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An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations (RNA-Seq)

ABSTRACT: An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations (RNA-Seq)

PROVIDER: PRJNA836122 | ENA |

REPOSITORIES: ENA

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An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations (RNA-Seq)

Project description:Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests (TDT) and association studies in microtia trios (parents and affected child) and microtia cohorts enrolled in Latin America, we map a ~10 kb microtia locus (OR 4.7; p=6.78e-18) to the intergenic region between Roundabout 1 (ROBO1) and Roundabout 2 (ROBO2) (chr3: 78546526-78555137). While alleles at the microtia locus significantly increase the risk of microtia, their penetrance is low (<1%). We demonstrate that the microtia locus contains a polymorphic complex repeat element that is expanded in affected individuals. The locus is located near a chromatin loop region that regulates ROBO1 and ROBO2 expression in induced pluripotent stem cell-derived neural crest cells. Furthermore, we use single nuclear RNA sequencing (snRNAseq) to demonstrate ROBO1 and ROBO2 expression in both fibroblasts and chondrocytes of the mature human pinna. Because the microtia allele is enriched in Amerindigenous populations and shared by some East Asian subjects with craniofacial malformations, we propose both populations share a mutation that arose in a common ancestor prior to the ancient migration of Eurasian populations into the Americas, and that the high incidence of microtia among Amerindigenous populations reflects the population bottleneck that occurred during the migration out of Eurasia.

2022-05-14 | GSE202440 | GEO

An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations (scRNA-Seq)

2022-05-14 | GSE202441 | GEO

An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations

Project description:An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations

| PRJNA836119 | ENA

An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations (scRNA-Seq)

Project description:An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations (scRNA-Seq)

| PRJNA836121 | ENA

An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-05-14 | GSE202442 | GEO

RNA-seq of nulliparus Robo1+/+ and Robo1-/- luminal progenitors

Project description:The goal of the study was to compare gene expression of Robo1+/+ and Robo1-/- luminal progenitors. Total RNAs were then extracted from FACS purified luminal progenitor cells, harvested from Robo1+/+ or Robo1-/- mice (n=3 per genotype, two animals per n) using TRIreagent LS (Sigma, T3934). Poly(A)+ RNA sequencing libraries were made from each sample using the TruSeq RNA library preparation kit v.1 (Illumina). Illumina RNA PolyA library preparation guide. A total of 6 libraries were created by PCR amplification with Illumina barcoding primers using kit recommended conditions and quantified using a Bioanalyzer DNA 1000 kit (Agilent).

2021-10-12 | GSE164707 | GEO

Single cell transcriptomic characterization of microtia reveals pathogenic dysregulation in previously unrecognized chondral stem/progenitor cell population

Project description:As one of most common birth defects worldwide, microtia results from auricular cartilage dysplasia and has unfortunate physical and psychological consequences for children. However, existing treatments have adverse outcomes and its pathogenesis is poorly understood. Since characterization of cell type composition and function in normal auricular cartilage can increase our understanding of microtia, we conducted single-cell transcriptomic profiling for 47,969 human auricular cartilage cells obtained from three microtia and six normal control (NC) samples. Comprehensive bioinformatic analysis identified seven cartilage-related cell subtypes belonging to the chondral and stromal lineages. We also found age-associated changes in gene expression shared across all subtypes in the chondral lineage of NC. Additionally, we revealed the previously unrecognized chondral stem/progenitor cells (CSPCs) that were mainly located in the chondrium and might have the potential for directed chondrogenic differentiation. Our results showed that dysregulation of SOX8 and EGR1 in CSPCs of microtia impaired cartilage development and enhanced oxidative stress response, respectively. These findings shed light on the potential mechanisms of microtia pathogenesis and offer novel avenues for the development of treatment strategies

2021-07-06 | GSE179135 | GEO

RNA-seq of nulliparus Robo1+/+ and Robo1-/- luminal progenitors

Project description:RNA-seq of nulliparus Robo1+/+ and Robo1-/- luminal progenitors

| PRJNA691604 | ENA

Identification of key genes and signaling pathways in microtia by the analysis of transcriptomics

Project description:Microtia is a complex congenital defect which is one of the most common birth defects in the world. Depending on the degree of deformity, microtia can be divided into many types. However, it is not clear whether the different degrees of microtia share the same underlying mechanism. The present study detected transcriptomic profiles of auricular cartilage tissues in 6 patients with mild and severe malformation and 3 control auricular cartilage tissues by RNA-seq technology. Relative mRNA abundances were compared and evaluated for their function and putative involvemen.t in microtia. A total of 1058, 1648 and 1150 differentially expressed genes respectively in the group of MIC-Ⅱ-vs-NOR, MIC-Ⅲ-vs-NOR and MIC-Ⅲ-vs-MIC-Ⅱwere identified. Bioinformatics analysis demonstrated that some of these genes showed potential associations with microtia. In the MIC-Ⅱ microtia, the changed biological processes mainly enriched in mitosis. And in the MIC-Ⅲ microtia, the changed biological processes not only enriched in mitosis but also in migration. The key genes, IL-6 and COMP, and key signaling pathway, PI3K-AKT signaling pathway, were found to be dysregulated, which could contribute to microtia. The present study was a report on the transcriptomic analysis of microtia using the auricular samples from different degrees of microtia. Additional studies are required to clarify the roles of potential key genes in microtia.

2023-06-01 | GSE227119 | GEO

Transcriptomic profiling of 4T1 cells depleted for Id1/3 and Robo1

Project description:Id1 and its closely related family member Id3 are expressed by a diversity of stem and progenitor cells. We show that Id1/3 are required for the self-renewal and proliferation of triple negative breast cancer (TNBC) cells both in vitro and in vivo. Furthermore, we identified that Id1/3 negatively regulates the tumour suppressor gene Robo1. Depletion of Robo1 could rescue the proliferative defect induced by Id1/3 knockdown. To understand the mechanisms by which Robo1 rescues cell proliferation in Id1/3 depleted cells, we performed RNA-Sequencing on 4T1 cells with Dox-inducible Id1/3 KD and/or Robo1 depletion using siRNA. We conclude that following Id1/3 knockdown, Robo1 is induced and exerts anti-proliferative effects via suppression of a Myc transcriptional program.

2020-10-31 | GSE129858 | GEO

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