scholarly journals Dosage analysis of the 7q11.23 Williams region identifies BAZ1B as a major human gene patterning the modern human face and underlying self-domestication

2019 ◽  
Vol 5 (12) ◽  
pp. eaaw7908 ◽  
Author(s):  
Matteo Zanella ◽  
Alessandro Vitriolo ◽  
Alejandro Andirko ◽  
Pedro Tiago Martins ◽  
Stefanie Sturm ◽  
...  
Keyword(s):  
Copy Number ◽  
Human Gene ◽  
Copy Number Variants ◽  
Modern Human ◽  
Human Face ◽  
Regulatory Changes ◽  
Gene Patterning ◽  
And Migration ◽  
In Vitro Induction

We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest (NC) stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 copy number variants. Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in NC-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we found a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the human self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face. In so doing, we provide experimental evidence that the craniofacial and cognitive/behavioral phenotypes caused by alterations of the Williams-Beuren syndrome critical region can serve as a powerful entry point into the evolution of the modern human face and prosociality.

scholarly journals 7q11.23 Syndromes Reveal BAZ1B as a Master Regulator of the Modern Human Face and Validate the Self-Domestication Hypothesis

2019 ◽  
Author(s):  
Matteo Zanella ◽  
Alessandro Vitriolo ◽  
Alejandro Andirko ◽  
Pedro Tiago Martins ◽  
Stefanie Sturm ◽  
...  
Keyword(s):  
Neural Crest ◽  
Copy Number Variants ◽  
Modern Human ◽  
The Self ◽  
Human Face ◽  
Master Regulator ◽  
Neural Crest Stem Cells ◽  
Regulatory Changes ◽  
And Migration

AbstractSymmetrical 7q11.23 dosage alterations cause craniofacial and cognitive/behavioral phenotypes that provide a privileged entry point into the evolution of the modern human face and (pro-) sociality. We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 Copy Number Variants (CNVs). Our results reveal a key contribution of BAZ1B to NCSCin vitroinduction and migration, coupled with a crucial involvement in neural crest (NC)-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we uncover a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face.One Sentence SummaryBAZ1B dosage shapes the modern human face.

scholarly journals Prevalence of pathogenic copy number variants among children conceived by donor oocyte

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sandra Monfort ◽  
Carmen Orellana ◽  
Silvestre Oltra ◽  
Mónica Rosello ◽  
Alfonso Caro-Llopis ◽  
...  
Keyword(s):  
In Vitro Fertilization ◽  
Copy Number ◽  
Assisted Reproductive Technologies ◽  
Copy Number Variants ◽  
Reproductive Technologies ◽  
Significant Excess ◽  
Vitro Fertilization ◽  
Donor Oocyte ◽  
Increased Risk

AbstractDevelopment of assisted reproductive technologies to address infertility has favored the birth of many children in the last years. The majority of children born with these treatments are healthy, but some concerns remain on the safety of these medical procedures. We have retrospectively analyzed both the fertilization method and the microarray results in all those children born between 2010 and 2019 with multiple congenital anomalies, developmental delay and/or autistic spectrum disorder (n = 486) referred for array study in our center. This analysis showed a significant excess of pathogenic copy number variants among those patients conceived after in vitro fertilization with donor oocyte with respect to those patients conceived by natural fertilization (p = 0.0001). On the other hand, no significant excess of pathogenic copy number variants was observed among patients born by autologous oocyte in vitro fertilization. Further studies are necessary to confirm these results and in order to identify the factors that may contribute to an increased risk of genomic rearrangements, as well as consider the screening for genomic alterations after oocyte donation in prenatal diagnosis.

scholarly journals Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype

2021 ◽  
Author(s):  
Satyamaanasa Polubothu ◽  
Davide Zecchin ◽  
Lara Al-Olabi ◽  
Daniël A. Lionarons ◽  
Mark Harland ◽  
...  
Keyword(s):  
Rare Disease ◽  
Copy Number ◽  
Pigment Cell ◽  
Copy Number Variants ◽  
Melanocytic Nevus ◽  
Congenital Melanocytic Nevus ◽  
Cellular Models ◽  
Genome Copy Number ◽  
Polymerase Chain ◽  
And Migration

Abstract Purpose Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach. Methods Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays. Results We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70. Conclusion This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching.

scholarly journals Influence of aflatoxin B1 on copy number variants in human leukocytes in vitro

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Tigran Harutyunyan ◽  
Galina Hovhannisyan ◽  
Nelly Babayan ◽  
Moneeb AK Othman ◽  
Thomas Liehr ◽  
...  
Keyword(s):  
Aflatoxin B1 ◽  
Copy Number ◽  
Copy Number Variants ◽  
Human Leukocytes

scholarly journals Genes Affecting Vocal and Facial Anatomy Went Through Extensive Regulatory Divergence in Modern Humans

2017 ◽  
Author(s):  
David Gokhman ◽  
Malka Nissim-Rafinia ◽  
Lily Agranat-Tamir ◽  
Genevieve Housman ◽  
Raquel García-Pérez ◽  
...  
Keyword(s):  
Vocal Tract ◽  
Modern Human ◽  
Human Face ◽  
Modern Humans ◽  
Regulatory Changes ◽  
Phenotypic Divergence ◽  
The Face ◽  
Key Drivers ◽  
Facial Anatomy ◽  
Human Specific

SummaryRegulatory changes are broadly accepted as key drivers of phenotypic divergence. However, identifying regulatory changes that underlie human-specific traits has proven very challenging. Here, we use 63 DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes affecting the face and vocal tract went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-affecting genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.

scholarly journals Downregulation of m6A reader YTHDC2 promotes the proliferation and migration of lung cancer and cigarette smoke-exposed BEAS-2B cells

2020 ◽  
Author(s):  
Jin Wang ◽  
Lirong Tan ◽  
Beibei Jia ◽  
Xiaofan Yu ◽  
Ruixin Yao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Cigarette Smoke ◽  
Copy Number ◽  
Number Variation ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: Lung cancer is one of the most common carcinomas worldwide. Cigarette smoking is considered as the leading cause of lung cancer. The aberrant expression of several YTH family proteins has been reported to be closely associated with several cancers. This study aims to evaluate the expression profile and function of YTHDC2, an RNA m6 A methylation reader protein, by in vitro and animal experiments and bioinformatics analysis. Methods: The expression of YTHDC2 gene and protein was analyzed by the GEPIA online tool and Gene Expression Omnibus (GEO) database, as well as immunohistochemistry of tissue arrays. The YTHDC2 expression in cigarette smoke-exposed cells was examined by RT-qPCR and western blot assays. The TCGA datasets and proteomic analysis of YTHDC2 knockdown cells were used to predict the clinical significance and biological function of YTHDC2. Functional assays, including wound healing, transwell migration, cell cycle and cell proliferation, were used to determine the biological role of YTHDC2 in lung cancer. The xenograft animal model further validated the tumor suppressor effect of YTHDC2 in vivo. The copy number variation of YTHDC2 was analyzed by TCGA datasets and TaqMan copy number assay. Results: YTHDC2 was significantly low-expressed in lung cancer and cigarette smoke-exposed cells. Notably, decreased YTHDC2 was found highly associated with smoking history, pathological stage, invasion depth, and lymph node metastasis, as well as poor outcomes. The YTHDC2 related genes and proteins were enriched in several cancer-related pathways, and several tumor suppressor genes were found positively correlated with YTHDC2. The in vivo and in vitro study revealed that overexpression of YTHDC2 inhibited the proliferation and migration ability of lung cancer cells, as well as the tumor growth in nude mice. Besides, a significant positive correlation between the copy number and expression level of YTHDC2 was found in lung cancer. Conclusions: Our results indicated that the smoking-related down-regulation of YTHDC2 was associated with enhanced proliferation and migration of lung cancer cells and appeared to be regulated by DNA copy number variation. Importantly, YTHDC2 may serve as a tumor suppressor gene and a favorable prognostic indicator in lung cancer patients.

scholarly journals FGFR2 alteration as a potential therapeutic target in poorly cohesive gastric carcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yue Wang ◽  
Tao Shi ◽  
Xuan Wang ◽  
Jinwei Hu ◽  
Lixia Yu ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Copy Number ◽  
Gene Rearrangement ◽  
Copy Number Variants ◽  
Molecular Characteristics ◽  
Gene Rearrangements ◽  
Histologic Subtype ◽  
Ffpe Samples ◽  
Formalin Fixed Paraffin Embedded

Abstract Background Poorly cohesive (PC) is a unique histologic subtype of gastric cancer (GC), with an increasing incidence in recent years. However, the molecular characteristics and therapeutic targets of PC GC are not yet well studied and there are no effective therapies for these patients. Methods Formalin fixed paraffin embedded (FFPE) samples of 556 GC patients, including 64 PC GC, were collected for next-generation sequencing (NGS). Clinical characteristics and genomic profiling were analyzed. FGFR2 expression was detected by quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). FGFR2 inhibitors response was studied in vitro. Results Among 556 GC patients, PC GC patients were younger (P = 0.004), had lower tumor mutation burden (TMB-L) (P = 0.001) than non-PC GC. The top 10 most frequently mutated genes in PC GC were TP53 (48%), CDH1 (31%), ARID1A (14%), FGFR2 (14%), ERBB2 (9%), CDKN2A (9%), FGF3 (8%), LRP1B (9%), FGF19 (8%) and FGF4 (8%). Noticeably, FGFR2 is more frequently mutated than non-PC GC (14% vs. 6%, P = 0.037), including copy number variants (CNVs, 12.5%) and gene rearrangements (3.1%, FGFR2/VTI1A and FGFR2/TACC2). Former studies have confirmed that gain of copy number could increase FGFR2 expression and sensitivity to FGFR2 inhibitors in GC. However, no research has verified the function of FGFR2 rearrangements in GC. Our results showed that cell lines of GC transfected with TACC2-FGFR2 fusion had increased mRNA and protein expression of FGFR2, and were more sensitive to FGFR2 inhibitors. FGFR2 inhibitors might be a new therapeutic target for PC GC. In addition, we found patients of PC GC harboring gene rearrangements (n = 9) had poorer overall survival (OS) in comparison with patients without any gene rearrangement (n = 19) (16.0 months vs 21.0 months, P = 0.043). Gene rearrangement might be an adverse prognostic factor for PC GC patients. Conclusions FGFR2 alterations were recurrent in PC GC and FGFR2 inhibitors might be a new therapeutic target for PC GC.

In Vitro Induction of Crystals of MT Protein by Vinblastine-Colcemid in Mouse Spermatids

1974 ◽  
Vol 32 ◽  
pp. 132-133
Author(s):  
John J. Wolosewick ◽  
John H. D. Bryan
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Endoplasmic Reticulum ◽  
Nuclear Ring ◽  
Rough Er ◽  
Distal Direction ◽  
In Vitro Induction

Early in spermiogenesis the manchette is rapidly assembled in a distal direction from the nuclear-ring-densities. The association of vesicles of smooth endoplasmic reticulum (SER) and the manchette microtubules (MTS) has been reported. In the mouse, osmophilic densities at the distal ends of the manchette are the organizing centers (MTOCS), and are associated with the SER. Rapid MT assembly and the lack of rough ER suggests that there is an existing pool of MT protein. Colcemid potentiates the reaction of vinblastine with tubulin and was used in this investigation to detect this protein.

Understanding Schizophrenia: Genetic Causes and Treatment

2019 ◽  
Vol 1 (1) ◽  
pp. 6-12
Author(s):  
Fatima Javeria ◽  
Shazma Altaf ◽  
Alishah Zair ◽  
Rana Khalid Iqbal
Keyword(s):  
Copy Number ◽  
Drug Targets ◽  
Disease Risk ◽  
Mental Disease ◽  
Copy Number Variants ◽  
Aminobutyric Acid ◽  
Epigenetic Mechanisms ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

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