A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21

Human nondisjunction errors in oocytes are the leading cause of pregnancy loss, and for pregnancies that continue to term, the leading cause of intellectual disabilities and birth defects. For the first time, we have conducted a candidate gene and genome-wide association study to identify genes associated with maternal nondisjunction of chromosome 21 as a first step to understand predisposing factors. A total of 2,186 study participants were genotyped on the HumanOmniExpressExome-8v1-2 array. These participants included 749 live birth offspring with standard trisomy 21 and 1,437 parents. Genotypes from the parents and child were then used to identify mothers with nondisjunction errors derived in the oocyte and to establish the type of error (meiosis I or meiosis II). We performed a unique set of subgroup comparisons designed to leverage our previous work suggesting that the etiologies of meiosis I and meiosis II nondisjunction differ for trisomy 21. For the candidate gene analysis, we selected genes associated with chromosome dynamics early in meiosis and genes associated with human global recombination counts. Several candidate genes showed strong associations with maternal nondisjunction of chromosome 21, demonstrating that genetic variants associated with normal variation in meiotic processes can be risk factors for nondisjunction. The genome-wide analysis also suggested several new potentially associated loci, although follow-up studies using independent samples are required

Pluralismus im Islam - ein Schlüssel zum Frieden: Erfahrungen aus dem Irak, Syrien, Türkei, Ägypten und Tunesien im Vergleich

Zentrales Thema dieser Studie ist die Frage, wie die islamische Staatenwelt mit dem Pluralismus in ihrer eigenen Religion umgeht. Die meisten Länder haben erst mit ihrer staatlichen Unabhängigkeit in der zweiten Hälfte des 20. Jahrhundert das religiöse Recht der weltlichen Gesetzgebung unterstellt. Dadurch wurden aus Untertanen unterschiedlicher Konfessionen und islamischer Glaubensrichtungen gleichberechtigte Staatsbürger. Die Verstaatlichung der islamischen Institutionen legitimiert die Regierungen allerdings zur Kontrolle über religiöse Doktrinen. So entstanden neben den klassischen Rechtsschulen nationale Varianten islamischer Glaubenslehren. Während Angehörige anderer Religionen teils Minderheitenrechte besitzen, wird die Vielfalt islamischer Lehrmeinungen von den Staaten selbst kaum anerkannt. Dieses Defizit nutzen islamistische Akteure wie Muslimbrüder oder Ennahdah, um sich als Opfer staatlicher Religionsbehörden darzustellen. Dabei zeigen sie selbst noch weniger Toleranz gegenüber dem religiösen Pluarlismus. Denn sie lehnen regionale und nationale Traditionen des Islam ab und wollen das religiöse Recht (Scharia) auf seine Ursprünge zurückführen (Salafismus, Wahhabismus). Die Anfänge islamischen Rechts lassen sich nur vage rekonstruieren, weshalb salafistische oder wahhabitische Doktrinen ebenfalls auf Interpretationen angewiesen sind. Der verstärkte Kampf um die Deutungshoheit im Islam kann nur gelöst werden, indem die Staaten den verschiedenen Glaubensrichtungen mit Toleranz begegnen und diese im Rahmen ihrer nationalen Gesetzgebung anerkennen. Den normativen Rahmen hierfür bilden die UN-Menschenrechtsdokumente wie die Anti-Rassismus-Konvention (1969), mit deren Unterzeichnung sich viele islamische Länder auch der Religionsfreiheit verschrieben haben. (Autorenreferat

Error-Prone ZW Pairing and No Evidence for Meiotic Sex Chromosome Inactivation in the Chicken Germ Line

In the male mouse the X and Y chromosomes pair and recombine within the small pseudoautosomal region. Genes located on the unsynapsed segments of the X and Y are transcriptionally silenced at pachytene by Meiotic Sex Chromosome Inactivation (MSCI). The degree to which MSCI is conserved in other vertebrates is currently unclear. In the female chicken the ZW bivalent is thought to undergo a transient phase of full synapsis at pachytene, starting from the homologous ends and spreading through the heterologous regions. It has been proposed that the repair of the ZW DNA double-strand breaks (DSBs) is postponed until diplotene and that the ZW bivalent is subject to MSCI, which is independent of its synaptic status. Here we present a distinct model of meiotic pairing and silencing of the ZW pair during chicken oogenesis. We show that, in most oocytes, DNA DSB foci on the ZW are resolved by the end of pachytene and that the ZW desynapses in broad synchrony with the autosomes. We unexpectedly find that ZW pairing is highly error prone, with many oocytes failing to engage in ZW synapsis and crossover formation. Oocytes with unsynapsed Z and W chromosomes nevertheless progress to the diplotene stage, suggesting that a checkpoint does not operate during pachytene in the chicken germ line. Using a combination of epigenetic profiling and RNA–FISH analysis, we find no evidence for MSCI, associated with neither the asynaptic ZW, as described in mammals, nor the synaptic ZW. The lack of conservation of MSCI in the chicken reopens the debate about the evolution of MSCI and its driving forces

Neuronal Aneuploidy in Health and Disease: A Cytomic Approach to Understand the Molecular Individuality of Neurons

Structural variation in the human genome is likely to be an important mechanism for neuronal diversity and brain disease. A combination of multiple different forms of aneuploid cells due to loss or gain of whole chromosomes giving rise to cellular diversity at the genomic level have been described in neurons of the normal and diseased adult human brain. Here, we describe recent advances in molecular neuropathology based on the combination of slide-based cytometry with molecular biological techniques that will contribute to the understanding of genetic neuronal heterogeneity in the CNS and its potential impact on Alzheimer's disease and age-related disorders

Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew

The relationship between increasing maternal age and trisomy has been recognized for over 50 years and is one of the most important etiological factors associated with any human genetic disorder. Specifically, the risk of trisomy in a clinically recognized pregnancy rises from about 2-3% for women in their twenties to an astounding 30% or more for women in their forties. Thus, as women approach the end of their child-bearing years, errors of chromosome segregation represent the most important impediment to a successful pregnancy. Despite the clinical importance of this relationship, we do not understand how age affects the likelihood of producing a normal egg. Errors that affect chromosome segregation could occur at several stages during the development of the oocyte: in the fetal ovary, either during the mitotic proliferation of oogonia or the early stages of meiosis; in the 'dictyate' oocyte, during the 10-50-year period of meiotic arrest; or during the final stages of oocyte growth and maturation, when meiosis resumes and the meiotic divisions take place. Recent evidence from studies of human oocytes and trisomic conceptions and from studies in model organisms implicates errors at each of these stages. It seems likely that there are multiple causes of human age-related nondisjunction, complicating our efforts to understand - and, ultimately, to provide preventive measures for - errors associated with increasing maternal age

Female meiosis: coming unglued with age

Chromosome abnormalities in humans are strikingly associated with increasing maternal age. Studies in mice implicate loss of chromosome cohesion as an important cause of age-related meiotic errors in the oocyte

The origin of human aneuploidy: where we have been, where we are going

Aneuploidy is the most common chromosome abnormality in humans, and is the leading genetic cause of miscarriage and congenital birth defects. Since the identification of the first human aneuploid conditions nearly a half-century ago, a great deal of information has accrued on its origin and etiology. We know that most aneuploidy derives from errors in maternal meiosis I, that maternal age is a risk factor for most, if not all, human trisomies, and that alterations in recombination are an important contributor to meiotic non-disjunction. In this review, we summarize some of the data that have led to these conclusions, and discuss some of the approaches now being used to address the underlying causes of meiotic non-disjunction in humans

Female Meiosis: Coming Unglued with Age

SummaryChromosome abnormalities in humans are strikingly associated with increasing maternal age. Studies in mice implicate loss of chromosome cohesion as an important cause of age-related meiotic errors in the oocyte