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PubMed2003

Mammalian mutation pressure, synonymous codon choice, and mRNA degradation.

The usage of synonymous codons (SCs) in mammalian genes is highly correlated with local base composition and is therefore thought to be determined by mutation pressure. The usage is nonetheless structured. For instance, mammals share with Saccharomyces and Drosophila most preferences for the C-ending over the G-ending codon (or vice versa) within each fourfold-degenerate SC family and the fact that their SCs are placed along coding regions in ways that minimize the number of T|A and C|G dinucleotides ("|" being the codon boundary). TA and CG underrepresentations are observed everywhere in the mammalian genome affecting the SC usage, the amino acid composition of proteins, and the primary structure of introns and noncoding DNA. While the rarity of CG is ascribed to the high mutability of this dinucleotide, the rarity of TA in coding regions is considered adaptive because UA dinucleotides are cleaved by endoribonucleases. Here we present in vivo experimental evidence indicating that the number of T|A and/or C|G dinucleotides of a human gene can affect strongly the expression level and degradation of its mRNA. Our results are consistent with indirect evidence produced by other workers and with the detailed work that has been devoted to characterize UA cleavage in vitro and in vivo. We conclude that SC choice can influence strongly mRNA function and gene expression through effects not directly related to the codon-anticodon interaction. These effects should constrain heavily the nucleotide motif composition of the most abundant mRNAs in the transcriptome, in particular, their SC usage, a usage that must be reflected by cellular tRNA concentrations and thus defines for all other genes which SCs are translated fastest and most accurately. Furthermore, the need to avoid such effects genome-wide appears serious enough to have favored the evolution of biases in context-dependent mutation that reduce the occurrence of intrinsically unfavorable motifs, and/or, when possible, to have induced the molecular machinery mediating such effects to rely opportunistically on already existing motif rarities and abundances. This may explain why nucleotide motif preferences are very similar in transcribed and nontranscribed mammalian DNA even though the preferences appear to be adaptive only in transcribed DNA.

Animals↗
PubMed2024

A novel splice-altering TNC variant (c.5247A > T, p.Gly1749Gly) in an Chinese family with autosomal dominant non-syndromic hearing loss.

BACKGROUND: This study aims to analyze the pathogenic gene in a Chinese family with non-syndromic hearing loss and identify a novel mutation site in the TNC gene. METHODS: A five-generation Chinese family from Anhui Province, presenting with autosomal dominant non-syndromic hearing loss, was recruited for this study. By analyzing the family history, conducting clinical examinations, and performing genetic analysis, we have thoroughly investigated potential pathogenic factors in this family. The peripheral blood samples were obtained from 20 family members, and the pathogenic genes were identified through whole exome sequencing. Subsequently, the mutation of gene locus was confirmed using Sanger sequencing. The conservation of TNC mutation sites was assessed using Clustal Omega software. We utilized functional prediction software including dbscSNV_AdaBoost, dbscSNV_RandomForest, NNSplice, NetGene2, and Mutation Taster to accurately predict the pathogenicity of these mutations. Furthermore, exon deletions were validated through RT-PCR analysis. RESULTS: The family exhibited autosomal dominant, progressive, post-lingual, non-syndromic hearing loss. A novel synonymous variant (c.5247A > T, p.Gly1749Gly) in TNC was identified in affected members. This variant is situated at the exon-intron junction boundary towards the end of exon 18. Notably, glycine residue at position 1749 is highly conserved across various species. Bioinformatics analysis indicates that this synonymous mutation leads to the disruption of the 5' end donor splicing site in the 18th intron of the TNC gene. Meanwhile, verification experiments have demonstrated that this synonymous mutation disrupts the splicing process of exon 18, leading to complete exon 18 skipping and direct splicing between exons 17 and 19. CONCLUSION: This novel splice-altering variant (c.5247A > T, p.Gly1749Gly) in exon 18 of the TNC gene disrupts normal gene splicing and causes hearing loss among HBD families.

Adult↗
PubMed2005

Geographical distribution of selected and putatively neutral SNPs in Southeast Asian malaria parasites.

Loci targeted by directional selection are expected to show elevated geographical population structure relative to neutral loci, and a flurry of recent papers have used this rationale to search for genome regions involved in adaptation. Studies of functional mutations that are known to be under selection are particularly useful for assessing the utility of this approach. Antimalarial drug treatment regimes vary considerably between countries in Southeast Asia selecting for local adaptation at parasite loci underlying resistance. We compared the population structure revealed by 10 nonsynonymous mutations (nonsynonymous single-nucleotide polymorphisms [nsSNPs]) in four loci that are known to be involved in antimalarial drug resistance, with patterns revealed by 10 synonymous mutations (synonymous single-nucleotide polymorphisms [sSNPs]) in housekeeping genes or genes of unknown function in 755 Plasmodium falciparum infections collected from 13 populations in six Southeast Asian countries. Allele frequencies at known nsSNPs underlying resistance varied markedly between locations (F(ST) = 0.18-0.66), with the highest frequencies on the Thailand-Burma border and the lowest frequencies in neighboring Lao PDR. In contrast, we found weak but significant geographic structure (F(ST) = 0-0.14) for 8 of 10 sSNPs. Importantly, all 10 nsSNPs showed significantly higher F(ST) (P < 8 x 10(-5)) than simulated neutral expectations based on observed F(ST) values in the putatively neutral sSNPs. This result was unaffected by the methods used to estimate allele frequencies or the number of populations used in the simulations. Given that dense single-nucleotide polymorphism (SNP) maps and rapid SNP assay methods are now available for P. falciparum, comparing genetic differentiation across the genome may provide a valuable aid to identifying parasite loci underlying local adaptation to drug treatment regimes or other selective forces. However, the high proportion of polymorphic sites that appear to be under balancing selection (or linked to selected sites) in the P. falciparum genome violates the central assumption that selected sites are rare, which complicates identification of outlier loci, and suggests that caution is needed when using this approach.

Animals↗
PubMed2004

Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003.

BACKGROUND: The SARS coronavirus is the etiologic agent for the epidemic of the Severe Acute Respiratory Syndrome. The recent emergence of this new pathogen, the careful tracing of its transmission patterns, and the ability to propagate in culture allows the exploration of the mutational dynamics of the SARS-CoV in human populations. METHODS: We sequenced complete SARS-CoV genomes taken from primary human tissues (SIN3408, SIN3725V, SIN3765V), cultured isolates (SIN848, SIN846, SIN842, SIN845, SIN847, SIN849, SIN850, SIN852, SIN3408L), and five consecutive Vero cell passages (SIN2774_P1, SIN2774_P2, SIN2774_P3, SIN2774_P4, SIN2774_P5) arising from SIN2774 isolate. These represented individual patient samples, serial in vitro passages in cell culture, and paired human and cell culture isolates. Employing a refined mutation filtering scheme and constant mutation rate model, the mutation rates were estimated and the possible date of emergence was calculated. Phylogenetic analysis was used to uncover molecular relationships between the isolates. RESULTS: Close examination of whole genome sequence of 54 SARS-CoV isolates identified before 14th October 2003, including 22 from patients in Singapore, revealed the mutations engendered during human-to-Vero and Vero-to-human transmission as well as in multiple Vero cell passages in order to refine our analysis of human-to-human transmission. Though co-infection by different quasipecies in individual tissue samples is observed, the in vitro mutation rate of the SARS-CoV in Vero cell passage is negligible. The in vivo mutation rate, however, is consistent with estimates of other RNA viruses at approximately 5.7 x 10-6 nucleotide substitutions per site per day (0.17 mutations per genome per day), or two mutations per human passage (adjusted R-square = 0.4014). Using the immediate Hotel M contact isolates as roots, we observed that the SARS epidemic has generated four major genetic groups that are geographically associated: two Singapore isolates, one Taiwan isolate, and one North China isolate which appears most closely related to the putative SARS-CoV isolated from a palm civet. Non-synonymous mutations are centered in non-essential ORFs especially in structural and antigenic genes such as the S and M proteins, but these mutations did not distinguish the geographical groupings. However, no non-synonymous mutations were found in the 3CLpro and the polymerase genes. CONCLUSIONS: Our results show that the SARS-CoV is well adapted to growth in culture and did not appear to undergo specific selection in human populations. We further assessed that the putative origin of the SARS epidemic was in late October 2002 which is consistent with a recent estimate using cases from China. The greater sequence divergence in the structural and antigenic proteins and consistent deletions in the 3'--most portion of the viral genome suggest that certain selection pressures are interacting with the functional nature of these validated and putative ORFs.

Animals↗
PubMed2004

Plasma RNA viral load is not associated with intrapatient quasispecies heterogeneity in HIV-1 infection.

The human immunodeficiency virus type 1 (HIV-1) viral set point has been associated with the rate of, disease progression and with the level of HIV-specific immune response. The analysis of the possible association between viral set point and quasispecies heterogeneity has important consequences in the understanding of HIV-1 in vivo evolution. In this study, we analyzed the association between intrapatient viral diversity and RNA viral load in 16 antiretroviral therapy-naive HIV-1-infected patients at a single time point, during the disease free period. Patients were separated into low and high viral load groups according to plasma RNA values. HIV-1 quasispecies complexity was assessed in the C2-V5 env region. The average intrapatient quasispecies heterogeneity in both groups was not significantly different (t-test, P > 0.05). However, while within the low viral load group both synonymous and non-synonymous mutations contribute to the variation observed, in the heterogeneity observed in the high viral load group there was an increase in the contribution of the non-synonymous mutations. Thus, this study show that although intrapatient quasispecies heterogeneity is not associated with viral set point in HIV-1 infection, some differences exist between the two groups in the pattern of mutation accumulation.

Amino Acid Substitution↗
PubMed2006

Evolution of amino-acid sequences and codon usage on the Drosophila miranda neo-sex chromosomes.

We have studied patterns of DNA sequence variation and evolution for 22 genes located on the neo-X and neo-Y chromosomes of Drosophila miranda. As found previously, nucleotide site diversity is greatly reduced on the neo-Y chromosome, with a severely distorted frequency spectrum. There is also an accelerated rate of amino-acid sequence evolution on the neo-Y chromosome. Comparisons of nonsynonymous and silent variation and divergence suggest that amino-acid sequences on the neo-X chromosome are subject to purifying selection, whereas this is much weaker on the neo-Y. The same applies to synonymous variants affecting codon usage. There is also an indication of a recent relaxation of selection on synonymous mutations for genes on other chromosomes. Genes that are weakly expressed on the neo-Y chromosome appear to have a faster rate of accumulation of both nonsynonymous and unpreferred synonymous mutations than genes with high levels of expression, although the rate of accumulation when both types of mutation are pooled is higher for the neo-Y chromosome than for the neo-X chromosome even for highly expressed genes.

Amino Acid Sequence↗
PubMed2006

Inferring the distribution of mutational effects on fitness in Drosophila.

The properties of the distribution of deleterious mutational effects on fitness (DDME) are of fundamental importance for evolutionary genetics. Since it is extremely difficult to determine the nature of this distribution, several methods using various assumptions about the DDME have been developed, for the purpose of parameter estimation. We apply a newly developed method to DNA sequence polymorphism data from two Drosophila species and compare estimates of the parameters of the distribution of the heterozygous fitness effects of amino acid mutations for several different distribution functions. The results exclude normal and gamma distributions, since these predict too few effectively lethal mutations and power-law distributions as a result of predicting too many lethals. Only the lognormal distribution appears to fit both the diversity data and the frequency of lethals. This DDME arises naturally in complex systems when independent factors contribute multiplicatively to an increase in fitness-reducing damage. Several important parameters, such as the fraction of effectively neutral non-synonymous mutations and the harmonic mean of non-neutral selection coefficients, are robust to the form of the DDME. Our results suggest that the majority of non-synonymous mutations in Drosophila are under effective purifying selection.

Animals↗
PubMed2003

[Mutations of fragile histidine triad gene in Peutz-Jeghers syndrome and canceration].

BACKGROUND & OBJECTIVE: Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited disease. Fragile histidine triad (FHIT) gene is an important tumor suppressor gene at the fragile sites region of 3p14. The authors' previous study suggested that PJS patients might have a susceptible gene at the region of 3p14.2. This study was designed to reveal the relationship between the variant of FHIT gene in PJS and its canceration. METHOD: Mutations of FHIT gene in 15 PJS patients and 20 unaffected members in 6 PJS families were determined using denaturing high-performance liquid chromatography (DHPLC), polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP) and DNA sequencing techniques. RESULTS: A non-sense mutation and a frame-shift mutation were identified at codon 54(GAA to TAA) (exon 6) which led to the change of the amino acid from glutamic acid (Glu) to stop codon, and a guanine insertion at codon 62 in exon 6 resulting in a premature stop codon TGA at codon 111 in one PJS patient. A homozygous deletion and a synonymous mutation were detected in exon 8. The homozygous deletion of exon 8 in FHIT gene was found in two polyps tissues and two cancerous tissues. And in 3 sporadic cases, the patients and their mothers have the same bands of SSCP and the same elution profiles of DHPLC when exon 8 was amplified. The DNA sequencing result showed that a synonymous mutation (polymorphism) occurred at codon 98 [CAT (H)-->CAC (H)], this mutation resulted in no change of amino acid. In addition, one base substitute from A to G mutation at 5'end, +42 nucleotide in intron 6 of FHIT gene was detected in seven patients and two unaffected members. CONCLUSION: PJS patients have low frequency point mutation of FHIT gene and their cancerous tissues had homozygous deletions in FHIT gene. This study indicated that the mutations and deletions of FHIT gene in PJS may play a role in the development of PJS and their cancerations.

Acid Anhydride Hydrolases↗
PubMed2002

Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians.

Adiponectin (ACRP30), an adipocyte-secreted protein encoded by the APM1 gene, is known to modulate insulin sensitivity and glucose homeostasis, those effects protecting obese mice from diabetes. Plasma adiponectin levels correlate well with insulin sensitivity in humans, and are decreased in both type 2 diabetes (T2D) and obesity. We screened for single-nucleotide polymorphisms (SNPs) the APM1 gene coding and 5' sequences in 40 French Caucasians: 12 SNPs and 4 rare non-synonymous mutations of exon 3 were detected. The 10 most frequent SNPs were genotyped in 1373 T2D and obese French Caucasian subjects and in all subjects available from 148 T2D multiplex families. The screening for rare mutations of exon 3 was extended to 1246 T2D and obese French subjects and to the members of the 148 T2D multiplex families. A haplotype including SNPs -11391 and -11377, both located in the 5' sequences, was associated with adiponectin levels (P<0.0001) and with T2D (P=0.004). The presence of at least one non-synonymous mutation in exon 3 showed evidence of association with adiponectin levels (P=0.0009) and with T2D (P=0.005). We failed to detect an association with insulin resistance indexes. Although family-based association analysis with T2D did not reach significance, our results suggest that an at-risk haplotype of common variants located in the promoter and rare mutations in exon 3 contribute to the variation of the adipocyte-secreted adiponectin hormone level, and may be part of the genetic determinants for T2D in the French Caucasian population.

Adipocytes↗
PubMed2005

High genetic variability and evidence for plant-to-plant transfer of Banana mild mosaic virus.

A total of 154 partial nucleotide sequences within the Banana mild mosaic virus (BanMMV) ORF1, which encodes the viral RNA-dependent RNA polymerase (RdRp), was obtained from 68 distinct infected banana accessions originating from various locations worldwide. The 310 nt sequences displayed a high level of variability with a mean pairwise nucleotide sequence divergence level of 20.4 %. This situation resulted essentially from a high rate of synonymous mutations. A similar analysis was performed for a limited selection of 10 banana accessions (30 sequences) on the region comprising approximately the last 310 nt of the BanMMV genome. This region corresponds to the 3' end of ORF5, which encodes the coat protein (234 nt), and to the 3' non-coding region. This analysis confirmed the high level of diversity observed in the RdRp dataset, characterized by a high level of synonymous mutations. Analysis of intra-host diversity indicated the existence of two distinct situations, with some plants containing only closely related sequence variants, whereas others contained widely divergent isolates. Analyses indicated that BanMMV genetic diversity is not structured by the geographical origin of the infected Musa accessions or by their genotype. This situation may be, in part, explained by the exchange of banana germplasm between different parts of the world and also by plant-to-plant transfer of virus isolates, the evidence for which is, for the first time, provided by this study.

Base Sequence↗
PubMed2006

Association of mitochondrial DNA transversion mutations with familial medullary thyroid carcinoma/multiple endocrine neoplasia type 2 syndrome.

Medullary thyroid carcinoma (MTC) is a malignant tumour of the calcitonin-secreting parafollicular C cells of the thyroid, and occurs sporadically or as a component of the multiple endocrine neoplasia (MEN) type 2/familial medullary thyroid carcinoma (FMTC) syndromes. In the present study, we investigated the frequency of mtDNA mutations in 26 MTC tumour specimens (13 sporadic and 13 familial MTC) and their matched normal tissues by sequencing the entire coding regions of mitochondrial genome. Nonsynonymous mutations were detected in 20 MTC samples (76.9%): nine out of 13 sporadic MTC (69.2%) and 11 out of 13 (84.6%) familial MTC/MEN2. Both transition and transversion types of mutations were found in the samples. Interestingly, 76.2% (16/21) of transversion mutations were found in FMTC/MEN2 patients, whereas 66.7% (12/18) of transition mutations were in sporadic MTC. Synonymous mutations were found in 12 MTC samples. In total, we identified 27 transversion mutations (21 nonsynonymous and six synonymous) in MTC. Of them, 22 (81.5%) were from FMTC/MEN2, and five (18.5%) were from sporadic MTC. The association of transversion mutation with familial MTC/MEN2 was statistically significant (P = 0.0015, binomial test). Majority of the mutations were involved in the genes located in the complex I of the mitochondrial genome, and were often resulting in a change of a moderately or highly conserved amino acid of their corresponding protein. Mitochondrial respiratory function was also compromised in a TT cell line, which carries mtDNA mutation at nt 4917 and 11,720, and in peripheral lymphocytes of MTC patients with mtDNA mutations. These data suggest that mtDNA mutation may be involved in MTC tumourigenesis and progression. Given that mtDNA mutation spectra are different between sporadic and familial MTC, different mechanisms of oxidative DNA damage may occur in the disease process.

Adolescent↗
PubMed2003

RevTrans: Multiple alignment of coding DNA from aligned amino acid sequences.

The simple fact that proteins are built from 20 amino acids while DNA only contains four different bases, means that the 'signal-to-noise ratio' in protein sequence alignments is much better than in alignments of DNA. Besides this information-theoretical advantage, protein alignments also benefit from the information that is implicit in empirical substitution matrices such as BLOSUM-62. Taken together with the generally higher rate of synonymous mutations over non-synonymous ones, this means that the phylogenetic signal disappears much more rapidly from DNA sequences than from the encoded proteins. It is therefore preferable to align coding DNA at the amino acid level and it is for this purpose we have constructed the program RevTrans. RevTrans constructs a multiple DNA alignment by: (i) translating the DNA; (ii) aligning the resulting peptide sequences; and (iii) building a multiple DNA alignment by 'reverse translation' of the aligned protein sequences. In the resulting DNA alignment, gaps occur in groups of three corresponding to entire codons, and analogous codon positions are therefore always lined up. These features are useful when constructing multiple DNA alignments for phylogenetic analysis. RevTrans also accepts user-provided protein alignments for greater control of the alignment process. The RevTrans web server is freely available at http://www.cbs.dtu.dk/services/RevTrans/.

Amino Acid Substitution↗
PubMed2006

[BCL-XL expression and mutation in non-Hodgkin's lymphoma].

The study was aimed to investigate the BCL-XL expression and mutation, and its clinical significance in non-Hodgkin's lymphoma. Lymphoma cells were selectively isolated by laser microdissection. BCL-XL expression from lymphoma tissue and microdissected lymphoma cells was measured by using real-time quantitative reverse transcription-polymerase chain reaction. BCL-XL mutation was analyzed by using direct sequencing of PCR products. The results showed that compared to 15 patients with reactive hyperplasia, BCL-XL was overexpressed in follicular lymphoma (n = 30), both in lymphoma tissue (P = 0.0064) and in microdissected lymphoma cells (P < 0.0001). No significant rise of BCL-XL expression was observed in patients with T-cell lymphoma (n = 24) and diffuse large B cell lymphoma (n = 24). In follicular lymphoma, high BCL-XL level was associated with multiple extranodal involvement (P = 0.0004), elevated lactate dehydrogenase level (P = 0.0019), high-risk international prognostic index (P = 0.0013) and a short overall survival time (P = 0.0451). Mutation analysis revealed one synonymous mutation (Codon 109 ACA-->ACC) in one case of follicular lymphoma patient. It is concluded that BCL-XL expression is closely correlated with progress of follicular lymphoma and prognosis of patients with follicular lymphoma. The value of BCL-XL expression as a prognostic marker in follicular lymphoma should be considered.

Base Sequence↗
PubMed1998

Hypermutability and silent mutations in human carcinogenesis.

Silent or synonymous mutations are nucleotide changes which do not result in an amino acid change. Such alterations make up approximately 4% of the total TP53 mutations in a database of almost 10,000 mutations. Insofar as these changes do not confer a selective advantage, silent mutations make it possible to estimate an unbiased mutation frequency. Since this frequency is at least 100 times higher than would be expected for normal tissue, tumors must be hypermutable. In addition, a class of tumors may be supermutable with a mutation frequency comparable to that observed in the generation of immune diversity.

Chromosome Aberrations↗
PubMed2003

Nucleotide polymorphism in the RpII215 gene region of the insular species Drosophila guanche: reduced efficacy of weak selection on synonymous variation.

An approximately 6.9-kb region encompassing the RpII215 gene was sequenced for 24 individuals of the island endemic species Drosophila guanche. The comparative analysis of synonymous polymorphism and divergence in D. guanche and D. subobscura, two species with pronounced differences in population size, allows contrasting the nearly neutral character of synonymous mutations. In D. guanche, unlike in D. subobscura, (1) the ratio of preferred to unpreferred synonymous changes was similar for polymorphic and fixed changes, (2) the numbers of preferred and unpreferred changes, both polymorphic and fixed, could be explained by the mutational process, and (3) the estimated scaled selection coefficient for unpreferred mutations did not differ significantly from zero. Additionally, the comparative analysis revealed that both the ratio of preferred to unpreferred synonymous changes and the frequency spectrum of unpreferred polymorphic mutations differed significantly between species. All these results indicate that a large fraction of synonymous mutations in the RpII215 gene behave as effectively neutral in D. guanche, whereas they are weakly selected in D. subobscura. The reduced efficacy of selection in the insular species constitutes strong evidence of the nearly neutral character of synonymous mutations and, therefore, of the role of weak selection in maintaining codon bias.

Animals↗
PubMed2025

SARS-CoV-2 genomic diversity and within-host evolution in individuals with persistent infection in the UK: an observational, longitudinal, population-based surveillance study.

BACKGROUND: Persistent SARS-CoV-2 infections in hospitalised immunocompromised individuals are known to facilitate accelerated within-host viral evolution, potentially contributing to the emergence of highly divergent variants. However, little is known about the evolutionary dynamics and transmission risks of persistent infections in the general population. We aimed to characterise the within-host evolution of SARS-CoV-2 during persistent infections identified through a large community surveillance study. METHODS: We used data from the Office for National Statistics COVID-19 Infection Survey (ONS-CIS), a large-scale, longitudinal, population-based surveillance study conducted in the UK from April, 2020, to March, 2023. For this analysis, we focused on infections with high viral load (cycle threshold &#x2264;30) and available genome sequences, from seven major SARS-CoV-2 lineages (alpha, delta, BA.1, BA.2, BA.4, BA.5, and XBB). ONS-CIS participants were randomly selected from the general population and tested regularly by RT-PCR, regardless of symptoms. We defined persistent infections as those with sustained or rebounding high viral RNA titres for 26 days or longer. We examined associated host characteristics and used raw sequence data to identify de novo mutations and estimate within-host synonymous and non-synonymous evolutionary rates across the SARS-CoV-2 genome. FINDINGS: Between Nov 2, 2020, and March 21, 2023, we identified 576 persistent infections with at least two sequences, including 11 alpha, 106 delta, 102 BA.1, 204 BA.2, 16 BA.4, 133 BA.5, and 4 XBB. Persistent infections were more common in males than females (p<0&#xb7;0001) and individuals older than 60 years (p=0&#xb7;0027). The median within-host genome-wide evolutionary rate was 7&#xb7;9&#x2009;&#xd7;&#x2009;10-4 substitutions per site per year (IQR 7&#xb7;0-9&#xb7;0&#x2009;&#xd7;&#x2009;10-4), with high inter-individual variability driven largely by non-synonymous mutations, particularly in the N-terminal and receptor-binding domains of the spike protein. Longer infection duration was associated with higher evolutionary rates, while no associations were found with age, sex, vaccination status, previous infection, or virus lineage. We found no clear evidence of transmission beyond the first month of infection in any of the 84 persistent infections lasting 56 days or longer. In total, we identified 379 recurrent mutations, including many with known or predicted negative fitness effects and low prevalence at the population level, as well as de novo reversions to the Wuhan-Hu-1 reference sequence, which were likely under positive selection within those individuals. INTERPRETATION: This study highlights the heterogeneous nature of within-host SARS-CoV-2 evolution in individuals with persistent infection in the community. Notably, a small subset of persistent infections with high viral loads underwent accelerated viral evolution or recurrently acquired hallmark mutations found in novel variants. In addition, onward transmission from a persistent infection during the later stages of infection is likely to be rare. These insights have important implications for prioritising genomic surveillance and managing patients with persistent infections. FUNDING: Department of Health and Social Care.

Humans↗
PubMed2005

[Analysis of CCM1 gene mutations in Chinese patients with intracranial cavernous malformations].

OBJECTIVE: To study the CCM1 gene (7q11.2 - q22) mutations in Chinese patients with intracranial cavernous malformations (ICM), METHODS: Peripheral blood samples were collected from 25 unrelated patients with ICM confirmed by post-operational pathology, 7 being with familial ICM, all of Han nationality, and from 30 healthy people as controls. The genomic DNA was extracted and the exons 8, 9, 11, 12, 13, 15, 16, 17, and 18 of CCM1 gene and part of intervening sequences near both sides of these exons were amplified by PCR. The PCR products were sequenced directly and then compared with the GenBank data. RESULTS: Seven new mutation sites of CCM1 gene were detected from 11 Chinese ICM patients with a total mutation rate of 44%. Of the seven new mutations there were three missense mutations: 1160A-->C (Q387P) and 1172C-->T (S391F) in exon12, and 1405A-->C (N469H) in exon13; two insertion mutations: 704insT (K246stop) in exon8, and 2138insG (T733stop) in exon18; one intervening sequence mutation: IVS12 - 4C-->T; and one synonymous mutation: 1875C-->T (F625F) in exon17. None mutation was detected in the control group. The CCM1 mutation rate of familial ICM was 85.7%, significantly higher than that of sporadic ICM (27.7%, P < 0.05). CONCLUSION: As the genetic basis of ICM, CCM1 gene mutation exists in Chinese ICM patients too, that leads to functional loss or changes of the gene encoding KRIT1 protein.

Adult↗