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

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

PROVIDER: PRJNA836121 | 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 (scRNA-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 | GSE202441 | GEO

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

2022-05-14 | GSE202440 | 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 (RNA-Seq)

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

| PRJNA836122 | 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

An ancient founder mutation located between <i>ROBO1</i> and <i>ROBO2</i> is responsible for increased microtia risk in Amerindigenous populations.

Project description:Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although the contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests and association studies in microtia trios (parents and affected child) and microtia cohorts enrolled in Latin America, we map an ∼10-kb microtia locus (odds ratio = 4.7; P = 6.78e-18) to the intergenic region between Roundabout 1 (ROBO1) and Roundabout 2 (ROBO2) (chr3: 78546526 to 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 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 is shared by some East Asian subjects with craniofacial malformations, we propose that 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.

| S-EPMC9173816 | biostudies-literature

Affymetrix SNP array data for myelodysplastic syndromes (MDS) samples

Project description:The progressive mechanism of myelodysplastic syndrome (MDS) remains unknown. We report that ROBO1 and ROBO2 are identified as novel progression-related somatic mutations using whole-exome and targeted sequencing in six of 16 (37.5%) paired MDS patients undergoing disease progression. To investigated the effect of ROBO1 or ROBO2 on ROBO1/2 CN number and LOH, we employed a Cytosan 750K chip to analyze the copy-number variations (CNVs) and loss of heterogeneity (LOH) in MDS patients with ROBO1&2 mutations. Copy number and LOH analysis of Affymetrix CytoScan 750K array was performed for 14 MDS patients with ROBO1 or ROBO2 mutations

2015-09-15 | E-GEOD-73005 | biostudies-arrayexpress

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

Affymetrix SNP array data for myelodysplastic syndromes (MDS) samples

2015-09-15 | GSE73005 | GEO

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

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

| PRJNA691604 | ENA