Parent-of-origin effects on nuclear chromatin organization and behavior in a Drosophila model for Williams–Beuren Syndrome

Prognosis of neuropsychiatric disorders in progeny requires consideration of individual (1) parent-of-origin effects (POEs) relying on (2) the nerve cell nuclear 3D chromatin architecture and (3) impact of parent-specific miRNAs. Additionally, the shaping of cognitive phenotypes in parents depends on both learning acquisition and forgetting, or memory erasure. These processes are independent and controlled by different signal cascades: the first is cAMPdependent, the second relies on actin remodeling by small GTPase Rac1 – LIMK1 (LIM-kinase 1). Simple experimental model systems such as Drosophila help probe the causes and consequences leading to human neurocognitive pathologies. Recently, we have developed a Drosophila model for Williams–Beuren Syndrome (WBS): a mutant agnts3 of the agnostic locus (X:11AB) harboring the dlimk1 gene. The agnts3 mutation drastically increases the frequency of ectopic contacts (FEC) in specific regions of intercalary heterochromatin, suppresses learning/memory and affects locomotion. As is shown in this study, the polytene X chromosome bands in reciprocal hybrids between agnts3 and the wild type strain Berlin are heterogeneous in modes of FEC regulation depending either on maternal or paternal gene origin. Bioinformatic analysis reveals that FEC between X:11AB and the other X chromosome bands correlates with the occurrence of short (~30 bp) identical DNA fragments partly homologous to Drosophila 372-bp satellite DNA repeat. Although learning acquisition in a conditioned courtship suppression paradigm is similar in hybrids, the middle-term memory formation shows patroclinic inheritance. Seemingly, this depends on changes in miR-974 expression. Several parameters of locomotion demonstrate heterosis. Our data indicate that the agnts3 locus is capable of trans-regulating gene activity via POEs on the chromatin nuclear organization, thereby affecting behavior.

“VAN DER WOUDE SYNDROME: REPORT OF TWO CASES”

Van Der Woude syndrome is a rare autosomal dominant condition which is associated with developmental malformations involving lips, palate. This syndrome can be a genetic origin due to Microdeletion of chromosome bands 1q32-q41 and also mutation of Interferon regulatory factor 6 (IRF-6) can be a pathogenic cause. We report two interesting cases of Van Der Woude syndrome with lip pits and orofacial features.

Non-randomness distribution of micro-RNAs on human chromosomes

Background Micro-RNA (miRNA) is one of the non-coding RNAs that exist in human genome. miRNAs play an important role in the expression of target genes. Several studies have indicated that organization of human genome is not random. In order to investigate the distribution of miRNAs on human chromosomes, the present study was carried out. Results Using the data from miRBase database, we found 1913 loci coding for miRNAs (MIRs). Human chromosome bands 1p36, 1q22, 1q24, 2q13, 2q35, 3p21, 6p21, 7q22, 8p23, 8q24, 9q22, 9q34, 11q12-q13, 12q13, 14q32, 16p13, 16q24, 17p13, 17q11, 17q21, 17q25, 19p13, 19q13, 20q13, 21p11, 22q13, and Xq26-q28 were significantly bearing higher number of MIRs. The 14q32 and 19q13 with 4.11 and 3.59 MIRs per mega-base pair, respectively, were the most MIR-richest human chromosomal bands. The number of MIRs on chromosomal bands significantly decreased as a function of distance from telomere (r = − 0.949, df = 5, P = 0.001). Conclusions Our current data suggest that MIRs are not randomly distributed on human genomes.

Systematic computational identification of prognostic cytogenetic markers in neuroblastoma

Background Neuroblastoma (NB) is the most common extracranial solid tumor found in children. The frequent gain/loss of many chromosome bands in tumor cells and absence of mutations found at diagnosis suggests that NB is a copy number-driven cancer. Despite the previous work, a systematic analysis that investigates the relationship between such frequent gain/loss of chromosome bands and patient prognosis has yet to be implemented. Methods First, we analyzed two NB CNV datasets to select chromosomal bands with a high frequency of gain or loss. Second, we applied a computational approach to infer sample-specific CNVs for each chromosomal band selected in step 1 based on gene expression data. Third, we applied univariate Cox proportional hazards models to examine the association between the resulting inferred copy number values (iCNVs) and patient survival. Finally, we applied multivariate Cox proportional hazards models to select chromosomal bands that remained significantly associated with prognosis after adjusting for critical clinical variables, including age, stage, gender, and MYCN amplification status. Results Here, we used a computational method to infer the copy number variations (CNVs) of sample-specific chromosome bands from NB patient gene expression profiles. The resulting inferred CNVs (iCNVs) were highly correlated with the experimentally determined CNVs, demonstrating CNVs can be accurately inferred from gene expression profiles. Using this iCNV metric, we identified 58 frequent gain/loss chromosome bands that were significantly associated with patient survival. Furthermore, we found that 7 chromosome bands were still significantly associated with patient survival even when clinical factors, such as MYCN status, were considered. Particularly, we found that the chromosome band chr11p14 has high potential as a novel candidate cytogenetic biomarker for clinical use. Conclusion Our analysis resulted in a comprehensive list of prognostic chromosome bands supported by strong statistical evidence. In particular, the chr11p14 gain event provided additional prognostic value in addition to well-established clinical factors, including MYCN status, and thereby represents a novel candidate cytogenetic biomarker with high clinical potential. Additionally, this computational framework could be readily extended to other cancer types, such as leukemia.

Chromosome 3p Inverted Duplication with Terminal Deletion: Second Postnatal Case Report with Additional Clinical Features

Distal deletions and duplications of 3p are individually well-characterized chromosome abnormalities. Here, we report an inverted duplication of 3p with an adjacent terminal 3p deletion in a 17-month-old girl who had prenatal intrauterine growth restriction and cardiac defects. Other findings included hemangiomas, neutropenia, umbilical hernia, hypotonia, gross motor delay, microcephaly, and ptosis. Family history was noncontributory. Microarray analysis revealed a 5.37 Mb deletion of chromosome bands 3p26.1 to 3p26.3 and a 13.68 Mb duplication of 3p24.3 to 3p26.1. FISH analysis confirmed that the duplication was inverted. Upon literature review, only one postnatal patient and one second trimester pregnancy have been reported with this finding. Many of our patient’s features are present in both 3p deletion and 3p duplication syndromes, including congenital heart disease, growth restriction, microcephaly, hypotonia, and developmental delay. Our patient has additional features not commonly reported in 3p deletion or duplication patients, such as aortic dilation, hemangiomas, and neutropenia. The identification of this patient contributes to additional understanding of features associated with concurrent deletion and inverted duplication in the distal 3p chromosome. This report may assist clinicians working with patients who have constellations of similar features or similar cytogenomic abnormalities.

Chromosome hydroxymethylation patterns in human zygotes and cleavage-stage embryos

We report the sequential changes in 5-hydroxymethylcytosine (5hmC) patterns in the genome of human preimplantation embryos during DNA methylation reprogramming. We have studied chromosome hydroxymethylation and methylation patterns in triploid zygotes and blastomeres of cleavage-stage embryos. Using indirect immunofluorescence, we have analyzed the localization of 5hmC and its co-distribution with 5-methylcytosine (5mC) on the QFH-banded metaphase chromosomes. In zygotes, 5hmC accumulates in both parental chromosome sets, but hydroxymethylation is more intensive in the poorly methylated paternal set. In the maternal set, chromosomes are highly methylated, but contain little 5hmC. Hydroxymethylation is highly region specific in both parental chromosome sets: hydroxymethylated loci correspond to R-bands, but not G-bands, and have well-defined borders, which coincide with the R/G-band boundaries. The centromeric regions and heterochromatin at 1q12, 9q12, 16q11.2, and Yq12 contain little 5mC and no 5hmC. We hypothesize that 5hmC may mark structural/functional genome ‘units’ corresponding to chromosome bands in the newly formed zygotic genome. In addition, we suggest that the hydroxymethylation of R-bands in zygotes can be treated as a new characteristic distinguishing them from G-bands. At cleavages, chromosomes with asymmetrical hydroxymethylation of sister chromatids appear. They decrease in number during cleavages, whereas totally non-hydroxymethylated chromosomes become numerous. Taken together, our findings suggest that, in the zygotic genome, 5hmC is distributed selectively and its pattern is determined by both parental origin of chromosomes and type of chromosome bands – R, G, or C. At cleavages, chromosome hydroxymethylation pattern is dynamically changed due to passive and non-selective overall loss of 5hmC, which coincides with that of 5mC.