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

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art_QUIAT_An_ancient_founder_mutation_located_between_ROBO1_and_2022.PDF (2.62 MB)
Citações na Scopus
2
Tipo de produção
article
Data de publicação
2022
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
NATL ACAD SCIENCES
Autores
QUIAT, Daniel
KIM, Seong Won
ZHANG, Qi
MORTON, Sarah U.
DEPALMA, Steven R.
WILLCOX, Jon A. L.
MCDONOUGH, Barbara
DELAUGHTER, Daniel M.
GORHAM, Joshua M.
Citação
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.119, n.21, article ID e2203928119, 9p, 2022
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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 similar to 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.
Palavras-chave
microtia, cniofacial microsomia, ancestry
URI
https://observatorio.fm.usp.br/handle/OPI/55030
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Coleções
Artigos e Materiais de Revistas Científicas - HC/InCor
Artigos e Materiais de Revistas Científicas - LIM/13