age. Moreover, the exponential models show that aneuploidy of the sex chromosomes provides a selective advantage. As there are no longitudinal data available (for the same individual at different time points), the parameters reported here are average values derived from a population. Hopefully, this study will stimulate further work based on next-generation technologies to obtain better estimates of sex chromosome aneuploidy and of the parameters of the models discussed here.
- Published
- 2018
- Full Text
- View/download PDF
48. Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency.
- Author
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Huhtaniemi I, Hovatta O, La Marca A, Livera G, Monniaux D, Persani L, Heddar A, Jarzabek K, Laisk-Podar T, Salumets A, Tapanainen JS, Veitia RA, Visser JA, Wieacker P, Wolczynski S, and Misrahi M
- Subjects
- Adult, Female, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Mutation genetics, Primary Ovarian Insufficiency genetics
- Abstract
Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
49. Dosage effects in morphogenetic gradients of transcription factors: insights from a simple mathematical model.
- Author
-
Veitia RA
- Subjects
- Animals, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Drosophila embryology, Drosophila genetics, Drosophila Proteins genetics, Drosophila Proteins metabolism, Models, Theoretical, Promoter Regions, Genetic genetics, Transcription Factors metabolism, Algorithms, Gene Expression Regulation, Developmental, Models, Genetic, Morphogenesis, Transcription Factors genetics
- Abstract
The classical Hill equation is the simplest way to model sharp transcriptional responses (TR) to changing concentrations of a regulator. Such steep sigmoidal transitions of the TR are often involved in the creation of boundaries or domains during development. Here, I use the Hill function to explore the response of a promoter to a gradient of a transcription factor (TF). Specifically, I examine how various sources of nonlinearity (such as that imposed by the number of TF-binding sites) and the nonlinearity of the gradient itself influence TR and modulate its robustness to variations in the dosage of morphogen. This qualitative analysis underscores how nonlinearities can modulate the robustness of TR and is a convenient way to convey concepts in a teaching setting.
- Published
- 2018
50. A role for SOX9 in post-transcriptional processes: insights from the amphibian oocyte.
- Author
-
Penrad-Mobayed M, Perrin C, L'Hôte D, Contremoulins V, Lepesant JA, Boizet-Bonhoure B, Poulat F, Baudin X, and Veitia RA
- Subjects
- Animals, Biological Evolution, Cell Nucleus metabolism, Chromosomes chemistry, Chromosomes metabolism, Cytosol metabolism, Female, Oocytes cytology, Pleurodeles growth & development, Pleurodeles metabolism, RNA, Messenger metabolism, Ribonucleoproteins genetics, Ribonucleoproteins metabolism, SOX9 Transcription Factor metabolism, Transcription, Genetic, Xenopus growth & development, Xenopus metabolism, Xenopus laevis growth & development, Xenopus laevis metabolism, Oocytes metabolism, Pleurodeles genetics, RNA Processing, Post-Transcriptional, RNA, Messenger genetics, SOX9 Transcription Factor genetics, Xenopus genetics, Xenopus laevis genetics
- Abstract
Sox9 is a member of the gene family of SOX transcription factors, which is highly conserved among vertebrates. It is involved in different developmental processes including gonadogenesis. In all amniote species examined thus far, Sox9 is expressed in the Sertoli cells of the male gonad, suggesting an evolutionarily conserved role in testis development. However, in the anamniotes, fishes and amphibians, it is also expressed in the oocyte but the significance of such an expression remains to be elucidated. Here, we have investigated the nuclear localization of the SOX9 protein in the oocyte of three amphibian species, the urodelan Pleurodeles waltl, and two anurans, Xenopus laevis and Xenopus tropicalis. We demonstrate that SOX9 is associated with ribonucleoprotein (RNP) transcripts of lampbrush chromosomes in an RNA-dependent manner. This association can be visualized by Super-resolution Structured Illumination Microscopy (SIM). Our results suggest that SOX9, known to bind DNA, also carries an additional function in the posttranscriptional processes. We also discuss the significance of the acquisition or loss of Sox9 expression in the oocyte during evolution at the transition between anamniotes and amniotes.
- Published
- 2018
- Full Text
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