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Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)

Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of...

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Autores principales: Chen, Che-Hong, Kraemer, Benjamin R., Lee, Lucia, Mochly-Rosen, Daria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533364/
https://www.ncbi.nlm.nih.gov/pubmed/34680056
http://dx.doi.org/10.3390/biom11101423
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author Chen, Che-Hong
Kraemer, Benjamin R.
Lee, Lucia
Mochly-Rosen, Daria
author_facet Chen, Che-Hong
Kraemer, Benjamin R.
Lee, Lucia
Mochly-Rosen, Daria
author_sort Chen, Che-Hong
collection PubMed
description Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of toxic aldehydes and abnormal carbonyl metabolism and serious human pathologies. However, the physiological functions and substrate specificity of many ALDH genes are still unknown. Although many genetic variants of the ALDH gene family exist in human populations, their phenotype or clinical consequences have not been determined. Using the most comprehensive global human Genome Aggregation Database, gnomAD, we annotated here 1350 common variants in the 19 ALDH genes. These 1350 common variants represent all known genetic polymorphisms with a variant allele frequency of ≥0.1% (or an expected occurrence of ≥1 carrier per 500 individuals) in any of the seven major ethnic groups recorded by gnomAD. We detailed 13 types of DNA sequence variants, their genomic positions, SNP ID numbers, and allele frequencies among the seven major ethnic groups worldwide for each of the 19 ALDH genes. For the 313 missense variants identified in the gnomAD, we used two software algorithms, Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT), to predict the consequences of the variants on the structure and function of the enzyme. Finally, gene constraint analysis was used to predict how well genetic mutations were tolerated by selection forces for each of the ALDH genes in humans. Based on the ratio of observed and expected variant numbers in gnomAD, the three ALDH1A gene members, ALDH1A1, ALDH1A2, and ALDH1A3, appeared to have the lowest tolerance for loss-of-function mutations as compared to the other ALDH genes (# observed/# expected ratio 0.15–0.26). These analyses suggest that the ALDH1A1, ALDH1A2, and ALDH1A3 enzymes may serve a more essential function as compared with the other ALDH enzymes; functional loss mutations are much less common in healthy human populations than expected. This informatic analysis may assist the research community in determining the physiological function of ALDH isozymes and associate common variants with clinical phenotypes.
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spelling pubmed-85333642021-10-23 Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD) Chen, Che-Hong Kraemer, Benjamin R. Lee, Lucia Mochly-Rosen, Daria Biomolecules Article Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of toxic aldehydes and abnormal carbonyl metabolism and serious human pathologies. However, the physiological functions and substrate specificity of many ALDH genes are still unknown. Although many genetic variants of the ALDH gene family exist in human populations, their phenotype or clinical consequences have not been determined. Using the most comprehensive global human Genome Aggregation Database, gnomAD, we annotated here 1350 common variants in the 19 ALDH genes. These 1350 common variants represent all known genetic polymorphisms with a variant allele frequency of ≥0.1% (or an expected occurrence of ≥1 carrier per 500 individuals) in any of the seven major ethnic groups recorded by gnomAD. We detailed 13 types of DNA sequence variants, their genomic positions, SNP ID numbers, and allele frequencies among the seven major ethnic groups worldwide for each of the 19 ALDH genes. For the 313 missense variants identified in the gnomAD, we used two software algorithms, Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT), to predict the consequences of the variants on the structure and function of the enzyme. Finally, gene constraint analysis was used to predict how well genetic mutations were tolerated by selection forces for each of the ALDH genes in humans. Based on the ratio of observed and expected variant numbers in gnomAD, the three ALDH1A gene members, ALDH1A1, ALDH1A2, and ALDH1A3, appeared to have the lowest tolerance for loss-of-function mutations as compared to the other ALDH genes (# observed/# expected ratio 0.15–0.26). These analyses suggest that the ALDH1A1, ALDH1A2, and ALDH1A3 enzymes may serve a more essential function as compared with the other ALDH enzymes; functional loss mutations are much less common in healthy human populations than expected. This informatic analysis may assist the research community in determining the physiological function of ALDH isozymes and associate common variants with clinical phenotypes. MDPI 2021-09-29 /pmc/articles/PMC8533364/ /pubmed/34680056 http://dx.doi.org/10.3390/biom11101423 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Che-Hong
Kraemer, Benjamin R.
Lee, Lucia
Mochly-Rosen, Daria
Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)
title Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)
title_full Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)
title_fullStr Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)
title_full_unstemmed Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)
title_short Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)
title_sort annotation of 1350 common genetic variants of the 19 aldh multigene family from global human genome aggregation database (gnomad)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533364/
https://www.ncbi.nlm.nih.gov/pubmed/34680056
http://dx.doi.org/10.3390/biom11101423
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