Leucine encoding codon TTG shows an inverse relationship with GC content in genes involved in neurodegeneration with iron accumulation.

Mohannad A Almikhlafi,Rekha Khandia,Nidhi Puranik,Taha Alqahtani,Mubarak Ali Algahtany,Ali M Alqahtani

doi:10.31083/j.jin2004092

Mohannad A Almikhlafi, Rekha Khandia + Show 4 more

Open Access

https://doi.org/10.31083/j.jin2004092

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Abstract

We determined various forces involved in shaping codon usage of the genes linked to brain iron accumulation and infantile neuroaxonal dystrophy. The analysis paved the way for determining the forces responsible for composition, expression level, physical properties and codon bias of a gene. An interesting observation related to composition was that, on all the three codon positions, any two of the four nucleotides had similar compositions. CpG, TpA, and GpT dinucleotides were underrepresented with the overrepresentation of TpG dinucleotide. CpG and TpA containing codons ATA, CTA, TCG, and GCG were underrepresented, while TpG dinucleotide containing codon CTG was overrepresented, indicative of compositional constraints importance. GC ending codons were favored when the genome is GC rich, except leucine encoding codon TTG, which exhibits an inverse relationship with GC content. Nucleotide disproportions are found associated with the physical properties of proteins. The values of CAI and ENc are suggestive of low codon bias in genes. Considering the results of neutrality analysis, parity analysis, underrepresentation of TpA and CpG codons, and over-representation of TpG codons, the correlation between the compositional constraints and skew relationships with protein properties suggested the role of all the three selectional, mutational and compositional forces in shaping codon usage with the dominance of selectional pressure.

Highlights

Iron in the brain plays a crucial role in sustaining homeostatic activity by participating in different physiological processes such as mitochondrial respiration, myelin formation, neurotransmitter synthesis, DNA synthesis, and metabolism [1]
A significant correlation between compositional constraints suggests that the above forces shape codon usage patterns in the envisaged genes
The same is not observed at all codon positions, indicating the presence of forces responsible for skewness in nucleotide composition

Summary

Introduction

Iron in the brain plays a crucial role in sustaining homeostatic activity by participating in different physiological processes such as mitochondrial respiration, myelin formation, neurotransmitter synthesis, DNA synthesis, and metabolism [1]. Abnormal iron homeostasis seems critical in potentiating neurodegeneration in disease conditions like traumatic brain injury, Alzheimer’s, Parkinson’s, Huntington’s diseases, and multiple sclerosis [2]. Neurological manifestations of disturbances in iron homeostasis are described in increased prevalence of headache [3], movement disorders [4], secondary dementia [5], epilepsy [6], multiple sclerosis [7], human immunodeficiency virus dementia [8], Freidrich ataxia [9], and Alzheimer and Parkinson diseases [10]. Iron accumulation can be visualized in MRI, and iron deposition in deep brain nuclei has been described as differing between patients with multiple system atrophy and progressive supranuclear palsy [11]. In a few rare neurodegenerative disorders, iron accumulation has been observed in various parts of the brain. In a few instances, hypo-intensities for iron content in MRI have been reported in diseases including restless legs syndrome and periodic limb movements in sleep [5], adaptor protein complex deficiency, DDHD Domain Containing 1 gene (DDHD1) pathogenic variants, and GTP Binding Protein 2 (GTPBP2) pathogenic variants [12]

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