scholarly journals The fitness effects of spontaneous mutations nearly unseen by selection in a bacterium with multiple chromosomes

2016 ◽  
Author(s):  
Marcus M. Dillon ◽  
Vaughn S. Cooper
Keyword(s):  
Genome Sequencing ◽  
Common Ancestor ◽  
Burkholderia Cenocepacia ◽  
Missense Mutations ◽  
Spontaneous Mutations ◽  
Nonsense Mutations ◽  
Deletion Mutations ◽  
Fitness Effects ◽  
Quantitative Understanding ◽  
Mutational Processes

ABSTRACTMutation accumulation (MA) experiments employ the strategy of minimizing the population size of evolving lineages to greatly reduce effects of selection on newly arising mutations. Thus, most mutations fix within MA lines independently of their fitness effects. This approach, more recently combined with genome sequencing, has detailed the rates, spectra, and biases of different mutational processes. However, a quantitative understanding of the fitness effects of mutations virtually unseen by selection has remained an untapped opportunity. Here, we analyzed the fitness of 43 sequenced MA lines of the multi-chromosome bacterium Burkholderia cenocepacia that had each undergone 5554 generations of MA and accumulated an average of 6.73 spontaneous mutations. Most lineages exhibited either neutral or deleterious fitness in three different environments in comparison with their common ancestor. The only mutational class that was significantly overrepresented in lineages with reduced fitness was the loss of the plasmid, though nonsense mutations, missense mutations, and coding insertion-deletion mutations were also overrepresented in MA lineages whose fitness had significantly declined. Although the overall distribution of fitness effects was similar between the three environments, the magnitude and even the sign of the fitness of a number of lineages changed with the environment, demonstrating that the fitness of some genotypes was environmentally dependent. These results present an unprecedented picture of the fitness effects of spontaneous mutations in a bacterium with multiple chromosomes and provide greater quantitative support of the theory that the vast majority of spontaneous mutations are neutral or deleterious.

scholarly journals The specific distribution pattern of IKZF1 mutation in acute myeloid leukemia

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiang Zhang ◽  
Xuewu Zhang ◽  
Xia Li ◽  
Yunfei Lv ◽  
Yanan Zhu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Genetic Alteration ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Specific Distribution ◽  
Aggressive Clinical Course ◽  
Acute Myeloid

Abstract IKZF1 belongs to the IKAROS family of transcription factors, and its deletion/mutation frequently affects acute lymphoblastic leukemia. In acute myeloid leukemia, IKZF1 deletion has been demonstrated recurrent, but whether IKZF1 mutation also exists in AML remained largely unknown. Herein, we analyzed the IKZF1 mutation in AML. In our cohort, the frequency of IKZF1 mutation was 2.6% (5/193), and 5 frameshift/nonsense mutations as well as 2 missense mutations were identified in total. Molecularly, IKZF1 mutation was absent in fusion gene-positive AML, but it was demonstrated as the significant concomitant genetic alteration with SF3B1 or bi-alleleCEBPA mutation in AML. Clinically, two IKZF1, PTPN11 and SF3B1-mutated AML patients exhibited one aggressive clinical course and showed primary resistant to chemotherapy. Furthermore, we confirmed the recurrent IKZF1 mutation in AML with cBioPortal tool from OHSU, TCGA and TARGET studies. Interestingly, OHSU study also showed that SF3B1 mutation was the significant concomitant genetic alteration with IKZF1 mutation, indicating their strong synergy in leukemogenesis. In conclusion, IKZF1 mutation recurrently affected AML.

scholarly journals Sexual reproduction and genetic exchange in parasitic protists

Parasitology ◽  
2014 ◽  
Vol 142 (S1) ◽  
pp. S120-S127 ◽  
Author(s):  
GARETH D. WEEDALL ◽  
NEIL HALL
Keyword(s):  
Life Cycle ◽  
Genome Sequencing ◽  
Common Ancestor ◽  
Life Cycles ◽  
Animal Disease ◽  
Eukaryotic Evolution ◽  
Sequencing Technology ◽  
Parasite Reproduction ◽  
The Common ◽  
Higher Eukaryotes

SUMMARYA key part of the life cycle of an organism is reproduction. For a number of important protist parasites that cause human and animal disease, their sexuality has been a topic of debate for many years. Traditionally, protists were considered to be primitive relatives of the ‘higher’ eukaryotes, which may have diverged prior to the evolution of sex and to reproduce by binary fission. More recent views of eukaryotic evolution suggest that sex, and meiosis, evolved early, possibly in the common ancestor of all eukaryotes. However, detecting sex in these parasites is not straightforward. Recent advances, particularly in genome sequencing technology, have allowed new insights into parasite reproduction. Here, we review the evidence on reproduction in parasitic protists. We discuss protist reproduction in the light of parasitic life cycles and routes of transmission among hosts.

scholarly journals Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline

PLoS ONE ◽  
2017 ◽  
Vol 12 (5) ◽  
pp. e0178169 ◽  
Author(s):  
Eleni Giannoulatou ◽  
Geoffrey J. Maher ◽  
Zhihao Ding ◽  
Ad J. M. Gillis ◽  
Lambert C. J. Dorssers ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Male Germline ◽  
Mutational Processes

scholarly journals Fitness Effects of Spontaneous Mutations in Picoeukaryotic Marine Green Algae

2016 ◽  
Vol 6 (7) ◽  
pp. 2063-2071 ◽  
Author(s):  
Marc Krasovec ◽  
Adam Eyre-Walker ◽  
Nigel Grimsley ◽  
Christophe Salmeron ◽  
David Pecqueur ◽  
...  
Keyword(s):  
Green Algae ◽  
Spontaneous Mutations ◽  
Fitness Effects

scholarly journals Characteristics of the mutation spectrum identified by comprehensive investigation of the CFTR gene in the Russian patients

2019 ◽  
Vol 47 (1) ◽  
pp. 38-46
Author(s):  
N. V. Petrova ◽  
A. Yu. Marakhonov ◽  
T. A. Vasilyeva ◽  
N. Yu. Kashirskaya ◽  
E. I. Kondratyeva ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Hereditary Disease ◽  
Mutation Spectrum ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Sequencing Method ◽  
Novel Variants ◽  
Frequent Mutations ◽  
Large Rearrangements

Rationale: Cystic fibrosis (CF; OMIM 219700) is a  common hereditary disease caused by mutations in the CFTR gene (OMIM 602421). The distribution and frequencies of the CFTR gene mutations vary considerably between countries and ethnic groups. By now about 11%  alleles of the CFTR gene remain unidentified after testing for frequent mutations in the Russian patients. A full determination of the mutation spectrum in the CFTR gene is necessary to optimize medical and genetic assistance to the population and to implement the achievements of targeted therapy in the treatment of CF patients.Materials and methods: The sample included 121 Russian CF patients, in whom testing for 34 routinely analyzed mutations did not identify one (n = 107) or both (n = 14) mutant alleles. Assessment of the coding sequence of the CFTR gene, including the regions of exon-intron junctions, 5’- and 3’-untranslated regions was performed by the Sanger sequencing method; in addition, the search for large rearrangements was conducted by the multiplex ligation-dependent probe amplification (MLPA) method.Results: In addition to the previously identified, 88  more variants were determined, including 28  missense mutations, 15  nonsense mutations, 18 frameshift mutations (14 deletions, 4  insertions), 14  splicing mutations, 1  in-frame insertion, 1  in-frame deletion, 1  in/del mutation, and 10  large rearrangements (7  deletions, 3  duplications). Twenty three (23) novel variants were sequenced. Four (4) complex mutant alleles were found. Sixty (60) variants are found once each. One hundred and thirty four (134) of 135 tested mutant alleles were identified.Conclusion: Consequent use of the sequencing and MLPA methods has allowed for identification of a high proportion of the tested mutant alleles in CF patients from Russia (134/135, > 99%), to detect a  significant diversity of the CFTR mutation spectrum (88  additional variants, 32  of them novel), a  number of repeated mutations (c.2353C>T, c.1240_1244delCAAAA, c.1766+1G>A and c.3929G>A) encountered in 5 or more unrelated patients, which could be included in the panel of routinely analyzed variants in the Russian CF patients; and a high proportion of large rearrangements of the CFTR gene. 

scholarly journals Changes in the distribution of fitness effects and adaptive mutational spectra following a single first step towards adaptation

2020 ◽  
Author(s):  
Dimitra Aggeli ◽  
Yuping Li ◽  
Gavin Sherlock
Keyword(s):  
Evolutionary Dynamics ◽  
Common Ancestor ◽  
Single Point ◽  
Relative Fitness ◽  
Single Point Mutation ◽  
Historical Contingency ◽  
Mutational Spectra ◽  
Fitness Effects ◽  
Mutational Step ◽  
Diminishing Returns

AbstractThe fitness effects of random mutations are contingent upon the genetic and environmental contexts in which they occur, and this contributes to the unpredictability of evolutionary outcomes at the molecular level. Despite this unpredictability, the rate of adaptation in homogeneous environments tends to decrease over evolutionary time, due to diminishing returns epistasis, causing relative fitness gains to be predictable over the long term. Here, we studied the extent of diminishing returns epistasis and the changes in the adaptive mutational spectra after yeast populations have already taken their first adaptive mutational step. We used three distinct adaptive clones that arose under identical conditions from a common ancestor, from which they diverge by a single point mutation, to found populations that we further evolved. We followed the evolutionary dynamics of these populations by lineage tracking and determined adaptive outcomes using fitness assays and whole genome sequencing. We found compelling evidence for diminishing returns: fitness gains during the 2nd step of adaptation are smaller than those of the 1st step, due to a compressed distribution of fitness effects in the 2nd step. We also found strong evidence for historical contingency at the genic level: the beneficial mutational spectra of the 2nd-step adapted genotypes differ with respect to their ancestor and to each other, despite the fact that the three founders’ 1st-step mutations provided their fitness gains due to similar phenotypic improvements. While some targets of selection in the second step are shared with those seen in the common ancestor, other targets appear to be contingent on the specific first step mutation, with more phenotypically similar founding clones having more similar adaptive mutational spectra. Finally, we found that disruptive mutations, such as nonsense and frameshift, were much more common in the first step of adaptation, contributing an additional way that both diminishing returns and historical contingency are evident during 2nd step adaptation.

TET2 SNP rs2454206 (I1762V) Correlates with Improved Survival In Pediatric Acute Myelogenous Leukemia, a Report From the Children's Oncology Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 949-949 ◽  
Author(s):  
Matthew A. Kutny ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Phoenix A. Ho ◽  
Daniel Geraghty ◽  
...  
Keyword(s):  
Overall Survival ◽  
African American ◽  
Complete Remission ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Free Survival ◽  
Patient Sample ◽  
Significant Difference ◽  
Tet2 Mutation ◽  
Pediatric Aml

Abstract Abstract 949 Deletions and rearrangements involving chromosome 4q24 in patients with myelodysplastic syndrome led to the discovery that the TET2 gene found in this genomic region may contribute to myeloid leukemogenesis. Mutations in this gene were identified in AML that correlated with clinical outcome. We screened genomic DNA extracted from diagnostic specimens of a cohort of 169 pediatric de novo AML patients treated on the Children's Cancer Group study CCG-2961 for genomic alterations in the TET2 gene. Twenty one primer pairs were used to amplify and sequence the entire coding sequence (11 exons) as well as flanking promoter and non-coding regions of TET2. We identified 10 different previously annotated single nucleotide polymorphisms (SNPs) with prevalence greater than 4% in addition to 12 disease associated mutations. Presence of each SNP as well as the mutations as a group were correlated with disease characteristics and clinical outcome. Of the 10 SNPs evaluated, one SNP correlated significantly with outcome. The minor allele of SNP rs2454206 (I1762V) was found in 54% of samples tested. There was no significant difference in the age or gender of patients with or without SNP rs2454206. The prevalence of SNP rs2454206 varied in different ethnic groups. Of the 92 patients with SNP rs2454206, 85% were Caucasian and 3% were African American compared to 56% and 15% of those without the SNP, respectively (p<0.001 and p=0.018). Conversely, 65% of all Caucasian patients and 21% of all African American patients with AML had SNP rs2454206, similar to the reported SNP frequency in general Caucasian and African American populations. There was no significant difference in presenting white blood cell count, blast percentage or FAB group in patients with and without SNP rs2454206. The prevalence of specific cytogenetic groups and mutations of FLT3/ITD, CEBPA and WT1 did not differ between the groups. There was a lower prevalence of NPM mutation in the SNP rs2454206 group compared to the SNP negative group (2.5% vs. 12.7%, p= 0.035). Patients with SNP rs2454206 were more likely to achieve a complete remission than those without the SNP (80% vs. 63%, p=0.028). Actuarial overall survival at 5 years from diagnosis for patients with SNP rs2454206 was 61±11% vs. 36±12% for those without the SNP (p=0.007). Corresponding event-free survival was 41±12% vs. 27±11% for those with and without the SNP (p=0.051). Of those who achieved a complete remission, overall survival from CR for those with and without SNP rs2454206 was 66% and 43%, respectively (p=0.022). Improved outcome may in part be due to lower treatment related mortality (TRM) where those with SNP rs2454206 had a lower rate of TRM 6±5% vs. 17±9% (p=0.043). We further evaluated the clinical implications of TET2 mutations. Disease associated mutations of the TET2 gene were identified in 11 patients with 9 heterozygous missense mutations (K423R, N767D, R814H, E1010D, S1039L, A1443V, V1718L, H1817N and E1973K), 2 heterozygous nonsense mutations (Q958X and E1323X) and one heterozygous single base insertion (ins1870-1871) which caused a frame shift beginning with T624N and causing an early termination codon (E637X). Each mutation was found in a single patient sample except for V1718L which was found in two samples. Also, one patient sample had two missense mutations (E1010D and E1973K) and another patient sample contained both nonsense mutations. Therefore a total of 11 out of 169 samples (6.5%) had a TET2 mutation. Of the TET2 mutant patients with available cytogenetics, 50% had t(8;21) compared to 14% of those without a mutation (p=0.026), and there was not an association of TET2 mutation with high risk cytogenetic features. Of the 11 patients with TET2 mutations, 6 patients failed to achieve a complete remission with a CR rate of 45% compared to that of 74% for those without a mutation (p=0.074). Patients with a TET2 mutation had a disease-free survival of 26±31% vs. 42±10% for those without the mutation (p=0.247). This study demonstrates the potential significance of genomic alterations of the TET2 gene in childhood AML. Further evaluation of TET2 mutations and the SNP rs2454206 in a larger cohort of pediatric AML patients is in process in order to determine if these will be useful markers for risk based stratification and allocation of therapy. The TET2 SNP rs2454206 may represent a new marker of favorable disease in pediatric AML as it does not overlap with other favorable prognostic markers. Disclosures: No relevant conflicts of interest to declare.

Domain Distribution of Type 1 VWD Sequence Variants and Impact on Clinical and Laboratory Phenotype in the Zimmerman Program

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 758-758
Author(s):  
Pamela A Christopherson ◽  
Veronica H Flood ◽  
Sandra L Haberichter ◽  
Daniel B Bellissimo ◽  
Kenneth D Friedman ◽  
...  
Keyword(s):  
Splice Site ◽  
Clinical Severity ◽  
Comparative Genomic ◽  
Sequence Variant ◽  
Sequence Variants ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Large Deletions ◽  
Von Willebrand

Type 1 von Willebrand disease (VWD) is a common inherited bleeding disorder, characterized by a quantitative deficiency of von Willebrand factor (VWF). The molecular basis continues to merit exploration, especially since the genetic cause has not been determined in 30-40% of cases in previous studies. As part of the Zimmerman Program for the Molecular and Biology of VWD (ZPMCB-VWD) study, we sought to identify the sequence variants (SV) within the VWF gene that result in type 1 VWD and correlate these to clinical laboratory phenotype and clinical severity and determine the frequency of type 1 subjects who do not have a gene defect. We also wanted to examine the types of sequence variants that cause type 1, type 1-Severe (1S), type 1C and low VWF (LVWF), and determine the influence of SV location on VWF levels and risk of bleeding. 310 type 1 Index Cases (IC) enrolled in the ZPMCB-VWD were analyzed, including 69 type 1 (VWF:Ag<30), 9 type 1S (VWF:Ag<5), 57 type 1C (VWF:Ag<30; VWFpp/VWF:Ag>3), and 175 LVWF (VWF:Ag or VWF:RCo 30-50). Bleeding symptoms were quantified using the ISTH bleeding score (ISTH BS). Clinical VWF testing was done in a central laboratory at BloodCenter of Wisconsin and included FVIII, VWF:Ag, VWF:RCo, VWFpp, and VWF:CB. Full-length VWF sequencing was performed, including 5' and 3' regions and intron/exon boundaries. SV found in >1% of the healthy control population were excluded from this analysis. Mutation negative cases were further investigated by comparative genomic hybridization (CGH) to identify any large deletions or duplications in the VWF gene. SV or large deletions were identified in 62% (n=192) of this cohort with quantitative VWF deficiency, whereas 38% (n=118) had no variants found. Of those with no sequence variant identified, 10% were type 1, 5% type 1C and 85% LVWF. There were 142 SV found in this cohort. 75% of the subjects had missense mutations, 8% small insertions/deletions, 9% splice site mutations, 3% nonsense mutations and 1% large deletions. The median number of SV found in individuals was 1, however 23% had more than 1 SV present (range 1 to 4). Mean VWF:Ag (IU/dl) was examined to determine the influence of SV location on levels and median ISTH BS was assessed as a measure of bleeding severity by domain: Table.VWF DomainD1D2D'D3A1A2A3D4C1-C6CKNone# Subjects24343460251324304118VWF:Ag (IU/dl)18211614311221253839ISTH BS5665495515 Type 1S subjects had SV that were enriched in D1, D2 and A3 domains. 52% of type 1C variants were found in the A1 domain followed by 19% in D'D3 and 17% in D4. Both type 1 and LVWF subjects had SV that were evenly distributed throughout the gene, but LVWF had the majority of SV found in the A2, D2 and C1-C6 domains. Type 1S subjects showed a difference in mutation type compared to rest of the type 1 cohort with 31% intronic/splice site mutations, 19% nonsense mutations, 19% insertions/deletions and only 25% missense mutations. In contrast, missense mutations accounted for 68% of the mutations in type 1, 91% in type 1C and 80% in LVWF. The presence of predominantly truncating or loss of function variants in type 1S correlates with lower VWF levels and increased bleeding. In conclusion, we found that 62% of our type 1 cohort did have potentially causative SVs identified, with the majority caused by missense mutations (75%). Type 1C and type 1S tend to have SV isolated in certain domains whereas SV in type 1 and LVWF tend to be spread throughout the gene. SVs in the A3 domain demonstrated the lowest VWF:Ag (12 IU/dl) and highest ISTH BS (9) while changes in the CK domain had the highest VWF:Ag (38 IU/dl) and lowest ISTH BS (1). SVs or large deletions were not found in 38% of this cohort, indicating that other molecular factors either intronic or outside of the VWF gene may be the cause of low VWF and bleeding in these subjects. Disclosures Friedman: CSL Behring: Consultancy; Instrumentation Laboratories: Consultancy; Novo Nordisk: Consultancy; Alexion: Speakers Bureau. Gill:Baxalta, Bayer, and CSL-Behring: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Genome sequencing of normal cells reveals developmental lineages and mutational processes

Nature ◽  
2014 ◽  
Vol 513 (7518) ◽  
pp. 422-425 ◽  
Author(s):  
Sam Behjati ◽  
Meritxell Huch ◽  
Ruben van Boxtel ◽  
Wouter Karthaus ◽  
David C. Wedge ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Normal Cells ◽  
Mutational Processes
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