scholarly journals Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Gerontology ◽  
2020 ◽  
Vol 66 (5) ◽  
pp. 514-522 ◽  
Author(s):  
Hossein Afshar ◽  
Fatemeh Adelirad ◽  
Ali Kowsari ◽  
Naser Kalhor ◽  
Ahmad Delbari ◽  
...  
Keyword(s):  
Natural Selection ◽  
Late Onset ◽  
Core Promoter ◽  
Neurocognitive Disorder ◽  
Ca Repeat

scholarly journals Natural Selection at an Exceptionally Long GGC Repeat in the Human RASGEF1C and Divergent Genotypes in Late-onset Neurocognitive Disorder

2021 ◽  
Author(s):  
Z Jafarian ◽  
S Khamse ◽  
H Afshar ◽  
Khorram Khorshid HR ◽  
A Delbari ◽  
...  
Keyword(s):  
Natural Selection ◽  
Evolutionary Biology ◽  
Late Onset ◽  
Core Promoter ◽  
Human Subjects ◽  
Specific Gene ◽  
Protein Coding ◽  
Repeat Allele ◽  
Complex Disorders ◽  
Selection For

Abstract Across the human protein-coding genes, the neuron-specific gene, RASGEF1C, contains the longest (GGC)-repeat, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). RASGEF1C expression dysregulation occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. 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 vertebrates. The 6-repeat allele of this repeat 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 (Mid-P exact = 0.004). We also detected divergent genotypes that were present in five NCD patients and not in the controls (Mid-P exact = 0.007). This STR 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. Indication of natural selection for predominantly abundant STR alleles and divergent genotypes enhance the perspective of evolutionary biology and disease pathogenesis in human complex disorders.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Z. Jafarian ◽  
S. Khamse ◽  
H. Afshar ◽  
H.R. Khorram Khorshid ◽  
A. Delbari ◽  
...  
Keyword(s):  
Natural Selection ◽  
Late Onset ◽  
Core Promoter ◽  
Human Subjects ◽  
Primate Species ◽  
Control Group ◽  
Specific Gene ◽  
Repeat Allele ◽  
The Status ◽  
Significant Divergence

AbstractExpression 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.

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

2021 ◽  
Author(s):  
Zahra Jafarian ◽  
Safoura Khamse ◽  
Hossein Afshar ◽  
Hamid Reza Khorram Khorshid ◽  
Ahmad Delbari ◽  
...  
Keyword(s):  
Natural Selection ◽  
Late Onset ◽  
Core Promoter ◽  
Human Subjects ◽  
Primate Species ◽  
Control Group ◽  
Specific Gene ◽  
Repeat Allele ◽  
The Status ◽  
Significant Divergence

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 in human and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences in human.

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

2021 ◽  
Author(s):  
Zahra Jafarian ◽  
Safoura Khamse ◽  
Hossein Afshar ◽  
Hamid Reza Khorram Khorshid ◽  
Ahmad Delbari ◽  
...  
Keyword(s):  
Natural Selection ◽  
Late Onset ◽  
Core Promoter ◽  
Human Subjects ◽  
Primate Species ◽  
Control Group ◽  
Specific Gene ◽  
Repeat Allele ◽  
The Status ◽  
Significant Divergence

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.

scholarly journals Natural selection increases mutational robustness in complex diseases: Mendelian evidence from early versus late onset common diseases

2013 ◽  
Author(s):  
Bora E Baysal
Keyword(s):  
Natural Selection ◽  
Early Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Phenotypic Expression ◽  
Complex Diseases ◽  
World Health ◽  
Common Disease ◽  
Common Diseases ◽  
Age Related

Background. Natural selection operates on genetically influenced phenotypic variations that confer differential survival or reproductive advantages. Common diseases are frequently associated with increased mortality and disability and complex heritable factors play an important role in their pathogenesis. Hence, common diseases should trigger the process of natural selection with subsequent population genetic response. However, empirical impact of natural selection on genetics of complex diseases is poorly understood. In this paper, I hypothesize that negative selection of diseased individuals leads to systemic genetic differences between common diseases that primarily occur before or during the reproductive years (early onset) and those that occur after the reproductive years (late onset). Methods. To test this hypothesis, a comprehensive literature survey of highly penetrant (80% or more) nonpleiotropic, nonsyndromic susceptibility genes (hereafter defined as Mendelian phenocopies) was completed for early versus late onset common diseases, organized using the World Health Organization (WHO) ICD-10 classification scheme. An average age at sporadic disease onset of 30 years was selected for dividing early versus late onset common diseases. Results. Mendelian phenocopies were identified for 16 primarily late onset common diseases from 9 distinct WHO diagnostic categories. Late onset common diseases with Mendelian phenocopies include papillary renal carcinoma, obesity, Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, primary open angle glaucoma, age-related hearing loss, coronary artery disease, stroke, pancreatitis, thrombotic thrombocytopenic purpura, systemic lupus erythematosus, inclusion body myositis, Paget's disease of bone and focal segmental glomerulosclerosis (steroid resistant). In contrast, no Mendelian phenocopy was found for any primarily early onset common disease (p<5.8x10-4). Thus, highly predictive rare variants are present for a subset of late onset common diseases, but not for early onset common diseases. Discussion. These findings suggest that genetic architecture of early onset common diseases is more robust against the phenotypic expression of highly penetrant predisposing mutations than is the case for late onset common diseases. The primary candidate for increased genetic robustness in early onset common diseases is proposed to be natural selection.

scholarly journals Natural selection increases mutational robustness in complex diseases: Mendelian evidence from early versus late onset common diseases

2013 ◽  
Author(s):  
Bora E Baysal
Keyword(s):  
Natural Selection ◽  
Early Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Phenotypic Expression ◽  
Complex Diseases ◽  
World Health ◽  
Common Disease ◽  
Common Diseases ◽  
Age Related

Background. Natural selection operates on genetically influenced phenotypic variations that confer differential survival or reproductive advantages. Common diseases are frequently associated with increased mortality and disability and complex heritable factors play an important role in their pathogenesis. Hence, common diseases should trigger the process of natural selection with subsequent population genetic response. However, empirical impact of natural selection on genetics of complex diseases is poorly understood. In this paper, I hypothesize that negative selection of diseased individuals leads to systemic genetic differences between common diseases that primarily occur before or during the reproductive years (early onset) and those that occur after the reproductive years (late onset). Methods. To test this hypothesis, a comprehensive literature survey of highly penetrant (80% or more) nonpleiotropic, nonsyndromic susceptibility genes (hereafter defined as Mendelian phenocopies) was completed for early versus late onset common diseases, organized using the World Health Organization (WHO) ICD-10 classification scheme. An average age at sporadic disease onset of 30 years was selected for dividing early versus late onset common diseases. Results. Mendelian phenocopies were identified for 16 primarily late onset common diseases from 9 distinct WHO diagnostic categories. Late onset common diseases with Mendelian phenocopies include papillary renal carcinoma, obesity, Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, primary open angle glaucoma, age-related hearing loss, coronary artery disease, stroke, pancreatitis, thrombotic thrombocytopenic purpura, systemic lupus erythematosus, inclusion body myositis, Paget's disease of bone and focal segmental glomerulosclerosis (steroid resistant). In contrast, no Mendelian phenocopy was found for any primarily early onset common disease (p<5.8x10-4). Thus, highly predictive rare variants are present for a subset of late onset common diseases, but not for early onset common diseases. Discussion. These findings suggest that genetic architecture of early onset common diseases is more robust against the phenotypic expression of highly penetrant predisposing mutations than is the case for late onset common diseases. The primary candidate for increased genetic robustness in early onset common diseases is proposed to be natural selection.

scholarly journals Novel implications of a strictly monomorphic (GCC) repeat in the human PRKACB gene

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Safoura Khamse ◽  
Zahra Jafarian ◽  
Ali Bozorgmehr ◽  
Mostafa Tavakoli ◽  
Hossein Afshar ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Late Onset ◽  
Core Promoter ◽  
Human Subjects ◽  
3D Structure ◽  
Three Dimensional ◽  
Dna Structure ◽  
Neuroprotective Effects ◽  
The Impact ◽  
The Brain

AbstractPRKACB (Protein Kinase CAMP-Activated Catalytic Subunit Beta) is predominantly expressed in the brain, and regulation of this gene links to neuroprotective effects against tau and Aβ-induced toxicity. Here we studied a (GCC)-repeat spanning the core promoter and 5′ UTR of this gene in 300 human subjects, consisting of late-onset neurocognitive disorder (NCD) (N = 150) and controls (N = 150). We also implemented several models to study the impact of this repeat on the three-dimensional (3D) structure of DNA. While the PRKACB (GCC)-repeat was strictly monomorphic at 7-repeats, we detected two 7/8 genotypes only in the NCD group. In all examined models, the (GCC)7 and its periodicals had the least range of divergence variation on the 3D structure of DNA in comparison to the 8-repeat periodicals and several hypothetical repeat lengths. A similar inert effect on the 3D structure was not detected in other classes of short tandem repeats (STRs) such as GA and CA repeats. In conclusion, we report monomorphism of a long (GCC)-repeat in the PRKACB gene in human, its inert effect on DNA structure, and enriched divergence in late-onset NCD. This is the first indication of natural selection for a monomorphic (GCC)-repeat, which probably evolved to function as an “epigenetic knob”, without changing the regional DNA structure.

An exceptionally long CA-repeat in the core promoter of SCGB2B2 links with the evolution of apes and Old World monkeys

Gene ◽  
2016 ◽  
Vol 576 (1) ◽  
pp. 109-114 ◽  
Author(s):  
M. Nikkhah ◽  
M. Rezazadeh ◽  
H.R. Khorram Khorshid ◽  
A. Biglarian ◽  
M. Ohadi
Keyword(s):  
Core Promoter ◽  
Old World Monkeys ◽  
Ca Repeat ◽  
Old World ◽  
The Core
Sign in / Sign up

Export Citation Format

Share Document