scholarly journals Mutation saturation for fitness effects at human CpG sites

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ipsita Agarwal ◽  
Molly Przeworski
Keyword(s):  
Missense Mutations ◽  
Loss Of Function ◽  
Synonymous Mutations ◽  
Fitness Effects ◽  
Cpg Sites ◽  
Synonymous Polymorphism ◽  
History Of ◽  
Elevated Rate ◽  
Current Sample ◽  
Natural Mutation

Whole exome sequences have now been collected for millions of humans, with the related goals of identifying pathogenic mutations in patients and establishing reference repositories of data from unaffected individuals. As a result, we are approaching an important limit, in which datasets are large enough that, in the absence of natural selection, every highly mutable site will have experienced at least one mutation in the genealogical history of the sample. Here, we focus on CpG sites that are methylated in the germline and experience mutations to T at an elevated rate of ~10-7 per site per generation; considering synonymous mutations in a sample of 390,000 individuals, ~99% of such CpG sites harbor a C/T polymorphism. Methylated CpG sites provide a natural mutation saturation experiment for fitness effects: as we show, at current sample sizes, not seeing a non-synonymous polymorphism is indicative of strong selection against that mutation. We rely on this idea in order to directly identify a subset of CpG transitions that are likely to be highly deleterious, including ~27% of possible loss-of-function mutations, and up to 20% of possible missense mutations, depending on the type of functional site in which they occur. Unlike methylated CpGs, most mutation types, with rates on the order of 10-8 or 10-9, remain very far from saturation. We discuss what these findings imply for interpreting the potential clinical relevance of mutations from their presence or absence in reference databases and for inferences about the fitness effects of new mutations.

scholarly journals Mutation saturation for fitness effects at human CpG sites

2021 ◽  
Author(s):  
Ipsita Agarwal ◽  
Molly Przeworski
Keyword(s):  
Missense Mutations ◽  
Loss Of Function ◽  
Fitness Effects ◽  
Cpg Sites ◽  
Whole Exome ◽  
History Of ◽  
Reference Databases ◽  
Elevated Rate ◽  
Current Sample ◽  
Natural Mutation

Whole exome sequences have now been collected for millions of humans, with the related goals of identifying pathogenic mutations in patients and establishing reference repositories of data from unaffected individuals. As a result, we are approaching an important limit, in which datasets are large enough that, in the absence of natural selection, every highly mutable site will have experienced at least one mutation in the genealogical history of the sample. Here, we focus on putatively-neutral, synonymous CpG sites that are methylated in the germline and experience mutations to T at an elevated rate of ~10-7 per site per generation; in a sample of 390,000 individuals, ~99% of such CpG sites harbor a C/T polymorphism. These CpG sites provide a natural mutation saturation experiment for fitness effects: as we show, at current sample sizes, not seeing a polymorphism is indicative of strong selection against that mutation. We rely on this idea in order to directly identify a subset of highly deleterious CpG transitions, including ~27% of possible loss-of-function mutations, and up to 21% of possible missense mutations, depending on the type of site in which they occur. Unlike methylated CpGs, most mutation types, with rates on the order of 10-8 or 10-9, remain very far from saturation. We discuss what this contrast implies about interpreting the potential clinical relevance of mutations from their presence or absence in reference databases and for inferences about the fitness effects of new mutations.

scholarly journals Using Patterns of Signed Linkage Disequilibria to Test for Epistasis in Flies and Plants

2020 ◽  
Author(s):  
George Sandler ◽  
Stephen I. Wright ◽  
Aneil F. Agrawal
Keyword(s):  
Biological Networks ◽  
Evolutionary Genetics ◽  
Fruit Fly ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Synonymous Mutations ◽  
Synonymous Sites ◽  
Significant Enrichment ◽  
Neutral Mutations ◽  
Open Question

AbstractWhether deleterious mutations affect fitness independently, or synergistically, remains an open question in evolutionary genetics. Previous work by Sohail et al. (2017) reported an abundance of negative linkage disequilibrium (LD) values among loss-of - function (LOF) mutations in several human and fruit fly datasets, a pattern the authors interpreted as evidence of negative synergistic epistasis. Here we re-visit this question in a population genomic dataset of plants (Capsella grandiflora), and a fruit fly (Drosophila melanogaster) dataset previously used by Sohail et al. When using synonymous sites as a control, as Sohail et al., we find that both species have significantly less positive LD at LOF sites than synonymous sites. However, LD is not significantly different from 0 for LOF mutations but is significantly positive for synonymous mutations in both species. We question the use of synonymous sites as an appropriate control when attempting to make inferences about LD at selected sites. We use simulations to show how admixture or mating bias towards physically proximal individuals can cause positive LD to build up among neutral mutations but has a much weaker effect on selected sites, regardless of the presence of epistasis. Finally, we use information from published biological networks to explore whether there is evidence for negative synergistic epistasis between interacting radical missense mutations. We report no significant enrichment for negative inter-network LD in C. grandiflora. However, we note a modest but significant enrichment of negative LD in D. melanogaster networks, suggestive of intra-network negative synergistic epistasis in this species.

scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

scholarly journals Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

2021 ◽  
Vol 22 (7) ◽  
pp. 3786
Author(s):  
Andreas Brodehl ◽  
Alexey Meshkov ◽  
Roman Myasnikov ◽  
Anna Kiseleva ◽  
Olga Kulikova ◽  
...  
Keyword(s):  
Medical History ◽  
Splice Site Mutation ◽  
Pathogenic Mutation ◽  
Large Deletion ◽  
Loss Of Function ◽  
Arrhythmogenic Cardiomyopathy ◽  
Site Mutation ◽  
Snp Arrays ◽  
Number Of Patients ◽  
History Of

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

Atopic Dermatitis: Case Series of Individualized Homoeopathic Treatment

2021 ◽  
Vol 11 (11) ◽  
pp. 115-123
Author(s):  
Mousumi Das
Keyword(s):  
Atopic Dermatitis ◽  
Family History ◽  
Case Series ◽  
Calcineurin Inhibitors ◽  
Loss Of Function ◽  
Key Words Atopic Dermatitis ◽  
Topical Calcineurin Inhibitors ◽  
History Of ◽  
Allergic Disorders ◽  
Positive Results

Atopic dermatitis is a common, chronic, intensely pruritic, relapsing inflammatory skin disease that affects both children and adults. Atopic dermatitis is often the originating of a series of allergic disorders, mentioned as the "atopic march".There are numerous risk factors correlated with AD development. However, only two have always been related, and they are (1) family history of atopy and (2) loss of function mutations in the FLG gene. Topical anti-inflammatory therapy with topical corticosteroids or topical calcineurin inhibitors treatment are available in conventional therapy but sometimes it has been reported that patients are also benefited from Homoeopathic treatment. Four patients who presented at the outpatient department at National Institute of Homoeopathy, Saltlake, Kolkata with Atopic dermatitis and a family history of asthma, allergic rhinitis were treated with constitutional homoeopathic medicine. Details of consultations, treatment and assessment are summarized. A constitutional treatment thus eliminates the symptoms locally and internally as well as long-lasting relief from complaints. Common remedies include Mercuris Solubilis, Sulphur. This case series shows positive results of homoeopathy in the treatment of Atopic dermatitis. Key words: Atopic dermatitis, Family history, Individualized Homoeopathic treatment, Case series, repertorisation.

scholarly journals PCNT point mutations and familial intracranial aneurysms

Neurology ◽  
2018 ◽  
Vol 91 (23) ◽  
pp. e2170-e2181 ◽  
Author(s):  
Oswaldo Lorenzo-Betancor ◽  
Patrick R. Blackburn ◽  
Emily Edwards ◽  
Rocío Vázquez-do-Campo ◽  
Eric W. Klee ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Intracranial Aneurysms ◽  
Point Mutations ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Interaction Domain ◽  
Knockout Mouse Model ◽  
Whole Exome ◽  
Primordial Dwarfism

ObjectiveTo identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.MethodsWe performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.ResultsWe identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases.ConclusionThe PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt−/−) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

scholarly journals Mutation profiling of anaplastic ependymoma grade III by Ion Proton next generation DNA sequencing

F1000Research ◽  
2020 ◽  
Vol 8 ◽  
pp. 613
Author(s):  
Ejaz Butt ◽  
Sabra Alyami ◽  
Tahani Nageeti ◽  
Muhammad Saeed ◽  
Khalid AlQuthami ◽  
...  
Keyword(s):  
Ependymal Cells ◽  
Acceptor Site ◽  
Missense Mutations ◽  
Next Generation ◽  
Anaplastic Ependymoma ◽  
Site Mutation ◽  
Synonymous Mutations ◽  
Ion Proton ◽  
Intronic Variants ◽  
Grade Iii

Background: Ependymomas are glial tumors derived from differentiated ependymal cells. In contrast to other types of brain tumors, histological grading is not a good prognostic marker for these tumors. In order to determine genomic changes in an anaplastic ependymoma, we analyzed its mutation patterns by next generation sequencing (NGS). Methods:  Tumor DNA was sequenced using an Ion PI v3 chip on Ion Proton instrument and the data were analyzed by Ion Reporter 5.6. Results: NGS analysis identified 19 variants, of which four were previously reported missense variants; c.395G>A in IDH1, c.1173A>G in PIK3CA, c.1416A>T in KDR and c.215C>G in TP53. The frequencies of the three missense mutations (PIK3CA c.1173A>G, KDR c.1416A>T, TP53, c.215C>G) were high, suggesting that these are germline variants, whereas the IDH1 variant frequency was low (4.81%). However, based on its FATHMM score of 0.94, only the IDH1 variant is pathogenic; other variants TP53, PIK3CA and KDR had FATHMM scores of 0.22, 0.56 and 0.07, respectively. Eight synonymous mutations were found in FGFR3, PDGFRA, EGFR, RET, HRAS, FLT3, APC and SMAD4 genes. The mutation in FLT3 p.(Val592Val) was the only novel variant found. Additionally, two known intronic variants in KDR were found and intronic variants were also found in ERBB4 and PIK3CA. A known splice site mutation at an acceptor site in FLT3, a 3’-UTR variant in the CSF1R gene and a 5’_UTR variant in the SMARCB1 gene were also identified. The p-values were below 0.00001 for all variants and the average coverage for all variants was around 2000x. Conclusions: In this grade III ependymoma, one novel synonymous mutation and one deleterious missense mutation is reported. Many of the variants reported here have not been detected in ependymal tumors by NGS analysis previously and we therefore report these variants in brain tissue for the first time.

scholarly journals Adaptive evolution of transcription factor binding affinities

2017 ◽  
Author(s):  
Jungeui Hong ◽  
Nathan Brandt ◽  
Ally Yang ◽  
Tim Hughes ◽  
David Gresham
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Adaptive Evolution ◽  
Consensus Sequence ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Missense Mutations ◽  
Binding Affinities ◽  
Synonymous Mutations

Understanding the molecular basis of gene expression evolution is a central problem in evolutionary biology. However, connecting changes in gene expression to increased fitness, and identifying the functional basis of those changes, remains challenging. To study adaptive evolution of gene expression in real time, we performed long term experimental evolution (LTEE) of Saccharomyces cerevisiae (budding yeast) in ammonium-limited chemostats. Following several hundred generations of continuous selection we found significant divergence of nitrogen-responsive gene expression in lineages with increased fitness. In multiple independent lineages we found repeated selection for non-synonymous mutations in the zinc finger DNA binding domain of the activating transcription factor (TF), GAT1, that operates within incoherent feedforward loops to control expression of the nitrogen catabolite repression (NCR) regulon. Missense mutations in the DNA binding domain of GAT1 reduce its binding affinity for the GATAA consensus sequence in a promoter-specific manner, resulting in increased expression of ammonium permease genes via both direct and indirect effects, thereby conferring increased fitness. We find that altered transcriptional output of the NCR regulon results in antagonistic pleiotropy in alternate environments and that the DNA binding domain of GAT1 is subject to purifying selection in natural populations. Our study shows that adaptive evolution of gene expression can entail tuning expression output by quantitative changes in TF binding affinities while maintaining the overall topology of a gene regulatory network.

scholarly journals FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1611
Author(s):  
Ningfei Liu ◽  
Minzhe Gao
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Clinical Signs ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
History Of ◽  
Endothelial Growth Factor

This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations.

scholarly journals Humeral shaft fracture associated with radial nerve palsy -a case report

2021 ◽  
pp. 54-55
Author(s):  
Rishitha M ◽  
Akasha Sindhu M
Keyword(s):  
Radial Nerve ◽  
Nerve Palsy ◽  
Wrist Joint ◽  
Shaft Fracture ◽  
Humeral Shaft Fracture ◽  
Humeral Shaft ◽  
Radial Nerve Palsy ◽  
Loss Of Function ◽  
History Of ◽  
The Right

Radial nerve palsy was induced by radial nerve compression, which was often caused by humerus bone fracture. This leads to pain, weakness, or loss of function mostly in the wrist, hand, and fingers. We reported a case of a 24-year-old male patient with complaints of swelling of the right-hand wrist joint and pain during extension and flexion while moving. He had a three-month history of mild displaced humeral shaft fracture from a traffic accident and an intramedullary Ender nailing was performed. He now has been admitted with swelling in his right wrist joint and pain while moving his hand. The case was diagnosed as Radial nerve palsy. Surgery was performed, the proximal and distal ends of the radial nerve were separated at the humeral bone's surface. The radial nerve stumps were enough long to be sutured. Our one-month follow-up shows no complications. The majority cases of radial nerve palsy will resolve within a few weeks after surgery, as our patient did, and the most prominent is patient education.

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