scholarly journals Mutations as Levy flights

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dario A. Leon ◽  
Augusto Gonzalez
Keyword(s):  
Copy Number ◽  
Copy Number Variations ◽  
Size Distribution Function ◽  
European Ancestry ◽  
Lévy Flights ◽  
Single Base ◽  
Levy Flights ◽  
Long Time ◽  
Evolution Experiment ◽  
Large Rearrangements

AbstractData from a long time evolution experiment with Escherichia Coli and from a large study on copy number variations in subjects with European ancestry are analyzed in order to argue that mutations can be described as Levy flights in the mutation space. These Levy flights have at least two components: random single-base substitutions and large DNA rearrangements. From the data, we get estimations for the time rates of both events and the size distribution function of large rearrangements.

scholarly journals Resistance to miltefosine results from amplification of the RTA3 floppase or inactivation of flippases in Candida parapsilosis

2021 ◽  
Author(s):  
Sean Bergin ◽  
Fang Zhao ◽  
Adam P Ryan ◽  
Carolin A Müller ◽  
Conrad A Nieduszynski ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Copy Number ◽  
Candida Parapsilosis ◽  
Copy Number Variations ◽  
Loss Of Function ◽  
Adaptive Laboratory Evolution ◽  
Pathogenic Yeast ◽  
Lipid Asymmetry ◽  
Evolution Experiment ◽  
Almost All

Flippases and floppases are two classes of proteins that have opposing functions in the maintenance of lipid asymmetry of the plasma membrane. Flippases translocate lipids from the exoplasmic leaflet to the cytosolic leaflet, and floppases act in the opposite direction. Phosphatidylcholine (PC) is a major component of the eukaryotic plasma membrane and is asymmetrically distributed, being more abundant in the exoplasmic leaflet. Here we show that gene amplification of a putative PC floppase or double disruption of two PC flippases in the pathogenic yeast Candida parapsilosis results in resistance to miltefosine, an alkylphosphocholine drug that affects PC metabolism that has recently been granted orphan drug designation approval by the US FDA for treatment of invasive candidiasis. We analysed the genomes of 170 C. parapsilosis isolates and found that 107 of them have copy number variations (CNVs) at the RTA3 gene. RTA3 encodes a putative PC floppase whose deletion is known to increase the inward translocation of PC in Candida albicans. RTA3 copy number ranges from 2 to >40 across the C. parapsilosis isolates. Interestingly, 16 distinct CNVs with unique endpoints were identified, and phylogenetic analysis shows that almost all of them have originated only once. We found that increased copy number of RTA3 correlates with miltefosine resistance. Additionally, we conducted an adaptive laboratory evolution experiment in which two C. parapsilosis isolates were cultured in increasing concentrations of miltefosine over 26 days. Two genes, CPAR2_303950 and CPAR2_102700, gained homozygous protein-disrupting mutations in the evolved strains and code for putative PC flippases homologous to S. cerevisiae DNF1. Our results indicate that alteration of lipid asymmetry across the plasma membrane is a key mechanism of miltefosine resistance. We also find that C. parapsilosis is likely to gain resistance to miltefosine rapidly, because many isolates carry loss-of-function alleles in one of the flippase genes.

Unusual genomic rearrangements in introns 1 and 22 of the F8 gene

2011 ◽  
Vol 31 (S 01) ◽  
pp. S69-S73 ◽  
Author(s):  
M. A. Zimmermann ◽  
J. Oldenburg ◽  
C. R. Müller ◽  
S. Rost
Keyword(s):  
Factor Viii ◽  
Copy Number ◽  
Copy Number Variations ◽  
Severe Phenotype ◽  
Factor Viii Gene ◽  
Intron 1 ◽  
Number Variation ◽  
Abnormal Band ◽  
Large Rearrangements

SummaryIntron 1 and intron 22 inversions, two large rearrangements of the factor VIII gene, are generally associated with a severe phenotype of haemophilia A and a high risk of inhibitor formation. In several haemophiliacs, diagnostic analyses for detection of these inversions revealed unusual band patterns. Upon further examination, different copy number variations were detected in the factor VIII gene of these patients by multiplex ligationdependent probe amplification (MLPA). Since these duplications or deletions alone could not sufficiently explain the abnormal band patterns of the first analyses, we assumed a combination of intron 1 or intron 22 inversions together with a copy number variation. Result We could confirm this hypothesis by specific long range PCRs but a detailed characterization of the breakpoints and the mechanisms for these complex rearrangements have yet to be elucidated.

X-linked CNV and skewed X-chromosome inactivation

2020 ◽  
pp. 19-21
Author(s):  
Е.А. Фонова ◽  
Е.Н. Толмачева ◽  
А.А. Кашеварова ◽  
М.Е. Лопаткина ◽  
К.А. Павлова ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Intellectual Disability ◽  
X Chromosome ◽  
Copy Number ◽  
Copy Number Variations ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Chromosome X ◽  
Skewed X Chromosome Inactivation

Смещение инактивации Х-хромосомы может быть следствием и маркером нарушения клеточной пролиферации при вариациях числа копий ДНК на Х-хромосоме. Х-сцепленные CNV выявляются как у женщин с невынашиванием беременности и смещением инактивации Х-хромосомы (с частотой 33,3%), так и у пациентов с умственной отсталостью и смещением инактивацией у их матерей (с частотой 40%). A skewed X-chromosome inactivation can be a consequence and a marker of impaired cell proliferation in the presence of copy number variations (CNV) on the X chromosome. X-linked CNVs are detected in women with miscarriages and a skewed X-chromosome inactivation (with a frequency of 33.3%), as well as in patients with intellectual disability and skewed X-chromosome inactivation in their mothers (with a frequency of 40%).

scholarly journals Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Nayoung Han ◽  
Jung Mi Oh ◽  
In-Wha Kim
Keyword(s):  
Copy Number ◽  
Genome Wide Association Study ◽  
Copy Number Gain ◽  
Copy Number Variations ◽  
Gene Gain ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Genome Wide ◽  
Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

scholarly journals Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 118
Author(s):  
Louisa Lepkes ◽  
Mohamad Kayali ◽  
Britta Blümcke ◽  
Jonas Weber ◽  
Malwina Suszynska ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
In Silico ◽  
Copy Number ◽  
Gc Content ◽  
Copy Number Variations ◽  
Cancer Predisposition ◽  
Predictive Values ◽  
Prediction Tools ◽  
Predisposition Genes ◽  
Female Index

The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than BRCA1/2, mostly in ATM, CHEK2, and RAD51C and less frequently in BARD1, MLH1, MSH2, PALB2, PMS2, RAD51D, and TP53. The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to BRCA1/2 due to the relevant proportion of CNVs in further BC/OC predisposition genes.

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