Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants
Genetic patterns of inter-population variation are a result of different demographic and adaptive histories, which gradually shape the frequency distribution of the variants. However, the study of clinically relevant mutations has a Eurocentric bias. The Romani, the largest transnational minority ethnic group in Europe, originated in South Asia and received extensive gene flow from West Eurasia. Most medical genetic studies have only explored founder mutations related to Mendelian disorders in this population. Here we analyze exome sequences and genome-wide array data of 89 healthy Spanish Roma individuals to study complex traits and disease. We apply a different framework and focus on variants with both increased and decreased allele frequencies, taking into account their local ancestry. We report several OMIM traits enriched for genes with deleterious variants showing increased frequencies in Roma or in non-Roma (e.g., obesity is enriched in Roma, with an associated variant linked to South Asian ancestry; while non-insulin dependent diabetes is enriched in non-Roma Europeans). In addition, previously reported pathogenic variants also show differences among populations, where some variants segregating at low frequency in non-Roma are virtually absent in the Roma. Lastly, we describe frequency changes in drug-response variation, where many of the variants increased in Roma are clinically associated with metabolic and cardiovascular-related drugs. These results suggest that clinically relevant variation in Roma cannot only be characterized in terms of founder mutations. Instead, we observe frequency differences compared to non-Roma: some variants are absent, while other have drifted to higher frequencies. As a result of the admixture events, these clinically damaging variants can be traced back to both European and South Asian-related ancestries. This can be attributed to a different prevalence of some genetic disorders or to the fact that genetic susceptibility variants are mostly studied in populations of European descent, and can differ in individuals with different ancestries.
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Language: | English |
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Frontiers Media
2021-06-16
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Subjects: | Romani, Whole-exome sequences, Clinically relevant variants, Drug-response variants, Local ancestry inference, Eurocentric bias, |
Online Access: | http://hdl.handle.net/10261/249079 http://dx.doi.org/10.13039/501100011033 |
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dig-ibe-es-10261-2490792021-12-27T16:24:52Z Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants Font-Porterias, Neus Giménez, Aaron Carballo-Mesa, Annabel Calafell, Francesc Comas, David Ministerio de Ciencia, Innovación y Universidades (España) Agencia Estatal de Investigación (España) Romani Whole-exome sequences Clinically relevant variants Drug-response variants Local ancestry inference Eurocentric bias Genetic patterns of inter-population variation are a result of different demographic and adaptive histories, which gradually shape the frequency distribution of the variants. However, the study of clinically relevant mutations has a Eurocentric bias. The Romani, the largest transnational minority ethnic group in Europe, originated in South Asia and received extensive gene flow from West Eurasia. Most medical genetic studies have only explored founder mutations related to Mendelian disorders in this population. Here we analyze exome sequences and genome-wide array data of 89 healthy Spanish Roma individuals to study complex traits and disease. We apply a different framework and focus on variants with both increased and decreased allele frequencies, taking into account their local ancestry. We report several OMIM traits enriched for genes with deleterious variants showing increased frequencies in Roma or in non-Roma (e.g., obesity is enriched in Roma, with an associated variant linked to South Asian ancestry; while non-insulin dependent diabetes is enriched in non-Roma Europeans). In addition, previously reported pathogenic variants also show differences among populations, where some variants segregating at low frequency in non-Roma are virtually absent in the Roma. Lastly, we describe frequency changes in drug-response variation, where many of the variants increased in Roma are clinically associated with metabolic and cardiovascular-related drugs. These results suggest that clinically relevant variation in Roma cannot only be characterized in terms of founder mutations. Instead, we observe frequency differences compared to non-Roma: some variants are absent, while other have drifted to higher frequencies. As a result of the admixture events, these clinically damaging variants can be traced back to both European and South Asian-related ancestries. This can be attributed to a different prevalence of some genetic disorders or to the fact that genetic susceptibility variants are mostly studied in populations of European descent, and can differ in individuals with different ancestries. This study was supported by the Spanish Ministry of Science, Innovation and Universities (MCIU), Agencia Estatal de Investigación (AEI) grant number PID2019-106485GB-I00/AEI/10.13039/501100011033, and “Unidad de Excelencia María de Maeztu” (AEI, CEX2018-000792-M). NF-P was supported by a FPU17/03501 fellowship. With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2018-000792-M). Peer reviewed 2021-08-31T09:17:16Z 2021-08-31T09:17:16Z 2021-06-16 artículo http://purl.org/coar/resource_type/c_6501 Frontiers in Genetics 12: 683880 (2021) CEX2018-000792-M http://hdl.handle.net/10261/249079 10.3389/fgene.2021.683880 1664-8021 http://dx.doi.org/10.13039/501100011033 34220960 en #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-106485GB-I00 Publisher's version https://doi.org/10.3389/fgene.2021.683880 Sí open Frontiers Media |
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Romani Whole-exome sequences Clinically relevant variants Drug-response variants Local ancestry inference Eurocentric bias Romani Whole-exome sequences Clinically relevant variants Drug-response variants Local ancestry inference Eurocentric bias |
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Romani Whole-exome sequences Clinically relevant variants Drug-response variants Local ancestry inference Eurocentric bias Romani Whole-exome sequences Clinically relevant variants Drug-response variants Local ancestry inference Eurocentric bias Font-Porterias, Neus Giménez, Aaron Carballo-Mesa, Annabel Calafell, Francesc Comas, David Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants |
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Genetic patterns of inter-population variation are a result of different demographic and adaptive histories, which gradually shape the frequency distribution of the variants. However, the study of clinically relevant mutations has a Eurocentric bias. The Romani, the largest transnational minority ethnic group in Europe, originated in South Asia and received extensive gene flow from West Eurasia. Most medical genetic studies have only explored founder mutations related to Mendelian disorders in this population. Here we analyze exome sequences and genome-wide array data of 89 healthy Spanish Roma individuals to study complex traits and disease. We apply a different framework and focus on variants with both increased and decreased allele frequencies, taking into account their local ancestry. We report several OMIM traits enriched for genes with deleterious variants showing increased frequencies in Roma or in non-Roma (e.g., obesity is enriched in Roma, with an associated variant linked to South Asian ancestry; while non-insulin dependent diabetes is enriched in non-Roma Europeans). In addition, previously reported pathogenic variants also show differences among populations, where some variants segregating at low frequency in non-Roma are virtually absent in the Roma. Lastly, we describe frequency changes in drug-response variation, where many of the variants increased in Roma are clinically associated with metabolic and cardiovascular-related drugs. These results suggest that clinically relevant variation in Roma cannot only be characterized in terms of founder mutations. Instead, we observe frequency differences compared to non-Roma: some variants are absent, while other have drifted to higher frequencies. As a result of the admixture events, these clinically damaging variants can be traced back to both European and South Asian-related ancestries. This can be attributed to a different prevalence of some genetic disorders or to the fact that genetic susceptibility variants are mostly studied in populations of European descent, and can differ in individuals with different ancestries. |
author2 |
Ministerio de Ciencia, Innovación y Universidades (España) |
author_facet |
Ministerio de Ciencia, Innovación y Universidades (España) Font-Porterias, Neus Giménez, Aaron Carballo-Mesa, Annabel Calafell, Francesc Comas, David |
format |
artículo |
topic_facet |
Romani Whole-exome sequences Clinically relevant variants Drug-response variants Local ancestry inference Eurocentric bias |
author |
Font-Porterias, Neus Giménez, Aaron Carballo-Mesa, Annabel Calafell, Francesc Comas, David |
author_sort |
Font-Porterias, Neus |
title |
Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants |
title_short |
Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants |
title_full |
Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants |
title_fullStr |
Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants |
title_full_unstemmed |
Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants |
title_sort |
admixture has shaped romani genetic diversity in clinically relevant variants |
publisher |
Frontiers Media |
publishDate |
2021-06-16 |
url |
http://hdl.handle.net/10261/249079 http://dx.doi.org/10.13039/501100011033 |
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