Allele frequency analysis of GALC gene causing Krabbe disease in human and its codon usage.

Krabbe disease is one of the rarest autosomal recessive disorders in human, caused by mutation in the GALC (ß-galactosylceramidase) gene, resulting in several mental and physical health issues. Due to its rarity and phenotypic heterogeneity, diagnosis rate of this disease is very low. This study generated information on the recessive allele frequency dynamics of GALC gene across 15 global populations, with the highest frequency detected in Druze (Israel) population and the lowest frequency in Turkey and the United States. The recessive allele would take more time period (about 24,975 years) to be completely removed from the population having the lowest frequency and vice versa. The codon usage patterns of four isoforms of GALC gene revealed that a few synonymous codons were used more frequently than others in the isoforms. The codon AGA (arginine) was found to be overrepresented in GALC gene, except for galactocerebrosidase isoform a precursor. Further, GALC gene showed low codon usage bias (CUB) as evident from high ENC values (55.7-58.2), with A/T ending codons more preferred to G/C ending codons. CUB analysis elucidated the dual role of mutational pressure (major role) and natural selection (minor role) in GALC gene evolution.

The significance of gene mutations across eight major cancer types.

Mutations occur spontaneously, which can be induced by either chemicals (e.g. benzene) or biological factors (e.g. virus). Not all mutations cause noticeable changes in cellular functions. However, mutation in key cellular genes leads to developmental disorders. It is one of the main ways in which proto-oncogenes can be changed into their oncogenic state. The progressive accumulation of multiple mutations throughout life leads to cancer. In the past few decades, extensive research on cancer biology has discovered many genes and pathways having role in cancer development. In this review, we tried to summarize the current knowledge of mutational effect on different cancer types and its consequences in brief for future reference and guidance of researchers in cancer biology.

Compositional bias coupled with selection and mutation pressure drives codon usage in Brassica campestris genes.

The plant Brassica campestris includes the vegetables turnip and Chinese cabbage, important plants of economic importance. Here, we have analysed the codon usage bias of B. campestris for 116 protein coding genes. Neutrality analysis showed that B. campestris had a wide range of GC3s, and a significant correlation was observed between GC12 and GC3. Nc versus GC3s plot showed a few genes on or proximate to the expected curve, but the majority of points were found to be scattered distantly from the expected curve. Correspondence analysis on codon usage revealed that the position preference of codons on multidimensional space totally depends on the presence of A and T at synonymous third codon position. These results altogether suggest that composition bias along with selection (major) and mutation pressure (minor) affects the codon usage pattern of the protein coding genes in Brassica campestris.

Codon usage vis-a-vis start and stop codon context analysis of three dicot species.

To understand the variation in genomic composition and its effect on codon usage, we performed the comparative analysis of codon usage and nucleotide usage in the genes of three dicots, Glycine max, Arabidopsis thaliana and Medicago truncatula. The dicot genes were found to be A/T rich and have predominantly A-ending and/or T-ending codons. GC3s directly mimic theusage pattern of global GC content. Relative synonymous codon usage analysis suggests that the high usage frequency of A/T over G/C mononucleotide containing codons in AT-rich dicot genome is due to compositional constraint as a factor of codon usage bias. Odds ratio analysis identified the dinucleotides TpG, TpC, GpA, CpA and CpT as over-represented, where, CpG and TpA as under-represented dinucleotides. The results of (NcExp-NcObs)/NcExp plot suggests that selection pressure other than mutation played a significant role in influencing the pattern of codon usage in these dicots. PR2 analysis revealed the significant role of selection pressure on codon usage. Analysis of varience on codon usage at start and stop site showed variation in codon selection in these sites. This study provides evidence that the dicot genes were subjected to compositional selection pressure.

Interplay between miRNAs and human diseases.

MicroRNAs (miRNAs) are endogenous, non-coding RNAs, which have evoked a great deal of interest due to their importance in many aspects of homeostasis and diseases. MicroRNAs are stable and are essential components of gene regulatory networks. They play a crucial role in healthy individuals and their dysregulations have also been implicated in a wide range of diseases, including diabetes, cardiovascular disease, kidney disease, and cancer. This review summarized the current understanding of interactions between miRNAs and different diseases and their role in disease diagnosis and therapy.

Codon usage and expression level of human mitochondrial 13 protein coding genes across six continents.

The study of codon usage coupled with phylogenetic analysis is an important tool to understand the genetic and evolutionary relationship of a gene. The 13 protein coding genes of human mitochondria are involved in electron transport chain for the generation of energy currency (ATP). However, no work has yet been reported on the codon usage of the mitochondrial protein coding genes across six continents. To understand the patterns of codon usage in mitochondrial genes across six different continents, we used bioinformatic analyses to analyze the protein coding genes. The codon usage bias was low as revealed from high ENC value. Correlation between codon usage and GC3 suggested that all the codons ending with G/C were positively correlated with GC3 but vice versa for A/T ending codons with the exception of ND4L and ND5 genes. Neutrality plot revealed that for the genes ATP6, COI, COIII, CYB, ND4 and ND4L, natural selection might have played a major role while mutation pressure might have played a dominant role in the codon usage bias of ATP8, COII, ND1, ND2, ND3, ND5 and ND6 genes. Phylogenetic analysis indicated that evolutionary relationships in each of 13 protein coding genes of human mitochondria were different across six continents and further suggested that geographical distance was an important factor for the origin and evolution of 13 protein coding genes of human mitochondria.

Dissimilar substitution rates between two strands of DNA influence codon usage pattern in some human genes.

We illustrated the descriptive aspects of codon usage of some important human genes and their expression potential in E. coli. By comparing the results of various codon usage parameters, effects that are due to selection and mutational pressures have been deciphered. The variation in GC3s explains a significant proportion of the variation in codon usage patterns. The codons CGC, CGG, CTG and GCG showed strong positive correlation with GC3, which suggested that codon usage had been influenced by GC bias. We also found that ACC (Thr, RSCU-1.77), GCC (Ala, RSCU-1.67), CCC (Pro, RSCU-1.54), TCC (Ser, RSCU-1.47) were frequently used which signified that C was common at 2nd and 3rd codon positions. Correspondence analysis revealed that F1 axis had significant correlation with various GC contents suggesting that compositional properties under mutation pressure might affect codon usage bias. Nc-GC3 plot analysis suggested that both mutation pressure and natural selection might affect the codon usage bias which is also supported by neutrality plot analysis. The dinucleotide CT, TG and AG were significantly over-represented and CG, TA, AT, TT, and GT were underrepresented due to high rate of spontaneous mutation resulting from cytosine deamination.

Codon usage and amino acid usage influence genes expression level.

Highly expressed genes in any species differ in the usage frequency of synonymous codons. The relative recurrence of an event of the favored codon pair (amino acid pairs) varies between gene and genomes due to varying gene expression and different base composition. Here we propose a new measure for predicting the gene expression level, i.e., codon plus amino bias index (CABI). Our approach is based on the relative bias of the favored codon pair inclination among the genes, illustrated by analyzing the CABI score of the Medicago truncatula genes. CABI showed strong correlation with all other widely used measures (CAI, RCBS, SCUO) for gene expression analysis. Surprisingly, CABI outperforms all other measures by showing better correlation with the wet-lab data. This emphasizes the importance of the neighboring codons of the favored codon in a synonymous group while estimating the expression level of a gene.

Nucleotide composition determines the role of translational efficiency in human genes.

The basic sequence features were analysed that influence gene expression via codon usage bias of the selected forty coding sequences of Homo sapiens in a simple prokaryotic model i.e. E. coli K-12 genome. The prime objective was to elucidate the interrelationships among tRNA gene copy numbers, synonymous codons, amino acids and translational efficiency using tRNA adaptation index. It was evident from RSCU scores and principal component analysis, that only those preferred codons were used by the isoacceptor tRNAs that had G and C base at their third codon position. Relationship between tRNA adaptation index and amino acids, revealed that valine, arginine, serine and isoleucine showed significant positive correlation with gene expression. Therefore, it could be inferred that GC content in these genes might have the major role in shaping the codon bias and affecting the translational efficiency of the coding sequences.

Cytochrome P450 genes in coronary artery diseases: Codon usage analysis reveals genomic GC adaptation.

Establishing codon usage biases are imperative for understanding the etiology of coronary artery diseases (CAD) as well as the genetic factors associated with these diseases. The aim of this study was to evaluate the contribution of 18 responsible cytochrome P450 (CYP) genes for the risk of CAD. Effective number of codon (Nc) showed a negative correlation with both GC3 and synonymous codon usage order (SCUO) suggesting an antagonistic relationship between codon usage and Nc of genes. The dinucleotide analysis revealed that CG and TA dinucleotides have the lowest odds ratio in these genes. Principal component analysis showed that GC composition has a profound effect in separating the genes along the first major axis. Our findings revealed that mutational pressure and natural selection could possibly be the major factors responsible for codon bias in these genes. The study not only offers an insight into the mechanisms of genomic GC adaptation, but also illustrates the complexity of CYP genes in CAD.

Allele frequency for Cystic fibrosis in Indians vis-a/-vis global populations.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. This gene encodes a protein involved in epithelial anion channel. Cystic fibrosis is the most common life-limiting genetic disorder in Caucasians; it also affects other ethnic groups like the Blacks and the Native Americans. Cystic fibrosis is considered to be rare among individuals from the Indian subcontinent. We analyzed a total of 29 world׳s populations for cystic fibrosis on the basis of gene frequency and heterozygosity. Among 29 countries Switzerland revealed the highest gene frequency and heterozygosity for CF (0.022, 0.043) whereas Japan recorded the lowest values (0.002, 0.004) followed by India (0.004, 0.008). Our analysis suggests that the prevalence of cystic fibrosis is very low in India.