scholarly journals Enrichment in conservative amino acid changes among fixed and standing missense variations in slowly evolving proteins

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9983
Author(s):  
Mingrui Wang ◽  
Dapeng Wang ◽  
Jun Yu ◽  
Shi Huang
Keyword(s):  
Amino Acid ◽  
Molecular Evolution ◽  
Rhesus Macaques ◽  
Neutral Theory ◽  
Evolutionary Rates ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Project Data ◽  
The Impact

The process of molecular evolution has many elements that are not yet fully understood. Evolutionary rates are known to vary among protein coding and noncoding DNAs, and most of the observed changes in amino acid or nucleotide sequences are assumed to be non-adaptive by the neutral theory of molecular evolution. However, it remains unclear whether fixed and standing missense changes in slowly evolving proteins are more or less neutral compared to those in fast evolving genes. Here, based on the evolutionary rates as inferred from identity scores between orthologs in human and Rhesus Macaques (Macaca mulatta), we found that the fraction of conservative substitutions between species was significantly higher in their slowly evolving proteins. Similar results were obtained by using four different methods of scoring conservative substitutions, including three that remove the impact of substitution probability, where conservative changes require fewer mutations. We also examined the single nucleotide polymorphisms (SNPs) by using the 1000 Genomes Project data and found that missense SNPs in slowly evolving proteins also had a higher fraction of conservative changes, especially for common SNPs, consistent with more non-conservative substitutions and hence stronger natural selection for SNPs, particularly rare ones, in fast evolving proteins. These results suggest that fixed and standing missense variants in slowly evolving proteins are more likely to be neutral.

scholarly journals Enrichment in conservative amino acid changes among fixed and standing missense variations in slow evolving proteins

2019 ◽  
Author(s):  
Mingrui Wang ◽  
Dapeng Wang ◽  
Jun Yu ◽  
Shi Huang
Keyword(s):  
Amino Acid ◽  
Nucleotide Polymorphisms ◽  
1000 Genomes Project ◽  
Single Nucleotide ◽  
1000 Genomes ◽  
Substitution Saturation ◽  
Dating Method ◽  
Selection For ◽  
Project Data ◽  
Molecular Clock Dating

AbstractProteins were first used in the early 1960s to discover the molecular clock dating method and remain in common usage today in phylogenetic inferences based on neutral variations. To avoid substitution saturation, it is necessary to use slow evolving genes. However, it remains unclear whether fixed and standing missense changes in such genes may qualify as neutral. Here, based on the evolutionary rates as inferred from identity scores between orthologs in human and Macaca monkey, we found that the fraction of conservative amino acid mismatches between species was significantly higher in slow evolving proteins. We also examined the single nucleotide polymorphisms (SNPs) by using the 1000 genomes project data and found that missense SNPs in slow evolving proteins also had higher fraction of conservative changes, especially for common SNPs, consistent with more natural selection for SNPs, particularly rare ones, in fast evolving proteins. These results suggest that fixed and standing missense variations in slow evolving proteins are more likely to be neutral and hence better qualified for use in phylogenetic inferences.

scholarly journals Implications of the Novel Mutations in the SARS-CoV-2 Genome for Transmission, Disease Severity, and the Vaccine Development

2021 ◽  
Vol 8 ◽  
Author(s):  
Hikmet Akkiz
Keyword(s):  
Amino Acid ◽  
Disease Severity ◽  
Vaccine Development ◽  
Experimental Studies ◽  
Spike Protein ◽  
Nucleotide Polymorphisms ◽  
Sequencing Data ◽  
Novel Mutations ◽  
Single Nucleotide ◽  
The Impact

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease 2019 (COVID-19), has been identified in China in late December 2019. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA betacoronavirus of the Coronaviridae family. Coronaviruses have genetic proofreading mechanism that corrects copying mistakes and thus SARS-CoV-2 genetic diversity is extremely low. Despite lower mutation rate of the virus, researchers have detected a total of 12,706 mutations in the SARS-CoV-2 genome, the majority of which were single nucleotide polymorphisms. Sequencing data revealed that the SARS-CoV-2 accumulates two-single nucleotide mutations per month in its genome. Recently, an amino acid aspartate (D) to glycine (G) (D614G) mutation due to an adenine to guanine nucleotide change at position 23,403 at the 614th amino-acid position of the spike protein in the original reference genotype has been identified. The SARS-CoV-2 viruses that carry the spike protein D614G mutation have become dominant variant around the world. The D614G mutation has been found to be associated with 3 other mutations in the spike protein. Clinical and pseudovirus experimental studies have demonstrated that the spike protein D614G mutation alters the virus phenotype. However, the impact of the mutation on the rate of transmission between people, disease severity and the vaccine and therapeutic development remains unclear. Three variants of SARS-CoV-2 have recently been identified. They are B.1.1.7 (UK) variant, B.1.351 (N501Y.V2, South African) variant and B.1.1.28 (Brazilian) variant. Epidemiological data suggest that they have a higher transmissibility than the original variant. There are reports that some vaccines are less efficacious against the B.1.351 variant. This review article discusses the effects of novel mutations in the SARS-CoV-2 genome on transmission, clinical outcomes and vaccine development.

scholarly journals Adaptive divergence in the bovine genome

2015 ◽  
Author(s):  
William Barendse ◽  
Sean McWilliam ◽  
Rowan J Bunch ◽  
Blair E Harrison
Keyword(s):  
Amino Acid ◽  
Positive Selection ◽  
Bovine Genome ◽  
Neutral Theory ◽  
Adaptive Divergence ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Adaptive Selection ◽  
Tropical Environments ◽  
Histocompatibility Complex

Cattle diverged during the Pleistocene into two subspecies, one in temperate and one in tropical environments. Here we have used next generation sequencing of the indicine subspecies of cattle and compared it to the taurine subspecies. Although 23.8 million single nucleotide polymorphisms (SNP) were found, the number of fixed amino acid substitutions between the taurine and indicine subspecies was low and consistent with the Haldane predictions for adaptive selection rather than with Neutral Theory. We noted 33 regions of enhanced divergence of nonsynonymous SNP between the subspecies, which included an increased rate of deleterious variants. Signals of positive selection were found for genes associated with immunity, including the Bovine Major Histocompatibility Complex, which also showed an increased rate of deleterious amino acid variants. The genes important in sensing the environment, especially the olfactory system, showed a network wide signal of positive selection.

Analysis of Inter-Chromosomal Distribution of Disease-Related Genes in Human Genome

2020 ◽  
Vol 21 (11) ◽  
pp. 1068-1077
Author(s):  
Xiaochao Sun ◽  
Bin Yang ◽  
Qunye Zhang
Keyword(s):  
Spatial Distribution ◽  
Model Organisms ◽  
Nucleotide Polymorphisms ◽  
Chromosomal Distribution ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Single Chromosome ◽  
Deletion Mutations ◽  
Protein Coding Genes ◽  
Disease Related Genes

: Many studies have shown that the spatial distribution of genes within a single chromosome exhibits distinct patterns. However, little is known about the characteristics of inter-chromosomal distribution of genes (including protein-coding genes, processed transcripts and pseudogenes) in different genomes. In this study, we explored these issues using the available genomic data of both human and model organisms. Moreover, we also analyzed the distribution pattern of protein-coding genes that have been associated with 14 common diseases and the insert/deletion mutations and single nucleotide polymorphisms detected by whole genome sequencing in an acute promyelocyte leukemia patient. We obtained the following novel findings. Firstly, inter-chromosomal distribution of genes displays a nonstochastic pattern and the gene densities in different chromosomes are heterogeneous. This kind of heterogeneity is observed in genomes of both lower and higher species. Secondly, protein-coding genes involved in certain biological processes tend to be enriched in one or a few chromosomes. Our findings have added new insights into our understanding of the spatial distribution of genome and disease- related genes across chromosomes. These results could be useful in improving the efficiency of disease-associated gene screening studies by targeting specific chromosomes.

scholarly journals Impact of PD-1 gene polymorphism and its interaction with tea drinking on susceptibility to tuberculosis

2021 ◽  
Vol 149 ◽  
Author(s):  
Jing Wang ◽  
Mian Wang ◽  
Zihao Li ◽  
Xinyin Wu ◽  
Xian Zhang ◽  
...  
Keyword(s):  
Case Control Study ◽  
Preventive Measures ◽  
Nucleotide Polymorphisms ◽  
Unconditional Logistic Regression ◽  
Negative Interaction ◽  
Single Nucleotide ◽  
High Risk Populations ◽  
Tea Drinking ◽  
The Impact ◽  
Control Study

Abstract The aim of this study was to explore the impact of polymorphism of PD-1 gene and its interaction with tea drinking on susceptibility to tuberculosis (TB). A total of 503 patients with TB and 494 controls were enrolled in this case–control study. Three single-nucleotide polymorphisms of PD-1 (rs7568402, rs2227982 and rs36084323) were genotyped and unconditional logistic regression analysis was used to identify the association between PD-1 polymorphism and TB, while marginal structural linear odds models were used to estimate the interactions. Genotypes GA (OR 1.434), AA (OR 1.891) and GA + AA (OR 1.493) at rs7568402 were more prevalent in the TB patients than in the controls (P < 0.05). The relative excess risk of interaction (RERI) between rs7568402 of PD-1 genes and tea drinking was −0.3856 (95% confidence interval −0.7920 to −0.0209, P < 0.05), which showed a negative interaction. However, the RERIs between tea drinking and both rs2227982 and rs36084323 of PD-1 genes were not statistically significant. Our data demonstrate that rs7568402 of PD-1 genes was associated with susceptibility to TB, and there was a significant negative interaction between rs7568402 and tea drinking. Therefore, preventive measures through promoting the consumption of tea should be emphasised in the high-risk populations.

scholarly journals PSI-40 Two mitochondrial lineages revealed in North American yak

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 477-477
Author(s):  
Leah K Treffer ◽  
Edward S Rice ◽  
Anna M Fuller ◽  
Samuel Cutler ◽  
Jessica L Petersen
Keyword(s):  
Sequence Data ◽  
Haplotype Network ◽  
Ovis Aries ◽  
Similar Species ◽  
Nucleotide Polymorphisms ◽  
Mt Dna ◽  
Protein Coding ◽  
Sister Clade ◽  
Mtdna Sequence ◽  
The Impact

Abstract Domestic yak (Bos grunniens) are bovids native to the Asian Qinghai-Tibetan Plateau. Studies of Asian yak have revealed that introgression with domestic cattle has contributed to the evolution of the species. When imported to North America (NA), some hybridization with B. taurus did occur. The objective of this study was to use mitochondrial (mt) DNA sequence data to better understand the mtDNA origin of NA yak and their relationship to Asian yak and related species. The complete mtDNA sequence of 14 individuals (12 NA yak, 1 Tibetan yak, 1 Tibetan B. indicus) was generated and compared with sequences of similar species from GeneBank (B. indicus, B. grunniens (Chinese), B. taurus, B. gaurus, B. primigenius, B. frontalis, Bison bison, and Ovis aries). Individuals were aligned to the B. grunniens reference genome (ARS_UNL_BGru_maternal_1.0), which was also included in the analyses. The mtDNA genes were annotated using the ARS-UCD1.2 cattle sequence as a reference. Ten unique NA yak haplotypes were identified, which a haplotype network separated into two clusters. Variation among the NA haplotypes included 93 nonsynonymous single nucleotide polymorphisms. A maximum likelihood tree including all taxa was made using IQtree after the data were partitioned into twenty-two subgroups using PartitionFinder2. Notably, six NA yak haplotypes formed a clade with B. indicus; the other four haplotypes grouped with B. grunniens and fell as a sister clade to bison, gaur and gayal. These data demonstrate two mitochondrial origins of NA yak with genetic variation in protein coding genes. Although these data suggest yak introgression with B. indicus, it appears to date prior to importation into NA. In addition to contributing to our understanding of the species history, these results suggest the two major mtDNA haplotypes in NA yak may functionally differ. Characterization of the impact of these differences on cellular function is currently underway.

scholarly journals Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity

2015 ◽  
Vol 308 (9) ◽  
pp. C758-C766 ◽  
Author(s):  
Xinjun Cindy Zhu ◽  
Rafiquel Sarker ◽  
John R. Horton ◽  
Molee Chakraborty ◽  
Tian-E Chen ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Large Fraction ◽  
Regulatory Protein ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Single Nucleotide ◽  
Mutant Proteins ◽  
Homologous Protein ◽  
Genetic Abnormalities ◽  
The Impact

Genetic determinants appear to play a role in susceptibility to chronic diarrhea, but the genetic abnormalities involved have only been identified in a few conditions. The Na+/H+ exchanger 3 (NHE3) accounts for a large fraction of physiologic intestinal Na+ absorption. It is highly regulated through effects on its intracellular COOH-terminal regulatory domain. The impact of genetic variation in the NHE3 gene, such as single nucleotide polymorphisms (SNPs), on transporter activity remains unexplored. From a total of 458 SNPs identified in the entire NHE3 gene, we identified three nonsynonymous mutations (R474Q, V567M, and R799C), which were all in the protein's intracellular COOH-terminal domain. Here we evaluated whether these SNPs affect NHE3 activity by expressing them in a mammalian cell line that is null for all plasma membrane NHEs. These variants significantly reduced basal NHE3 transporter activity through a reduction in intrinsic NHE3 function in variant R474Q, abnormal trafficking in variant V567M, or defects in both intrinsic NHE3 function and trafficking in variant R799C. In addition, variants NHE3 R474Q and R799C failed to respond to acute dexamethasone stimulation, suggesting cells with these mutant proteins might be defective in NHE3 function during postprandial stimulation and perhaps under stressful conditions. Finally, variant R474Q was shown to exhibit an aberrant interaction with calcineurin B homologous protein (CHP), an NHE3 regulatory protein required for basal NHE3 activity. Taken together, these results demonstrate decreased transport activity in three SNPs of NHE3 and provide mechanistic insight into how these SNPs impact NHE3 function.

scholarly journals Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

2018 ◽  
Vol 47 (4) ◽  
pp. 1604-1616 ◽  
Author(s):  
Yan Fang ◽  
Na Gao ◽  
Xin Tian ◽  
Jun Zhou ◽  
Hai-Feng Zhang ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
High Performance ◽  
Liver Microsomes ◽  
Nucleotide Polymorphisms ◽  
Liquid Chromatograph ◽  
Single Nucleotide ◽  
P450 Oxidoreductase ◽  
Human Livers ◽  
Metabolic Activities ◽  
The Impact

Background/ Aims: Little is known about the effect of P450 oxidoreductase (POR) gene polymorphisms on the activities of CYPs with multiple genotypes. Methods: We genotyped 102 human livers for 18 known POR single nucleotide polymorphisms (SNPs) with allelic frequencies greater than 1% as well as for 27 known SNPs in 10 CYPs. CYP enzyme activities in microsomes prepared from these livers were determined by measuring probe substrate metabolism by high performance liquid chromatograph. Results: We found that the effects of the 18 POR SNPs on 10 CYP activities were CYP genotype-dependent. The POR mutations were significantly associated with decreased overall Km for CYP2B6 and 2E1, and specific genotypes within CYP1A2, 2A6, 2B6, 2C8, 2D6 and 2E1 were identified as being affected by these POR SNPs. Notably, the effect of a specific POR mutation on the activity of a CYP genotype could not be predicted from other CYP genotypes of even the same CYP. When combining one POR SNP with other POR SNPs, a hitherto unrecognized effect of multiple-site POR gene polymorphisms (MSGP) on CYP activity was uncovered, which was not necessarily consistent with the effect of either single POR SNP. Conclusions: The effects of POR SNPs on CYP activities were not only CYP-dependent, but more importantly, CYP genotype-dependent. Moreover, the effect of a POR SNP alone and in combination with other POR SNPs (MSGP) was not always consistent, nor predictable. Understanding the impact of POR gene polymorphisms on drug metabolism necessitates knowing the complete SNP complement of POR and the genotype of the relevant CYPs.

scholarly journals The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

2012 ◽  
Vol 40 (5) ◽  
pp. 856-864 ◽  
Author(s):  
Tobias Hartmann ◽  
Mineko Terao ◽  
Enrico Garattini ◽  
Christian Teutloff ◽  
Joshua F. Alfaro ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Aldehyde Oxidase ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
The Impact
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