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

• Published in: Scientific reports Vol. 11; no. 1; p. 19235
• Main Authors: Jafarian, Z., Khamse, S., Afshar, H., Khorshid, H.R. Khorram, Delbari, A., Ohadi, M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-09-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 5' Untranslated Regions; 631/181; 631/208; 631/337; 631/378; Alleles; Alzheimer's disease; Case-Control Studies; Cognition; Divergence; Gene frequency; Genetic Predisposition to Disease; Genotypes; Guanine nucleotide exchange factor; Humanities and Social Sciences; Humans; Iran - epidemiology; Late Onset Disorders - epidemiology; Late Onset Disorders - genetics; Microsatellite Repeats; Monkeys & apes; multidisciplinary; Natural selection; Neurocognitive Disorders - epidemiology; Neurocognitive Disorders - genetics; Neurodegenerative diseases; ras Guanine Nucleotide Exchange Factors - genetics; Science; Science (multidisciplinary); Selection, Genetic; Iran
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-98725-y

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.