Parental Origin of the Retained X Chromosome in Monosomy X Miscarriages and Ongoing Pregnancies

Grande, Maribel; Stergiotou, Iosifina; Pauta, Montse; Marquès, Borja; Badenas, Cèlia; Soler, Anna; Yaron, Yuval; Borrell, Antoni

doi:10.1159/000480499

Cited by 6 publications

(2 citation statements)

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“…2007; Grande et al. 2019). Circumstantial evidence supporting the hypothesis that aberrant epigenetic effects of the X chromosome contribute to male‐biased placental growth dysplasia includes our finding of elevated mean LFC in methylation levels on the M. m. domesticus X chromosome in hybrid versus Dom males and the fact that, in crosses using subcongenic mice with intervals of the M. spretus X on an M. m. domesticus autosomal background, the degree of placental overgrowth increases with the size, rather than the location, of the M. spretus ‐derived interval (Hemberger et al.…”

Section: Discussionmentioning

confidence: 99%

Haldane's rule in the placenta: Sex‐biased misregulation of the Kcnq1 imprinting cluster in hybrid mice

2020

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Hybrid phenotypes that contribute to postzygotic reproductive isolation often exhibit pronounced asymmetry, both between reciprocal crosses and between the sexes in accordance with Haldane's rule. Inviability in mammalian hybrids is associated with parent‐of‐origin placental growth abnormalities for which misregulation of imprinted gene (IGs) is the leading candidate mechanism. However, direct evidence for the involvement of IGs in hybrid growth dysplasia is limited. We used transcriptome and reduced representation bisulfite sequencing to conduct the first genome‐scale assessment of the contribution of IGs to parent‐of‐origin placental growth dysplasia in the cross between the house mouse (Mus musculus domesticus) and the Algerian mouse (Mus spretus). IGs with transgressive expression and methylation were concentrated in the Kcnq1 cluster, which contains causal genes for prenatal growth abnormalities in mice and humans. Hypermethylation of the cluster's imprinting control region, and consequent misexpression of the genes Phlda2 and Ascl2, is a strong candidate mechanism for transgressive placental undergrowth. Transgressive placental and gene regulatory phenotypes, including expression and methylation in the Kcnq1 cluster, were more extreme in hybrid males. Although consistent with Haldane's rule, male‐biased defects are unexpected in rodent placenta because the X‐chromosome is effectively hemizygous in both sexes. In search of an explanation, we found evidence of leaky imprinted (paternal) X‐chromosome inactivation in hybrid female placenta, an epigenetic disturbance that may buffer females from the effects of X‐linked incompatibilities to which males are fully exposed. Sex differences in chromatin structure on the X and sex‐biased maternal effects are nonmutually exclusive alternative explanations for adherence to Haldane's rule in hybrid placenta. The results of this study contribute to understanding the genetic basis of hybrid inviability in mammals, and the role of IGs in speciation.

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Section: Discussionmentioning

confidence: 99%

Haldane's rule in the placenta: Sex‐biased misregulation of the Kcnq1 imprinting cluster in hybrid mice

2020

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“…Identification of genetic causes of stillbirth provides multiple clinical benefits. Firstly, the risk of recurrence can be established if parents carry an inheritable anomaly or an autosomal trisomy. Secondly, finding an explanation for fetal demise has been shown to confer a psychological benefit to women and may reduce stigma and marginalization.…”

Section: Discussionmentioning

confidence: 99%

Added value of chromosomal microarray analysis over conventional karyotyping in stillbirth work‐up: systematic review and meta‐analysis

Martinez‐Portilla

Pauta

Hawkins-Villarreal

et al. 2019

Ultrasound in Obstet & Gyne

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Objective To assess the added value of chromosomal microarray analysis (CMA) over conventional karyotyping to assess the genetic causes in stillbirth. Methods To identify relevant studies, published in English or Spanish and without publication time restrictions, we performed a systematic search of PubMed, SCOPUS and ISI Web of Science databases, The Cochrane Library and the PROSPERO register of systematic reviews, for case series of fetal loss ≥ 20 weeks of gestation, with normal or suspected normal karyotype, undergoing CMA and with at least five subjects analyzed. To investigate quality, two reviewers evaluated independently the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool. For the meta‐analysis, the incremental yield of CMA over karyotyping was assessed by single‐proportion analysis using a random‐effects model (weighting by inverse variance). We assessed heterogeneity between studies and performed a sensitivity analysis and a subgroup analysis of structurally abnormal (malformed or growth‐restricted) and normal fetuses. Results Included in the meta‐analysis were seven studies involving 903 stillborn fetuses which had normal karyotype. The test success rate achieved by conventional cytogenetic analysis was 75%, while that for CMA was 90%. The incremental yield of CMA over conventional karyotyping based on the random‐effects model was 4% (95% CI, 3–5%) for pathogenic copy‐number variants (pCNVs) and 8% (95% CI, 4–17%) for variants of unknown significance. Subgroup analysis showed a 6% (95% CI, 4–10%) incremental yield of CMA for pCNVs in structurally abnormal fetuses and 3% (95% CI, 1–5%) incremental yield for those in structurally normal fetuses. The pCNV found most commonly was del22q11.21. Conclusions CMA, incorporated into the stillbirth work‐up, improves both the test success rate and the detection of genetic anomalies compared with conventional karyotyping. To achieve a genetic diagnosis in stillbirth is particularly relevant for the purpose of counseling regarding future pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

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Haldane’s rule in the placenta: sex-biased misregulation of theKcnq1imprinting cluster in hybrid mice

Arévalo

Gardner

Campbell

2020

Preprint

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24Mammalian hybrids often show striking asymmetries in their phenotypes both between 25 reciprocal crosses, and between sexes in accordance with Haldane's rule. Hybrid inviability is 26 associated with parent-of-origin placental growth abnormalities for which misregulation of 27 imprinted genes is a strong candidate mechanism. However, direct evidence for the involvement 28 of abnormal imprinting and the mechanisms behind this proposed misregulation is limited. We 29 used transcriptome and reduced representation bisulfite sequencing to evaluate the contribution 30 of imprinted genes to a long-standing example of parent-of-origin placental growth dysplasia in 31 the cross between the house mouse (Mus musculus domesticus) and the Algerian mouse (Mus 32 spretus). We found little evidence for loss of imprinting and imprinted genes with biallelic 33 expression were not misexpressed. Instead, imprinted genes with transgressive expression and 34 methylation were concentrated in the Kcnq1 cluster, which contains causal genes for prenatal 35 growth abnormalities in both mice and humans. Hypermethylation of the cluster's imprinting 36 control region, and consequent misexpression of the genes Phlda2 and Ascl2, is a strong 37 candidate mechanism for hybrid placental undergrowth. Transgressive placental and gene 38 regulatory phenotypes, including expression and methylation in the Kcnq1 cluster, were more 39 extreme in hybrid males. While consistent with Haldane's rule, male-biased defects are not 40 expected in rodent placenta because the maternal X chromosome is effectively hemizygous in 41 both sexes. In search of an explanation we found evidence of leaky imprinted X-chromosome 42 inactivation in hybrid females. Supplementary expression from the paternal X-chromosome may 43 buffer the females from the effects of X-linked incompatibilities to which males are fully 44 exposed. Sex differences in chromatin structure on the X and sex-biased maternal effects are 45 non-mutually exclusive alternative explanations for adherence to Haldane's rule in hybrid 46 3 placenta. The results of this study contribute to understanding of the genetic basis of hybrid X-linked incompatibilities that are exposed in males. 126 127 METHODS 128 Animals, tissue collection, and phenotypic analyses 129 Mice used in this study were maintained on a 12:12 light:dark cycle with lights on at 9:00 AM 130 and were provided with 5001 Rodent Diet (LabDiet, Brentwood, MO, U.S.A.) and water ad lib. 131 All animal procedures were approved by the Oklahoma State University IACUC under protocol 132 #141-AS. M. m. domesticus (hereafter, Dom) was represented by the wild-derived inbred strain 133 WSB/EiJ (Jackson Laboratory) and M. spretus (hereafter, Spret) was represented by the wild-134 derived inbred strain SFM/Pas (Montpellier Wild Mice Genetic Repository). We conducted three 135 crosses (female listed first): Dom X Dom, Dom X Spret, Spret X Spret. Prior to pairing, females 136were placed in a cage with soiled conspecific male bedding for ~48 hrs. to indu...

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Parental Origin of the Retained X Chromosome in Monosomy X Miscarriages and Ongoing Pregnancies

Cited by 6 publications

References 34 publications

Haldane's rule in the placenta: Sex‐biased misregulation of the Kcnq1 imprinting cluster in hybrid mice

Haldane's rule in the placenta: Sex‐biased misregulation of the Kcnq1 imprinting cluster in hybrid mice

Added value of chromosomal microarray analysis over conventional karyotyping in stillbirth work‐up: systematic review and meta‐analysis

Haldane’s rule in the placenta: sex-biased misregulation of theKcnq1imprinting cluster in hybrid mice

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