Utility of 2-Diphenylphosphoryloxy-1,3-Dienes in Multicomponent Hetero-Diels-Alder Reactions to Construct Functionalized Six-Membered Nitrogen Heterocycles.

The utility of 2-diphenylphosphoryloxy-1,3-dienes for the construction of substituted six-membered nitrogen heterocycles is presented. These dienes undergo boron trifluoride-promoted aza-Diels-Alder reactions when reacted with imines or related species formed in situ using aldehydes and amine derivatives. The stability of the dienes allows this three-component reaction to be carried out with no special precautions to eliminate water or air. Thirty-one examples of this process are presented. The usefulness of the enol phosphate functional group is highlighted in further reactions after the cycloaddition step to generate functionalized piperidenes or pyridines.

Comparison of Imine- and Phosphinimine-Supported Indium Complexes: Tuning the Reactivity for the Sequential and Simultaneous Copolymerization of Lactide and ε-Caprolactone.

Imine- and phosphinimine-supported indium complexes were used as catalysts in the polymerization of racemic lactide and ε-caprolactone as well as their copolymerization by the sequential and simultaneous addition of monomers. Tuning the electronics and sterics of the indium centers by either (i) changing the nature of the nitrogen donors and (ii) coordinating a hemilabile side group had a significant effect on the reactivity of the complexes, their stability, and their control in the synthesis of block copolymers. Specifically, the imine-supported complex (5) showed the highest activity in the homo- and copolymerization of the cyclic esters, in contrast to the phosphinimine-supported complex (7), which was significantly slower and less stable. The presence of morpholine and thiomorpholine hemilabile side groups either reduced the activity or prevented the formation of alkoxide complexes.

Modelling the association between COVID-19 transmissibility and D614G substitution in SARS-CoV-2 spike protein: using the surveillance data in California as an example.

BACKGROUND: The COVID-19 pandemic poses a serious threat to global health, and pathogenic mutations are a major challenge to disease control. We developed a statistical framework to explore the association between molecular-level mutation activity of SARS-CoV-2 and population-level disease transmissibility of COVID-19. METHODS: We estimated the instantaneous transmissibility of COVID-19 by using the time-varying reproduction number (Rt). The mutation activity in SARS-CoV-2 is quantified empirically depending on (i) the prevalence of emerged amino acid substitutions and (ii) the frequency of these substitutions in the whole sequence. Using the likelihood-based approach, a statistical framework is developed to examine the association between mutation activity and Rt. We adopted the COVID-19 surveillance data in California as an example for demonstration. RESULTS: We found a significant positive association between population-level COVID-19 transmissibility and the D614G substitution on the SARS-CoV-2 spike protein. We estimate that a per 0.01 increase in the prevalence of glycine (G) on codon 614 is positively associated with a 0.49% (95% CI: 0.39 to 0.59) increase in Rt, which explains 61% of the Rt variation after accounting for the control measures. We remark that the modeling framework can be extended to study other infectious pathogens. CONCLUSIONS: Our findings show a link between the molecular-level mutation activity of SARS-CoV-2 and population-level transmission of COVID-19 to provide further evidence for a positive association between the D614G substitution and Rt. Future studies exploring the mechanism between SARS-CoV-2 mutations and COVID-19 infectivity are warranted.

Real-time quantification of the transmission advantage associated with a single mutation in pathogen genomes: a case study on the D614G substitution of SARS-CoV-2.

BACKGROUND: The COVID-19 pandemic poses serious threats to global health, and the emerging mutation in SARS-CoV-2 genomes, e.g., the D614G substitution, is one of the major challenges of disease control. Characterizing the role of the mutation activities is of importance to understand how the evolution of pathogen shapes the epidemiological outcomes at population scale. METHODS: We developed a statistical framework to reconstruct variant-specific reproduction numbers and estimate transmission advantage associated with the mutation activities marked by single substitution empirically. Using likelihood-based approach, the model is exemplified with the COVID-19 surveillance data from January 1 to June 30, 2020 in California, USA. We explore the potential of this framework to generate early warning signals for detecting transmission advantage on a real-time basis. RESULTS: The modelling framework in this study links together the mutation activity at molecular scale and COVID-19 transmissibility at population scale. We find a significant transmission advantage of COVID-19 associated with the D614G substitution, which increases the infectivity by 54% (95%CI: 36, 72). For the early alarming potentials, the analytical framework is demonstrated to detect this transmission advantage, before the mutation reaches dominance, on a real-time basis. CONCLUSIONS: We reported an evidence of transmission advantage associated with D614G substitution, and highlighted the real-time estimating potentials of modelling framework.

miR-605-5p promotes invasion and proliferation by targeting TNFAIP3 in non-small-cell lung cancer.

Lung cancer is an significant cause of death worldwide, and non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. MicroRNAs (miRNAs) have been identified to play key roles in NSCLC development. Recently, it has been reported that miR-605-5p is a cancer-related miRNA in several types of tumors. In this study, we study the role of miR-605-5p in NSCLC cells. We find that miR-605-5p is upregulated in NSCLC cells. Overexpression of miR-605-5p significantly promotes lung cancer invasion and migration in H460 and H1299 cells. Besides this, miR-605-5p also promotes lung cancer cell carcinoma proliferation and metastasis in vivo. However, downregulation of miR-605-5p inhibits cell invasion and migration by inhibiting lung cancer cell carcinoma proliferation and metastasis. In addition, the luciferase report assay identifies 3'-untranslated region tumor necrosis factor α-induced protein 3 (TNFAIP3) as a target of miR-605-5p. Silencing of TNFAIP3 promotes invasion and proliferation in lung cancer. In addition, the knockdown of TNFAIP3 restores the significant decrease in invasion and proliferation in miR-605-5p-inhibitor-transfected lung cancer cells. In conclusion, miR-605-5p promotes invasion and proliferation by targeting TNFAIP3 in NSCLC, and may provide possible biomarkers for NSCLC therapy.

Sirtuin 6 mitigated LPS-induced human umbilical vein endothelial cells inflammatory responses through modulating nuclear factor erythroid 2-related factor 2.

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) protects the lung from sepsis-induced injury through activating Nrf2-regulated multiple phase 2 detoxification genes, including NAD(P)H: quinine oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO1). Based on the positive effect of Sirtuin 6 on Nrf2, we aim to explore the potential role of SIRT6 in the mechanism of sepsis-induced acute lung injury (ALI). METHODS: Mouse models of sepsis were constructed by instilling intratracheal of lipopolysaccharide (LPS; 4 ml/kg). After 48-hour treatment, lung tissues were collected to measure the degree of lung injury. The SIRT6, siSIRT6, and siNrf2 plasmids were cotransfected into various concentrations of LPS-treated human umbilical vein endothelial cells (HUVECs; 0, 1, 5, 10, and 50 µg/ml) using Lipofectamine 2000. Tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 levels were determined by enzyme-linked immunosorbent assay. Expression levels of SIRT6, Nrf2, NQO1, and HO1 was measured by quantitative polymerase chain reaction and Western blot analysis. Cell apoptosis was determined by flow cytometry. RESULTS: Lung tissues in the model group already had basic characteristics of ALI. Compared with the control model, TNF-α and IL-6 levels were much higher (P < 0.01), the levels of SIRT6, Nrf2, and Nrf2-modulated detoxification factors were downregulated (P < 0.01). SIRT6 overexpression decreased the apoptosis below to 10% (P < 0.01), significantly increased the Nrf2 expression, effectively inhibited TNF-α and IL-6 releases, and enhanced NQO1 and HO1 levels (P < 0.01). siNrf2 abolished the protective effects of SIRT6 overexpression, including increasing apoptosis and inhibiting anti-inflammatory and antioxidative genes expressions (P < 0.01). CONCLUSIONS: Our study suggested SIRT6 positively regulated Nrf2 expression and activated Nrf2-regulated anti-inflammatory and antioxidative enzymes, which could effectively mitigate LPS-induced HUVECs inflammatory responses. This might reflect the mechanism of ALI induced by sepsis.

Clinical diagnosis and mutation analysis of four Chinese families with succinic semialdehyde dehydrogenase deficiency.

BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessively-inherited defect of γ-aminobutyric acid (GABA) metabolism. The absence of SSADH, which is encoded by aldehyde dehydrogenase family 5 member A1 (ALDH5A1) gene, leads to the accumulation of GABA and γ-hydroxybutyric acid (GHB). Few cases with SSADH deficiency were reported in China. CASE PRESENTATION: In this study, four Chinese patients were diagnosed with SSADH deficiency in Tianjin Children's Hospital. We conducted a multidimensional analysis with magnetic resonance imaging (MRI) of the head, semi quantitative detection of urine organic acid using gas chromatography-mass spectrometry, and analysis of ALDH5A1 gene mutations. Two of the patients were admitted to the hospital due to convulsions, and all patients were associated with developmental delay. Cerebral MRI showed symmetrical hyperintense signal of bilateral globus pallidus and basal ganglia in patient 1; hyperintensity of bilateral frontal-parietal lobe, widened ventricle and sulci in patient 2; and widened ventricle and sulci in patient 4. Electroencephalogram (EEG) revealed the background activity of epilepsy in patient 1 and the disappearance of sleep spindle in patient 2. Urine organic acid analysis revealed elevated GHB in all the patients. Mutational analysis, which was performed by sequencing the 10 exons and flanking the intronic regions of ALDH5A1 gene for all the patients, revealed mutations at five sites. Two cases had homozygous mutations with c.1529C > T and c.800 T > G respectively, whereas the remaining two had different compound heterozygous mutations including c.527G > A/c.691G > A and c.1344-2delA/c.1529C > T. Although these four mutations have been described previously, the homozygous mutation of c.800 T > G in ALDH5A1 gene is a novel discovery. CONCLUSION: SSADH deficiency is diagnosed based on the elevated GHB and 4, 5DHHA by urinary organic acid analysis. We describe a novel mutation p.V267G (c.800 T > G) located in the NAD binding domain, which is possibly crucial for this disease's severity. Our study expands the mutation spectrum of ALDH5A1 and highlights the importance of molecular genetic evaluation in patients with SSADH deficiency.

Correction to: Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China.

The original version of this article unfortunately contained an error.

Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China.

PURPOSE: Neural tube defects (NTDs) are one of the most prevalent and the most severe congenital malformations worldwide. Studies have confirmed that folic acid supplementation could effectively reduce NTDs risk, but the genetic mechanism remains unclear. In this study, we explored association of single nucleotide polymorphisms (SNP) within folate metabolic pathway genes with NTDs in Han population of Northern China. METHODS: We performed a case-control study to compare genotype and allele distributions of SNPs in 152 patients with NTDs and 169 controls. A total of 16 SNPs within five genes were genotyped by the Sequenom MassARRAY assay. RESULTS: Our results indicated that three SNPs associated significantly with NTDs (P<0.05). For rs2236225 within MTHFD1, children with allele A or genotype AA had a high NTDs risk (OR=1.500, 95%CI=1.061~2.120; OR=2.862, 95%CI=1.022~8.015, respectively). For rs1801133 within MTHFR, NTDs risk markedly increased in patients with allele T or genotype TT (OR=1.552, 95%CI=1.130~2.131; OR=2.344, 95%CI=1.233~4.457, respectively). For rs1801394 within MTRR, children carrying allele G and genotype GG had a higher NTDs risk (OR=1.533, 95%CI=1.102~2.188; OR=2.355, 95%CI=1.044~5.312, respectively). CONCLUSIONS: Our results suggest that rs2236225 of MTHFD1 gene, rs1801133 of MTHFR gene and rs1801394 of MTRR gene were associated with NTDs in Han population of Northern China.

Association of neural tube defects with gene polymorphisms in one-carbon metabolic pathway.

PURPOSE: Neural tube defects (NTDs) are common congenital malformations. In this study, we aimed to explore the association between single nucleotide polymorphisms (SNPs) related to one-carbon metabolism (OCM) and NTDs in Han population of Northern China. METHODS: A case-control study was conducted in 152 children with NTDs and 169 controls. Twenty-nine SNPs in five genes were genotyped by Sequenom MassARRAY technology, and haplotype analysis was done by Haploview4.2 software. RESULTS: The allele frequency of rs3733890 in betaine-homocysteine methyltransferase (BHMT) gene was statistically different between NTDs and control groups (P = 0.041), and the children with A allele had higher risk for NTDs than G allele (OR = 1.408, 95%CI 1.013-1.956). In addition, there was a statistical difference in the allele and genotype frequencies of rs1051266 in reduced folate carrier1 (RFC1) gene between cases and controls (P = 0.013, 0.034), and the risk for NTDs was also higher in children with G allele and GG genotype, compared with A allele and AA genotype, respectively (OR = 1.492, 95%CI 1.089-2.044; OR = 2.020, 95%CI 1.081-3.780). The statistical significant difference was also found in allele frequency of rs1805087 in methionine synthetase (MTR) gene between cases and controls (P = 0.031), and the children with G allele were associated with an increased NTDs risk, compared with A allele (OR = 1.664, 95%CI 1.045-2.647). Meanwhile, haplotype analysis showed C-A-A-A haplotype of BHMT, and G-G-G-T haplotype of RFC1 was correlated with an increased risk of NTDs, but C-G-A-A haplotype of BHMT and G-G-C-A haplotype of MTR might decrease the risk of NTDs. CONCLUSIONS: The BHMT gene rs3733890, RFC1 gene rs1051266 and MTR gene rs1805087 were associated with the occurrence of NTDs in Han population of Northern China. It was confirmed that the gene variation related to OCM was one of the susceptibility factors for NTDs.

Choroid Plexus Papilloma of Bilateral Lateral Ventricle in an Infant Conceived by in vitro Fertilization.

Choroid plexus papilloma (CPP) is a rare benign tumor of the central nervous system. Bilateral lateral ventricle CPP is extremely uncommon. In this case report, we described a case of bilateral lateral ventricle CPP in a 4-month-old female patient conceived by in vitro fertilization (IVF). Neurological examination and imaging were performed. In neurological examination, meningeal irritation signs and sunset phenomenon were positive. Brain computed tomography (CT) and magnetic resonance imaging (MRI) displayed masses located in the trigone of the bilateral lateral ventricle with hydrocephalus. Contrast-enhanced MRI showed intense homogeneous enhancement. The diagnoses of bilateral lateral ventricle CPP related to hydrocephalus and extravasation of cerebrospinal fluid (CSF) were made. Repeated surgical procedures via parietotemporal craniotomy were performed, and the diagnosis was confirmed by histopathology examination. The patient presented with delayed development during a follow-up period of 1 year. In conclusion, imaging is an effective approach of investigation. CPP could be highly suspected according to the features of hydrocephalus, lobulated appearance, and homogeneous enhancement on imaging. Total surgical removal is a valid curative method for CPP.

A unique methylation pattern co-segregates with neural tube defect statuses in Han Chinese pedigrees.

Neural tube defects (NTDs) are a complex trait associated with gene-environment interactions. Folic acid deficiency and planar cell polarity gene mutations account for some NTD cases; however, the etiology of NTDs is still little understood. In this study, in three Han Chinese NTD pedigrees (two with multiple affected children), with no information on folic acid deficiency or supplement, we examined genome-wide methylation profiles of each individual in these families. We further compared methylation status among cases and normal individuals within the pedigrees. A unique methylation pattern co-segregated with affected status: NTD cases had more hypermethylated than hypomethylated CpG islands; genes with different methylations clustered in pathways associated with epithelial-to-mesenchymal transition (ZEB2, SMAD6, and CDH23), folic acid/homocysteine metabolism (MTHFD1L), transcription/nuclear factors (HDAC4, HOXB7, SOX18), cell migration/motility/adhesion, insulin and cell growth, and neuron/axon development. Although the genetics of NTD are likely complex, epigenetic changes may concentrate in certain key pathways.

Identification of lncRNA-based regulatory mechanisms of Takifugu rubripes growth traits in fast and slow-growing family lines.

Family selection is an important method in fish aquaculture because growth is the most important economic trait. Fast-and slow-growing families of tiger puffer fish (Takifugu rubripes) have been established through family selection. The development of teleost fish is primarily controlled by the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis that includes the hypothalamus-pituitary-liver. In this study, the molecular mechanisms underlying T. rubripes growth were analyzed by comparing transcriptomes from fast- and slow-growing families. The expressions of 214 lncRNAs were upregulated, and those of 226 were downregulated in the brain tissues of the fast-growing T. rubripes family compared to those of the slow-growing family. Differentially expressed lncRNAs centrally regulate mitogen-activated protein kinase (MAPK) and forkhead box O (FoxO) signaling pathways. Based on the results of lncRNA-gene network construction, we found that lncRNA3133.13, lncRNA23169.1, lncRNA23145.1, and lncRNA23141.3 regulated all four genes (igf1, mdm2, flt3, and cwf19l1). In addition, lncRNA7184.10 may be a negative regulator of rasgrp2 and a positive regulator of gadd45ga, foxo3b, and dusp5. These target genes are associated with the growth and development of organisms through the PI3K/AKT and MAPK/ERK pathways. Overall, transcriptomic analyses of fast- and slow-growing families of T. rubripes provided insights into the molecular mechanisms of teleost fish growth rates. Further, these analyses provide evidence for key genes related to growth regulation and the lncRNA expression regulatory network that will provide a framework for improving puffer fish germplasm resources.

Predictive evolutionary modelling for influenza virus by site-based dynamics of mutations.

Influenza virus continuously evolves to escape human adaptive immunity and generates seasonal epidemics. Therefore, influenza vaccine strains need to be updated annually for the upcoming flu season to ensure vaccine effectiveness. We develop a computational approach, beth-1, to forecast virus evolution and select representative virus for influenza vaccine. The method involves modelling site-wise mutation fitness. Informed by virus genome and population sero-positivity, we calibrate transition time of mutations and project the fitness landscape to future time, based on which beth-1 selects the optimal vaccine strain. In season-to-season prediction in historical data for the influenza A pH1N1 and H3N2 viruses, beth-1 demonstrates superior genetic matching compared to existing approaches. In prospective validations, the model shows superior or non-inferior genetic matching and neutralization against circulating virus in mice immunization experiments compared to the current vaccine. The method offers a promising and ready-to-use tool to facilitate vaccine strain selection for the influenza virus through capturing heterogeneous evolutionary dynamics over genome space-time and linking molecular variants to population immune response.

The mechanism shaping the logistic growth of mutation proportion in epidemics at population scale.

Virus evolution is a common process of pathogen adaption to host population and environment. Frequently, a small but important fraction of virus mutations are reported to contribute to higher risks of host infection, which is one of the major determinants of infectious diseases outbreaks at population scale. The key mutations contributing to transmission advantage of a genetic variant often grow and reach fixation rapidly. Based on classic epidemiology theories of disease transmission, we proposed a mechanistic explanation of the process that between-host transmission advantage may shape the observed logistic curve of the mutation proportion in population. The logistic growth of mutation is further generalized by incorporating time-varying selective pressure to account for impacts of external factors on pathogen adaptiveness. The proposed model is implemented in real-world data of COVID-19 to capture the emerging trends and changing dynamics of the B.1.1.7 strains of SARS-CoV-2 in England. The model characterizes and establishes the underlying theoretical mechanism that shapes the logistic growth of mutation in population.

C, N, and P stoichiometry for leaf litter of 62 woody species in a subtropical evergreen broadleaved forest.

To understand leaf litter stoichiometry in a subtropical evergreen broadleaved forest, we measured the contents of carbon (C), nitrogen (N) and phosphorus (P) in leaf litters of 62 main woody species in a natural forest of C. kawakamii Nature Reserve in Sanming, Fujian Province. Differences in leaf litter stoichiometry were analyzed across leaf forms (evergreen, deciduous), life forms (tree, semi-tree or shrub), and main families. Additionally, the phylogenetic signal was measured by Blomberg's K to explore the correlation between family level differentiation time and litter stoichiometry. Our results showed that the contents of C, N and P in the litter of 62 woody species were 405.97-512.16, 4.45-27.11, and 0.21-2.53 g·kg-1, respectively. C/N, C/P and N/P were 18.6-106.2, 195.9-2146.8, and 3.5-68.9, respectively. Leaf litter P content of evergreen tree species was significantly lower than that of deciduous tree species, and C/P and N/P of evergreen tree species were significantly higher than those of deciduous tree species. There was no significant difference in C, N content and C/N between the two leaf forms. There was no significant difference in litter stoichiometry among trees, semi-trees and shrubs. Effects of phylogeny on C, N content and C/N in leaf litter was significant, but not on P content, C/P and N/P. Family differentiation time was negatively correlated with leaf litter N content, and positively correlated with C/N. Leaf litter of Fagaceae had high C and N contents, C/P and N/P, and low P content and C/N, with an opposite trend for Sapidaceae. Our findings indicated that litter in subtropical forest had high C, N content and N/P, but low P content, C/N, and C/P, compared with the global scale average value. Litter of tree species in older sequence of evolutionary development had lower N content but higher C/N. There was no difference of leaf litter stoichiometry among life forms. There were significant differences in P content, C/P, and N/P between different leaf forms, with a characteristic of convergence.

Domestication and geographic origin of Oryza sativa in China: insights from multilocus analysis of nucleotide variation of O. sativa and O. rufipogon.

Previous studies have indicated that China is one of the domestication centres of Asian cultivated rice (Oryza sativa), and common wild rice (O. rufipogon) is the progenitor of O. sativa. However, the number of domestication times and the geographic origin of Asian cultivated rice in China are still under debate. In this study, 100 accessions of Asian cultivated rice and 111 accessions of common wild rice in China were selected to examine the relationship between O. sativa and O. rufipogon and thereby infer the domestication and evolution of O. sativa in China through sequence analyses of six gene regions, trnC-ycf6 in chloroplast genomes, cox3 in mitochondrial genomes and ITS, Ehd1, Waxy, Hd1 in nuclear genomes. The results indicated that the two subspecies of O. sativa (indica and japonica) were domesticated independently from different populations of O. rufipogon with gene flow occurring later from japonica to indica; Southern China was the genetic diversity centre of O. rufipogon, and the Pearl River basin near the Tropic of Cancer was the domestication centre of O. sativa in China.

Differences in the case fatality risks associated with SARS-CoV-2 Delta and non-Delta variants in relation to vaccine coverage: An early ecological study in the United Kingdom.

The circulation of SARS-CoV-2 Delta (i.e., B.1.617.2) variants challenges the pandemic control. Our analysis showed that in the United Kingdom (UK), the reported case fatality ratio (CFR) decreased from May to July 2021 for non-Delta variant, whereas the decreasing trends of the CFR of Delta variant appeared weak and insignificant. The association between vaccine coverage and CFR might be stratified by different circulating variants. Due to the limitation of ecological study design, the interpretation of our results should be treated with caution.

Quantifying the effect of government interventions and virus mutations on transmission advantage during COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a major public health threat. This study aims to evaluate the effect of virus mutation activities and policy interventions on COVID-19 transmissibility in Hong Kong. METHODS: In this study, we integrated the genetic activities of multiple proteins, and quantified the effect of government interventions and mutation activities against the time-varying effective reproduction number Rt. FINDINGS: We found a significantly positive relationship between Rt and mutation activities and a significantly negative relationship between Rt and government interventions. The results showed that the mutations that contributed most to the increase of Rt were from the spike, nucleocapsid and ORF1b genes. Policy of prohibition on group gathering was estimated to have the largest impact on mitigating virus transmissibility. The model explained 63.2% of the Rt variability with the R2. CONCLUSION: Our study provided a convenient framework to estimate the effect of genetic contribution and government interventions on pathogen transmissibility. We showed that the S, N and ORF1b protein had significant contribution to the increase of transmissibility of SARS-CoV-2 in Hong Kong, while restrictions of public gathering and suspension of face-to-face class are the most effective government interventions strategies.

Temporal Patterns in the Evolutionary Genetic Distance of SARS-CoV-2 during the COVID-19 Pandemic.

During coronavirus disease 2019 (COVID-19) pandemic, the genetic mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred frequently. Some mutations in the spike protein are considered to promote transmissibility of the virus, while the mutation patterns in other proteins are less studied and may also be important in understanding the characteristics of SARS-CoV-2. We used the sequencing data of SARS-CoV-2 strains in California to investigate the time-varying patterns of the evolutionary genetic distance. The accumulative genetic distances were quantified across different time periods and in different viral proteins. The increasing trends of genetic distance were observed in spike protein (S protein), the RNA-dependent RNA polymerase (RdRp) region and nonstructural protein 3 (nsp3) of open reading frame 1 (ORF1), and nucleocapsid protein (N protein). The genetic distances in ORF3a, ORF8, and nsp2 of ORF1 started to diverge from their original variants after September 2020. By contrast, mutations in other proteins appeared transiently, and no evident increasing trend was observed in the genetic distance to the original variants. This study presents distinct patterns of the SARS-CoV-2 mutations across multiple proteins from the aspect of genetic distance. Future investigation shall be conducted to study the effects of accumulative mutations on epidemics characteristics.