ABSTRACT
Miscarriage is the spontaneous termination of a pregnancy before 24 weeks of gestation. We studied the genome of euploid miscarried embryos from mothers in the range of healthy adult individuals to understand genetic susceptibility to miscarriage not caused by chromosomal aneuploidies. We developed GP , a pipeline that we used to prioritize 439 unique variants in 399 genes, including genes known to be associated with miscarriages. Among the prioritized genes we found STAG2 coding for the cohesin complex subunit, for which inactivation in mouse is lethal, and TLE4 a target of Notch and Wnt, physically interacting with a region on chromosome 9 associated to miscarriages.
Subject(s)
Abortion, Spontaneous/genetics , Aneuploidy , Genetic Association Studies , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Animals , Cell Cycle Proteins/genetics , Chromosomal Proteins, Non-Histone/genetics , Chromosomes, Human, Pair 9/genetics , Female , Humans , Mice , Nuclear Proteins , Pregnancy , Receptors, Notch/genetics , Repressor Proteins , Wnt Proteins/genetics , CohesinsABSTRACT
BACKGROUND: The study of ascidians (Chordata, Tunicata) has made a considerable contribution to our understanding of the origin and evolution of basal chordates. To provide further information to support forward genetics in Ciona intestinalis, we used a combination of natural variation and neutral population genetics as an approach for the systematic identification of new mutations. In addition to the significance of developmental variation for phenotype-driven studies, this approach can encompass important implications in evolutionary and population biology. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a preliminary survey for naturally occurring mutations in three geographically interconnected populations of C. intestinalis. The influence of historical, geographical and environmental factors on the distribution of abnormal phenotypes was assessed by means of 12 microsatellites. We identified 37 possible mutant loci with stereotyped defects in embryonic development that segregate in a way typical of recessive alleles. Local populations were found to differ in genetic organization and frequency distribution of phenotypic classes. CONCLUSIONS/SIGNIFICANCE: Natural genetic polymorphism of C. intestinalis constitutes a valuable source of phenotypes for studying embryonic development in ascidians. Correlating genetic structure and the occurrence of abnormal phenotypes is a crucial focus for understanding the selective forces that shape natural finite populations, and may provide insights of great importance into the evolutionary mechanisms that generate animal diversity.
Subject(s)
Ciona intestinalis/physiology , Genetic Variation , Animals , Ciona intestinalis/genetics , Genetics, Population , Microsatellite Repeats/genetics , Mutation , PhenotypeABSTRACT
Members of the GATA family of zinc finger transcription factors have been shown to play important roles in controlling gene expression in a variety of cell types in many metazoan. Here, we describe the identification of Ci-GATAa, a member of this gene family, in the ascidian Ciona intestinalis. Whole-mount in situ hybridization showed that Ci-GATAa was expressed in a highly dynamic manner. The maternal transcript was evenly distributed in the embryo during early stages of development; however, the signal gradually decreased until it disappeared at the 64-cell stage. A zygotic transcript was detected at the 110-cell stage in the blastomeres precursors of three different tissues (brain vesicle, mesenchyme, and trunk lateral cells) and the signal was conserved in these territories up to the larval stage, indicating an important role for Ci-GATAa during ascidian differentiation.