Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder

Abstract Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GGC)13, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST000003611...

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Autores principales:	Z. Jafarian, S. Khamse, H. Afshar, H.R. Khorram Khorshid, A. Delbari, M. Ohadi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c431754e097749c7afdc969c662bfffe
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spelling	oai:doaj.org-article:c431754e097749c7afdc969c662bfffe2021-12-02T17:37:35ZNatural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder10.1038/s41598-021-98725-y2045-2322https://doaj.org/article/c431754e097749c7afdc969c662bfffe2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98725-yhttps://doaj.org/toc/2045-2322Abstract Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GGC)13, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact = 0.004). A number of those genotypes were not detected in the control group (Mid-P exact = 0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences.Z. JafarianS. KhamseH. AfsharH.R. Khorram KhorshidA. DelbariM. OhadiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Z. Jafarian S. Khamse H. Afshar H.R. Khorram Khorshid A. Delbari M. Ohadi Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder
description	Abstract Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GGC)13, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact = 0.004). A number of those genotypes were not detected in the control group (Mid-P exact = 0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences.
format	article
author	Z. Jafarian S. Khamse H. Afshar H.R. Khorram Khorshid A. Delbari M. Ohadi
author_facet	Z. Jafarian S. Khamse H. Afshar H.R. Khorram Khorshid A. Delbari M. Ohadi
author_sort	Z. Jafarian
title	Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder
title_short	Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder
title_full	Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder
title_fullStr	Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder
title_full_unstemmed	Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder
title_sort	natural selection at the rasgef1c (ggc) repeat in human and divergent genotypes in late-onset neurocognitive disorder
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c431754e097749c7afdc969c662bfffe
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Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder

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