scholarly journals Fitness Effects of Somatic Mutations Accumulating during Vegetative Growth

2018 ◽  
Author(s):  
Mitchell B. Cruzan ◽  
Matthew A. Streisfeld ◽  
Jaime A. Schwoch
Keyword(s):  
Sexual Reproduction ◽  
Somatic Mutation ◽  
Vegetative Growth ◽  
Somatic Mutations ◽  
Life Form ◽  
Deleterious Mutations ◽  
Mimulus Guttatus ◽  
Next Generation ◽  
Fitness Effects ◽  
Offspring Fitness

AbstractThe unique life form of plants promotes the accumulation of somatic mutations that can be passed to offspring in the next generation, because the same meristem cells responsible for vegetative growth also generate gametes for sexual reproduction. However, little is known about the consequences of somatic mutation accumulation for offspring fitness. We evaluate the fitness effects of somatic mutations in Mimulus guttatus by comparing progeny from self-pollinations made within the same flower (autogamy) to progeny from self-pollinations made between stems on the same plant (geitonogamy). The effects of somatic mutations are evident from this comparison, as autogamy leads to homozygosity of a proportion of somatic mutations, but progeny from geitonogamy remain heterozygous for mutations unique to each stem. In two different experiments, we find consistent fitness effects of somatic mutations from individual stems. Surprisingly, several progeny groups from autogamous crosses displayed increases in fitness compared to progeny from geitonogamy crosses, indicating that beneficial somatic mutations were prevalent in some stems. These results support the hypothesis that somatic mutations accumulate during vegetative growth, but they are filtered by different forms of selection that occur throughout development, resulting in the culling of expressed deleterious mutations and the retention of beneficial mutations.

scholarly journals Inbreeding Load, Average Dominance and the Mutation Rate for Mildly Deleterious Alleles in Mimulus guttatus

Genetics ◽  
1999 ◽  
Vol 153 (4) ◽  
pp. 1885-1898 ◽  
Author(s):  
John H Willis
Keyword(s):  
Inbreeding Depression ◽  
Deleterious Mutations ◽  
Mimulus Guttatus ◽  
Fitness Component ◽  
Fitness Effects ◽  
Fitness Traits ◽  
Deleterious Alleles ◽  
Degree Of Dominance ◽  
Almost All ◽  
Load Average

Abstract The goal of this study is to provide information on the genetics of inbreeding depression in a primarily outcrossing population of Mimulus guttatus. Previous studies of this population indicate that there is tremendous inbreeding depression for nearly every fitness component and that almost all of this inbreeding depression is due to mildly deleterious alleles rather than recessive lethals or steriles. In this article I assayed the homozygous and heterozygous fitnesses of 184 highly inbred lines extracted from a natural population. Natural selection during the five generations of selfing involved in line formation essentially eliminated major deleterious alleles but was ineffective in purging alleles with minor fitness effects and did not appreciably diminish overall levels of inbreeding depression. Estimates of the average degree of dominance of these mildly deleterious alleles, obtained from the regression of heterozygous fitness on the sum of parental homozygous fitness, indicate that the detrimental alleles are partially recessive for most fitness traits, with h~∼0.15 for cumulative measures of fitness. The inbreeding load, B, for total fitness is ~1.0 in this experiment. These results are consistent with the hypothesis that spontaneous mildly deleterious mutations occur at a rate >0.1 mutation per genome per generation.

scholarly journals Somatic Mutations Predict Poor Prognosis in Myelodysplastic Syndrome Patients with Normal Karyotypes

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Xiangzong Zeng ◽  
Min Dai ◽  
Yu Zhang ◽  
Lingling Zhou ◽  
Ya Zhou ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myelodysplastic Syndrome ◽  
Somatic Mutation ◽  
Poor Prognosis ◽  
Somatic Mutations ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Normal Karyotype ◽  
Next Generation ◽  
Generation Sequencing

Purpose: Somatic mutations are common in myelodysplastic syndrome (MDS), but its risk stratification is mainly based on cytogenetics. This study was to explore the prognostic significance of somatic mutations in MDS patients with normal karyotypes. Patients and Methods: Three hundred and four patients with MDS were enrolled in this retrospective study. A genomic panel of 127 gene targets were detected by next-generation sequencing. Results: Two hundred and Eighty-one (92.4%) patients carried at least one somatic mutation, while cytogenetics identified abnormalities in 140 (46.1%) patients. The 5 most frequently mutated genes were TET2, ASXL1, EZH2, TET1, FAT1, and TET2, TP53, TET1, EP300, SF3B1 in the patients with normal karyotypes and aberrant karyotypes, respectively. When mutations detected in >5% of the whole cohort, they were included in analysis and the results showed that the frequency of TET2, TP53, ASXL1, CD101, KDM6A, SH2B3 and IL-3RA mutations was different between two groups(all P<0.05). ASXL1, CD101, KDM6A, SH2B3, IL-3RA mutations were more common in normal karyotype group, while TET2 and TP53 were more common in aberrant karyotype group. Multivariable analysis showed that age (HR 1.02; P=0.027), IPSS-R(HR 1.80; P<0.0001), TP53(HR 2.36; P<0.0001) and DNMT3A (HR 1.83, P=0.044) were the risk factors while allo-HSCT(HR 0.50; P=0.001) was a protect factor for OS in the whole cohort. For sub-group analysis, IPSS-R(HR 1.54; P=0.005; HR 1.80; P<0.0001, respectively), TP53 mutation(HR 2.49; P=0.030; HR 2.13; P=0.005, respectively) and allo-HSCT(HR 0.52; P=0.040; HR 0.37; P<0.0001, respectively) retained the prognostic significance in both the normal karyotype and aberrant karyotype group. FAT1(HR 2.32; P=0.019), DNMT3A(HR 3.32; P=0.006) and IL-7R(HR 4.35; P=0.002) mutations were unfavorable factors for OS only in the normal karyotype group. Conclusion: FAT1, IL-7R and DNMT3A mutations pretict poor prognosis in MDS patients with normal karyotypes. Key words: Somatic mutation, Next-generation sequencing, Prognosis, Myelodysplastic syndrome Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Implications of Copy Number Alteration Detection Using Panel-Based Next-Generation Sequencing Data in Myelodysplastic Syndrome

2020 ◽  
Author(s):  
Yoo-Jin Kim ◽  
SeungHyun Jung ◽  
Eun-Hye Hur ◽  
Eun-Ji Choi ◽  
Kyoo-Hyung Lee ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myelodysplastic Syndrome ◽  
Somatic Mutation ◽  
Copy Number ◽  
Somatic Mutations ◽  
Clinical Implications ◽  
Next Generation ◽  
Clinical Variables ◽  
Ngs Data ◽  
Generation Sequencing

Abstract Background: Recent advancements in next-generation sequencing (NGS) technologies allow the simultaneous identification of targeted copy number alterations (CNAs) as well as somatic mutations using the same panel-based NGS data. We investigated whether CNAs detected by the targeted NGS data provided additional clinical implications, over somatic mutations, in myelodysplastic syndrome (MDS). Methods: Targeted deep sequencing of 28 well-known MDS-related genes was performed for 266 patients with MDS. Results: Overall, 215 (80.8%) patients were found to have at least one somatic mutation; 67 (25.2%) had at least one CNA; 227 (85.3%) had either a somatic mutation or CNA; 160 had somatic mutations without CNA; and 12 had CNA without somatic mutations. Considering the clinical variables and somatic mutations alone, multivariate analysis demonstrated that sex, revised International Prognostic Scoring System (IPSS-R) and NRAS and TP53 mutations were independent prognostic factors for overall survival. For AML-free survival, these factors were sex, IPSS-R, and mutations in NRAS, DNMT3A, and complex karyotype/TP53 mutations. When we consider clinical variables along with somatic mutations and CNAs, genetic alterations in TET2, LAMB4, U2AF1, and CBL showed additional significant impact on the survivals. Conclusions: Our study suggests that the concurrent detection of somatic mutations and targeted CNAs may provide clinically useful information for the prognosis of MDS patients.

scholarly journals Limited Dispersal, Deleterious Mutations and the Evolution of Sex

Genetics ◽  
1996 ◽  
Vol 142 (3) ◽  
pp. 1053-1060
Author(s):  
Joel R Peck
Keyword(s):  
Mathematical Model ◽  
Sexual Reproduction ◽  
Genetic Locus ◽  
Genetic Material ◽  
Plant Population ◽  
Deleterious Mutations ◽  
Animal Populations ◽  
Offspring Sex ◽  
Limited Dispersal ◽  
Hermaphroditic Plant

Abstract This study presents a mathematical model that allows for some offspring to be dispersed at random, while others stay close to their mothers. A single genetic locus is assumed to control fertility, and this locus is subject to the occurrence of deleterious mutations. It is shown that, at equilibrium, the frequency of deleterious mutations in the population is inversely related to the rate of dispersal. This is because dispersal of offspring leads to enhanced competition among adults. The results also show that sexual reproduction can lead to a decrease in the equilibrium frequency of deleterious mutations. The reason for this relationship is that sex involves the dispersal of genetic material, and thus, like the dispersal of offspring, sex enhances competition among adults. The model is described using the example of a hermaphroditic plant population. However, the results should apply to animal populations as well.

scholarly journals The Advantages of Segregation and the Evolution of Sex

Genetics ◽  
2003 ◽  
Vol 164 (3) ◽  
pp. 1099-1118 ◽  
Author(s):  
Sarah P Otto
Keyword(s):  
Sexual Reproduction ◽  
Asexual Reproduction ◽  
Deleterious Mutations ◽  
Evolution Of Sex ◽  
Beneficial Mutations ◽  
Selection Regime ◽  
Strong Selection ◽  
Genome Wide ◽  
Low Levels

AbstractIn diploids, sexual reproduction promotes both the segregation of alleles at the same locus and the recombination of alleles at different loci. This article is the first to investigate the possibility that sex might have evolved and been maintained to promote segregation, using a model that incorporates both a general selection regime and modifier alleles that alter an individual’s allocation to sexual vs. asexual reproduction. The fate of different modifier alleles was found to depend strongly on the strength of selection at fitness loci and on the presence of inbreeding among individuals undergoing sexual reproduction. When selection is weak and mating occurs randomly among sexually produced gametes, reductions in the occurrence of sex are favored, but the genome-wide strength of selection is extremely small. In contrast, when selection is weak and some inbreeding occurs among gametes, increased allocation to sexual reproduction is expected as long as deleterious mutations are partially recessive and/or beneficial mutations are partially dominant. Under strong selection, the conditions under which increased allocation to sex evolves are reversed. Because deleterious mutations are typically considered to be partially recessive and weakly selected and because most populations exhibit some degree of inbreeding, this model predicts that higher frequencies of sex would evolve and be maintained as a consequence of the effects of segregation. Even with low levels of inbreeding, selection is stronger on a modifier that promotes segregation than on a modifier that promotes recombination, suggesting that the benefits of segregation are more likely than the benefits of recombination to have driven the evolution of sexual reproduction in diploids.

scholarly journals Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Tarun Karthik Kumar Mamidi ◽  
Jiande Wu ◽  
Chindo Hicks
Keyword(s):  
Signaling Pathways ◽  
Somatic Mutation ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Multiple Gene ◽  
Gene Regulatory ◽  
Aggressive Tumors ◽  
Prostate Cancers ◽  
Mutation Information

Background. A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa. Materials and Methods. We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis. Results. We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa. Conclusion. The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape.

scholarly journals A Meta-analysis of Somatic Mutations from Next Generation Sequencing of 241 Melanomas: A Road Map for the Study of Genes with Potential Clinical Relevance

2014 ◽  
Vol 13 (7) ◽  
pp. 1918-1928 ◽  
Author(s):  
Junfeng Xia ◽  
Peilin Jia ◽  
Katherine E. Hutchinson ◽  
Kimberly B. Dahlman ◽  
Douglas Johnson ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Clinical Relevance ◽  
Somatic Mutations ◽  
Meta Analysis ◽  
Next Generation ◽  
Road Map ◽  
Generation Sequencing
Sign in / Sign up

Export Citation Format

Share Document