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PubMed2025

Deep Sequencing Reveals Dual Evolution of SARS-CoV-2: Insights Into Defective Genomes From Wuhan-Hu-1 Variants to Omicron Subvariants.

SARS-CoV-2 has evolved from early variants dominating the first (B.1.5, B.1.1) and second (B.1.177) pandemic waves, which exhibited a higher frequency of minority mutants with deletions leading to Defective Viral Genomes (DVGs) in the spike region near the S1/S2 cleavage site than the Alpha, Beta, and Delta variants. The emergence of Omicron has significantly altered the dominant variant profile, with Omicron subvariants now representing 100% of circulating viruses. To monitor the evolution and adaptation of Omicron in the human population, a deep-sequencing study was performed in RNA samples of BA.1, BA.1.1, BA.2, BA.5, BQ.1.1, XBB.1.5 and BA.2.86 Omicron subvariants. The findings reveal two occurrences of similar evolutionary patterns within SARS-CoV-2 characterized by a shift from a significant to a very low production of DVGs. This event suggests that DVGs might play a role in the virus's spread and adaptation for persistence in infected humans.

SARS-CoV-2↗
PubMed1998

Fertile homozygous transgenic mice expressing a functional truncated herpes simplex thymidine kinase delta TK gene.

Dividing cells expressing the Herpes simplex type 1 thymidine kinase (TK) can be killed upon ganciclovir treatment. Likewise, conditional cell knock-out can be obtained in transgenic mice expressing a TK gene placed under the control of tissue-specific regulatory sequences. Such animals provide powerful experimental systems for assessing the functional role of specific cell populations through their time-controlled ablation. However, whatever the regulatory sequences used, a leaky toxic overexpression of TK in testis renders male TK-transgenic mice sterile and prevents the generation of homozygous TK-expressing animals. To solve this problem, we designed a truncated TK variant (delta TK) not expressed in the testis. We generated transgenic mice expressing delta TK under the control of lymphocyte-specific regulatory sequences derived from the CD4 gene. The delta TK protein expressed in T-lymphocytes allowed the conditional ablation of activated T-cells in vitro and in vivo. Importantly, for one transgenic line we could generate fertile homozygous mice harboring a functional delta TK transgene. delta TK should thus dramatically facilitate the development of transgenic mice expressing a conditional suicide gene.

Animals↗
PubMed2002

Identification of amino acids involved in protein structural uniqueness: implication for de novo protein design.

Structural uniqueness is characteristic of native proteins and is essential to express their biological functions. The major factors that bring about the uniqueness are specific interactions between hydrophobic residues and their unique packing in the protein core. To find the origin of the uniqueness in their amino acid sequences, we analyzed the distribution of the side chain rotational isomers (rotamers) of hydrophobic amino acids in protein tertiary structures and derived deltaS(contact), the conformational-entropy changes of side chains by residue-residue contacts in each secondary structure. The deltaS(contact) values indicate distinct tendencies of the residue pairs to restrict side chain conformation by inter-residue contacts. Of the hydrophobic residues in alpha-helices, aliphatic residues (Leu, Val, Ile) strongly restrict the side chain conformations of each other. In beta-sheets, Met is most strongly restricted by contact with Ile, whereas Leu, Val and Ile are less affected by other residues in contact than those in alpha-helices. In designed and native protein variants, deltaS(contact) was found to correlate with the folding-unfolding cooperativity. Thus, it can be used as a specificity parameter for designing artificial proteins with a unique structure.

Amino Acid Sequence↗
PubMed2002

Fetal hemoglobin elevation in Hb Lepore heterozygotes and its correlation with beta globin cluster linked determinants.

We have analysed, at the hematological and molecular level, 51 Hb lepore heterozygotes and three compound heterozygotes for Hb Lepore and HbS (HbLep/HbS) in 26 unselected Portuguese families. The Lepore Boston variant was present in one family, in association with classical haplotype V. All of the other Lepore alleles present haplotype III in association with XmnI (+)5' of (G)gamma gene, in tight linkage disequilibrium to the major mutation found in the Portuguese population, the Lepore Baltimore variant ( delta(68Leu)-beta(84Thr)). The three compound heterozygotes are the first HbLep/HbS individuals reported in the literature, with the Lepore Baltimore mutation linked to haplotype III. In agreement with other studies, these Lepore Baltimore heterozygotes have higher HbF (1.4-14.1% of total hemoglobin) than published cases of Lepore Boston (0.8-5.4%), which is associated with XmnI(-). Among the Lepore Baltimore heterozygotes, the (AT)xTy repeat region at -540 bp of the beta globin gene in trans to the Lepore chromosome, can account for much of the variability in HbF level. The allele (AT)7T7 is associated with lower HbF, and (AT)9T5 is associated with higher HbF. As we previously reported for beta thalassemic carriers, we observe in Lepore Baltimore carriers an effector in trans, linked to the (AT)xTy sequence, acting as an HPFH (Hereditary Persistence of Fetal Hemoglobin) determinant.

Adolescent↗
PubMed1993

An insertion-deletion event in murine immunoglobulin kappa gene resembles mutations at heavy-chain disease loci.

The analysis of spontaneous somatic mutants gives insights into the regulation of gene expression. Human heavy-chain disease (HCD) is a monoclonal lymphoproliferative disorder characterized by the presence of truncated immunoglobulin (Ig) heavy chains without associated light chains. To better understand the molecular mechanisms leading to the loss of light-chain production, we have examined a murine cell line model of heavy-chain disease. R15, a spontaneous mutant of the IgA, kappa-producing myeloma cell line W3129, produces heavy chain but no light chain. The variant delta 15 derived from R15 resembles human HCD in that it secretes a shortened heavy chain with no associated light chain. Cloning and analysis of the R15 kappa light-chain gene revealed that a 358-nucleotide insertion of unknown origin replaced 22 bases of the wild-type leader-variable region (L-V) intron (IVS). Although this genomic change left the light-chain exons and known regulatory elements intact, it altered the mRNA processing pathway, yielding two alternative RNA products, neither of which encodes a functional protein. This mutant therefore provides new insights into how genomic changes can influence gene expression.

Animals↗
PubMed2002

Epidemiological profile of hemoglobinopathies in the Mauritanian population.

We performed a study of hemoglobin in 700 blood donors attending the Centre Hospitalier National de Nouakchott in Mauritania. We detected 116 cases of anomalies corresponding to a global prevalence of 16.6%. The analysis of the samples studied showed that 72.3 % of the donors were Blacks and 28.7 % were White Maurs ( Maures blancs). In the Black population the prevalence of hemoglobinopathies is 21.44% whereas among the White Maurs it is 4.47%. In this study, the six ethnic groups that constitute the Mauritanian population were also represented in the sample, but with different numbers. We noted some differences in the repartition of anomalies among these groups. The hemoglobin anomalies that were found are sickle cell anemia, beta-thalassemia, and delta-variant, all in heterozygous form. Geographical repartition revealed that the hemoglobin abnormalities are mostly encountered in the Southeast and the Southwestern parts of the country, which could be considered areas of high risk for hemoglobinopathies.

Blood Donors↗
PubMed1994

The dimerization domain of R6K plasmid replication initiator protein pi revealed by analysis of a truncated protein.

Replication of plasmid R6K is controlled by the homodimeric initiator protein pi, which binds to seven 22-bp direct repeats (iterons) in the gamma-origin. One of the genetically engineered pi variants (delta C164 pi) contains only the 164 N-terminal amino acids (aa) of the 305-aa pi molecule. This truncated pi polypeptide retains the ability to function as a specific inhibitor of R6K replication in vivo, though it neither drives replication, nor binds to iterons [Greener et al., Mol. Gen. Genet. 224 (1990) 24-32]. In order to define the region of pi responsible for dimerization, we have performed chemical crosslinking experiments with purified delta C164 pi and shown that this polypeptide is dimeric. We did not observe an exchange between protein monomers upon mixing of wild-type pi and delta C164 pi homodimers. However, heterodimers, as well as each type of homodimers, were formed when these polypeptides refolded after guanidine hydrochloride treatment. Thus, both dimerization and dimer stability are determined by the N-terminal domain of pi. We speculate that these properties might depend on the leucine zipper and RGD motifs that have been identified in the two regions of the N-terminal domain of pi.

Amino Acid Sequence↗
PubMed1993

Energetic cost and structural consequences of burying a hydroxyl group within the core of a protein determined from Ala-->Ser and Val-->Thr substitutions in T4 lysozyme.

In order to determine the thermodynamic cost of introducing a polar group within the core of a protein, a series of nine Ala-->Ser and 3 Val-->Thr substitutions was constructed in T4 lysozyme. The sites were all within alpha-helices but ranged from fully solvent-exposed to totally buried. The range of destabilization incurred by the Ala-->Ser substitutions was found to be very similar to that for the Val-->Thr replacements. For the solvent-exposed and partly exposed sites the destabilization was modest (approximately less than 0.5 kcal/mol). For the completely buried sites the destabilization was larger, but variable (approximately 1-3 kcal/mol). Crystal structure determinations showed that the Ala-->Ser mutant structures were, in general, very similar to their wild-type counterparts, even though the replacements introduce a hydroxyl group. This is in part because the introduced serines are all within alpha-helices and at congested sites can avoid steric clashes with surrounding atoms by making a hydrogen bond to a backbone carbonyl oxygen in the preceding turn of the helix. The three substituted threonine side chains essentially superimpose on their valine counterparts but display somewhat larger conformational adjustments. The results illustrate how a protein structure will adapt in different ways to avoid the presence of an unsatisfied hydrogen bond donor or acceptor. In the most extreme case, Val 149-->Thr, which is also the most destabilizing variant (delta delta G = 2.8 kcal/mol), a water molecule is incorporated in the mutant structure in order to provide a hydrogen-bonding partner. The results are consistent with the view that many hydrogen bonds within proteins contribute only marginally to stability but that noncharged polar groups that lack a hydrogen-bonding partner are very destabilizing (delta delta G approximately greater than 3 kcal/mol). Supportive of other studies, the alpha-helix propensity of alanine is seen to be higher than that of serine (delta delta G = 0.46 +/- 0.04 kcal/mol), while threonine and valine are similar in alpha-helix propensity.

Alanine↗
PubMed2004

Normal modes and frequencies from covariances in molecular dynamics or Monte Carlo simulations.

We propose a simple method to obtain normal modes (NMs) and their characteristic frequencies from molecular dynamics or Monte Carlo simulations at any temperature. The resulting NM are consistent with the vibrational density of states (DOS) (every feature of the DOS can be attributed to one or few NMs). At low temperatures they coincide with the ones obtained from the Hessian matrix. We define the NMs (rho(i)) by imposing the condition that their velocities be uncorrelated to each other: rho(i)(t)rho(j)(t) proportional, variant delta(ij), where denotes time average and delta(ij) is Kronecker's delta. With this definition the modes are the eigenvectors of the matrix K(ij)(v)=1/2 [i, j=1,...,3N (N being the number of atoms); m are masses and v atomic velocities]. The eigenvalues of K(ij)(v), lambda(i)(v), represent the kinetic energy in each NM. The ratio between the eigenvalues (lambda(i)(v)) and those obtained using positions (lambda(i)(r)), accelerations (lambda(i)(a)) in K(ij)(v) instead of velocities are a very good approximation to the mode frequencies: 2pinu(i) approximately (lambda(i)(v)/lambda(i)(x))((1/2)) approximately (lambda(i)(a)/lambda(i)(x))((1/4)). We demonstrate the new method using with two cases: an isolated water molecule and a crystalline polymer.

Journal Article↗
PubMed2004

The long and short flavodoxins: II. The role of the differentiating loop in apoflavodoxin stability and folding mechanism.

Flavodoxins are classified in two groups according to the presence or absence of a approximately 20-residue loop of unknown function. In the accompanying paper (36), we have shown that the differentiating loop from the long-chain Anabaena PCC 7119 flavodoxin is a peripheral structural element that can be removed without preventing the proper folding of the apoprotein. Here we investigate the role played by the loop in the stability and folding mechanism of flavodoxin by comparing the equilibrium and kinetic behavior of the full-length protein with that of loop-lacking, shortened variants. We show that, when the loop is removed, the three-state equilibrium thermal unfolding of apoflavodoxin becomes two-state. Thus, the loop is responsible for the complexity shown by long-chain apoflavodoxins toward thermal denaturation. As for the folding reaction, both shortened and wild type apoflavodoxins display three-state behavior but their folding mechanisms clearly differ. Whereas the full-length protein populates an essentially off-pathway transient intermediate, the additional state observed in the folding of the shortened variant analyzed seems to be simply an alternative native conformation. This finding suggests that the long loop may also be responsible for the accumulation of the kinetic intermediate observed in the full-length protein. Most revealing, however, is that the influence of the loop on the overall conformational stability of apoflavodoxin is quite low and the natively folded shortened variant Delta(120-139) is almost as stable as the wild type protein. The fact that the loop, which is not required for a proper folding of the polypeptide, does not even play a significant role in increasing the conformational stability of the protein supports our proposal (36) that the differentiating loop of long-chain flavodoxins may be related to a recognition function, rather than serving a structural purpose.

Anabaena↗
PubMed1996

Biopolymer-surfactant interaction: 4. Kinetics of binding of cetyltrimethyl ammonium bromide with gelatin, hemoglobin, beta-lactoglobulin and lysozyme.

The binding of CTAB with the proteins, gelatin, hemoglobin, beta-lactoglobulin and lysozyme follow first order kinetics and occurs either in two or three distinct stages. The number of stages depends on the overall configuration of the biopolymers. The denatured protein, gelatin has shown three-stage kinetics under all conditions, whereas the native proteins, hemoglobin, beta-lactoglobulin and lysozyme have exhibited two stage kinetics. Heat treated lysozyme in 8 mol dm-3 urea medium has also shown a two-stage kinetics. On the basis of non interacting binding sites on the proteins and independent sequential binding, the rates of reaction have been observed to increase with temperature and follow the trend k1 >> k2 > k3. The interaction of CTA+ with the proteins is both electrostatic and hydrophobic. Hemoglobin has shown maximum reaction rate whereas, beta-lactoglobulin has shown a minimum. The activation parameters for the kinetic process have exhibited almost non-variant delta G++ and delta H++ < T delta S++. The formation of activation complex in the Eyring model is entropy controlled so also the overall kinetics. An isokinetic entropy-enthalpy compensation phenomenon has been observed for the respective kinetic stages.

Biopolymers↗
PubMed1994

Mutational analysis and molecular modeling of the N-terminal kringle-containing domain of hepatocyte growth factor identifies amino acid side chains important for interaction with the c-Met receptor.

The hepatocyte growth factor receptor (HGFr) transduces a wide range of biological signals, including mitogenesis, motogenesis and morphogenesis. We recently localized a region within the N-terminal 175 amino acids of hepatocyte growth factor (HGF), termed HGF/NK1, that is necessary and sufficient for binding to the HGFr. HGF/NK1 contains an as-yet structurally undefined N-terminal region followed by the first of four HGF kringles. We have used a combination of molecular modeling and mutagenesis to dissect the function of this region of HGF. Two mutation-sensitive patches on the proposed surface regions of HGF kringle one (K1) were identified. The first patch consists of residues E159, S161, E195 and R197, all of which are predicted to be close to each other in the tertiary structure of K1. The second patch, lying on the opposite side of the kringle, consists of residues D171 and Q173. Mutational analysis of the N-terminal region of HGF identified residue D117 which also appeared to influence receptor binding. We also investigated the properties of a naturally occurring HGF variant (delta 5-HGF) that arises from an alternatively spliced transcript and therefore lacks five residues within K1. Our data suggest that in wild-type HGF, F162 is crucial in maintaining the hydrophobic core of the kringle. In delta 5-HGF, the loss of this residue is compensated for by a functional substitution of F162 with Y167, which is predicted to occupy the delta 5-HGF K1 core. Comparison of the models of wild-type and delta 5 kringles reveals that the positions of the presumed receptor binding determinants remain unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1999

Dynamics of irregular copolymers.

Reptation dynamics of AB copolymers with irregular chemical structure are considered theoretically. It is shown that interactions between A and B monomers could result in a significant slowdown of copolymer dynamics in the disordered (macroscopically homogeneous) state. The dynamical copolymer length N* showing the crossover to the strongly retarded dynamics is calculated. It is shown that contour-length fluctuations (internal reptation modes) give rise to a strong reduction of the slowdown effect and to a strong increase of N* which becomes unrealistically high in the case of a genuinely random chemical structure. The following scaling dependence of N* is predicted for irregular block copolymers: N* proportional, variant delta(-8)chi(-8)n(-8)(0)N(3)(e), where delta is the degree of block polydispersity, chi the Flory AB interaction parameter, and n(0) the mean block length. The strongest dynamical effect of AB interactions is predicted for correlated random copolymers near the critical point related to the formation of microdomain superstructures.

Journal Article↗
PubMed1991

Thrombin cleavage analysis of a novel antihaemophilic factor variant, factor VIII delta II.

Factor VIII delta II is a genetically engineered deletion variant of factor VIII expressed by recombinant Chinese hamster ovary cells, in which a major portion of the central (B) domain and a part of the light chain (Pro771-Asp1666) are missing. After immunoaffinity purification, the kinetics of thrombin cleavage of the novel molecule was analysed by SDS/PAGE, Western blotting and N-terminal amino acid sequencing. Thrombin first cleaves factor VIII delta II at Arg740-Ser741 to generate the 90-kDa heavy chain and an 80-kDa fusion polypeptide consisting of the remaining portion of the B domain and the 73-kDa light chain. The 90-kDa fragment is further cleaved, giving rise to 50-kDa and 40-kDa fragments while the 80-kDa fragment generates a 71/73-kDa doublet. The 71/73-kDa doublet, 50-kDa and 40-kDa fragments were further analysed by N-terminal amino acid sequencing and found to correspond to the predicted amino acid sequences. Our study shows that, in spite of the 900 amino acid deletion present in factor VIII delta II, the essential structural elements required for thrombin activation are conserved.

Amino Acid Sequence↗
PubMed2003

Abnormal hemoglobins found in Hunan.

OBJECTIVE: To summarize the results of general survey, primary structure analysis and related functional studies of abnormal hemoglobins (Hbs) found in Hunan Province. DATA SOURCES: International Hb journals, Chinese biochemical and biomedical journals and other articles relevant to hematology. STUDY SELECTION: All Hb variants found in Hunan and identified by primary structure analysis during 1980 - 1991 were included. DATA EXTRACTION: Data concerning 11 types of Hb variants found in 3 districts and 7 counties in Hunan Province were briefly documented. Their frequencies of occurrence were calculated and their distributions among Han, Yao, Tujia and Dong ethnic groups were listed. RESULTS: Thirty-six cases with abnormal Hb were identified out of 7412 individuals screened in Hunan. 11 different types of Hb variants were recognized by primary structure analysis in 19 propositi along with their family members, including 5 alpha-chain variants, 4 beta-chain variants, 1 delta-chain variant and 1 delta-beta chain fusion variant. Oxygen equilibrium characteristics, reaction dynamics, the rate of globin chain synthesis (RGCS), morphology observation by electron microscopy and DNA analysis were all used in the functional studies of hemoglobinopathies. CONCLUSIONS: The average incidence of abnormal Hbs in Hunan is 0.486%. In Jianghua County, whose inhabitants are mostly of the Yao ethnic group, the incidence is significantly higher (1.09%). Hb Jianghua [beta120(GH3) Lys-->lle] and Hb Shuangfeng (SF) [alpha27(B8) Glu-->Lys] were two new variants first reported in international literature; whereas Hb Lille [alpha74(EF3) Asp-->Ala], HbA(2) Flatbush [delta22(B4) Ala-->Glu] and Hb Lepore-Boston [delta87(F3)-beta116(G18)] were the first three instances to be found in China. Hb SF displayed an oxygen affinity 1.5-fold higher than that of HbA at pH 7.4 and 25 degrees C with its oxygen equilibrium curve shifted to the left. Reticulocytes of Hb SF heterozygote showed unbalanced RGCS, quite similar to that found in beta-thalassemia minor. Erythrocytes of Hb SF heterozygote were changed to spherocytes and began to lyse after incubation with sodium salicylate or sulfadiazine (pH 7.4, 37 degrees C) for 2 - 4 h. These findings explained the sudden attack of hemolytic anemia provoked by two drugs in Hb SF propositus. The genotype of a patient with Hb Q-H disease is identified as -,-/-,alpha(Q) by DNA restriction mapping.

Erythrocytes↗
PubMed1999

Adipocyte differentiation is modulated by secreted delta-like (dlk) variants and requires the expression of membrane-associated dlk.

Previous studies demonstrate that the delta-like (dlk) and preadipocyte factor 1 (Pref-1) genes encode similar proteins. Pref-1 is downregulated during adipocyte differentiation, and expression of ectopic Pref-1 inhibits adipogenesis. We explored whether dlk functions similarly to Pref-1 and studied the role of alternately spliced dlk variants encoding membrane-associated or -secreted forms. We also studied whether enforced downregulation of dlk/Pref-1 may enhance the differentiation response of non-committed cells. Ectopic expression of a potentially secreted dlk variant, conditioned media from dlk expressing cells or several individual epidermal-growth-factor-dlk peptides inhibited 3T3-L1 differentiation. This demonstrates that dlk and Pref-1 are functionally equivalent. dlk gene mRNA encoding for secreted variants decreased much faster than total dlk gene mRNA during differentiation of 3T3-L1 cells. In fact, total dlk or membrane-associated dlk protein expression increased during the first hours of differentiation. Cells sorted for lowest levels of dlk protein diminished or lost their ability to differentiate. These data suggest that membrane and secreted dlk protein variants play opposite roles in the control of adipogenesis. In addition, enforced downregulation of dlk protein expression in the weakly adipogenic Balb/c 3T3 cell line dramatically enhanced adipogenesis in response to insulin. These results indicate that dlk protein not only participates in processes leading to inhibition of adipogenesis but that the control of its expression and different spliced variants is essential for the adipogenic response to extracellular signals.

3T3 Cells↗
PubMed2006

Ethnicity affects the distribution of delta-aminolevulinic acid dehydratase (ALAD) genetic variants.

BACKGROUND: delta-Aminolevulinic acid dehydratase (ALAD) catalyzes the second step of heme synthesis. The ALAD gene shows a polymorphism (G-to-C transversion at position 177) leading to 2 alleles (ALAD1 and ALAD2) and 3 phenotypes (ALAD 1-1, ALAD 1-2 and ALAD 2-2). This polymorphism has been shown to affect lead toxicity and the risk of meningioma. In addition, there is little evidence showing interethnic differences in the distribution this polymorphism, especially in heterogeneous populations such as the present-day Brazilian population. We examined the distribution of genetic variants of the G177C ALAD polymorphism in black and white Brazilians. METHODS: We studied 115 subjects self-reported as black and 119 subjects as white (total N=234; 135 men and 99 women; age range: 18-60 years). Genomic DNA was extracted from venous blood and the genotypes for the ALAD polymorphism were determined by PCR followed by RFLP digestion and gel electrophoresis. RESULTS: We found a notable interethnic disparity in the distribution of G177C ALAD genotypes and alleles. The ALAD2 allele was more common in whites (12%) than in blacks (4%) (P<0.05). Correspondingly, the heterozygote (ALAD 1-2) or homozygote variant (ALAD 2-2) genotypes for this polymorphism were more common in whites than in blacks (P<0.05). CONCLUSIONS: The significant interethnic differences in the distribution of G177C ALAD variants found in the Brazilian population is consistent with differences previously reported in other countries. These findings may help us understand the interethnic disparities in susceptibility to lead toxicity and brain tumors.

Adolescent↗