scholarly journals Cassava HapMap: Masking deleterious mutations in a clonal crop species

2016 ◽  
Author(s):  
Punna Ramu ◽  
Williams Esuma ◽  
Robert Kawuki ◽  
Ismail Y Rabbi ◽  
Chiedozie Egesi ◽  
...  
Keyword(s):  
Manihot Esculenta ◽  
Clonal Propagation ◽  
Human Consumption ◽  
Deleterious Mutations ◽  
Common Variants ◽  
Food Crop ◽  
Crop Species ◽  
Recessive Mutations ◽  
Mutational Burden ◽  
Mutation Burden

Cassava (Manihot esculenta Crantz) is an important staple food crop in Africa and South America, however, ubiquitous deleterious mutations may severely reduce its fitness. To evaluate these deleterious mutations in the cassava genome, we constructed a cassava haplotype map using deep sequencing from 241 diverse accessions and identified over 28 million segregating variants. We found that, 1) while domestication modified starch and ketone metabolism pathways for human consumption, the concomitant bottleneck and clonal propagation resulted in a large proportion of fixed deleterious amino acid changes, raised the number of deleterious mutations by 26%, and shifted the mutational burden towards common variants; 2) deleterious mutations are ineffectively purged due to limited recombination in cassava genome; 3) recent breeding efforts maintained the yield by masking the most damaging recessive mutations in the heterozygous state, but unable to purge the mutation burden, which should be a key target for future cassava breeding.

scholarly journals Expansion load: recessive mutations and the role of standing genetic variation

2014 ◽  
Author(s):  
Stephan Peischl ◽  
Laurent Excoffier
Keyword(s):  
Genetic Variation ◽  
Species Range ◽  
Human Populations ◽  
Deleterious Mutations ◽  
Recessive Mutations ◽  
Mutation Burden ◽  
Natural Range ◽  
Mean Fitness ◽  
Expansion Load

Expanding populations incur a mutation burden – the so-called expansion load. Previous studies of expansion load have focused on co-dominant mutations. An important consequence of this assumption is that expansion load stems exclusively from the accumulation of new mutations occurring in individuals living at the wave front. Using individual-based simulations we study here the dynamics of standing genetic variation at the front of expansions, and its consequences on mean fitness if mutations are recessive. We find that deleterious genetic diversity is quickly lost at the front of the expansion, but the loss of deleterious mutations at some loci is compensated by an increase of their frequencies at other loci. The frequency of deleterious homozygotes therefore increases along the expansion axis whereas the average number of deleterious mutations per individual remains nearly constant across the species range. This reveals two important differences to co-dominant models: (i) mean fitness at the front of the expansion drops much faster if mutations are recessive, and (ii) mutation load can increase during the expansion even if the total number of deleterious mutations per individual remains constant. We use our model to make predictions about the shape of the site frequency spectrum at the front of range expansion, and about correlations between heterozygosity and fitness in different parts of the species range. Importantly, these predictions provide opportunities to empirically validate our theoretical results. We discuss our findings in the light of recent results on the distribution of deleterious genetic variation across human populations, and link them to empirical results on the correlation of heterozygosity and fitness found in many natural range expansions.

scholarly journals A BRIEF REVIEW FOR IDENTIFICATION AND DETECTION OF POTATO VIRUSES

2016 ◽  
Vol 1 (1) ◽  
pp. 33 ◽  
Author(s):  
Madiha Urooj ◽  
Uzma Arif ◽  
Anisa Intikhab
Keyword(s):  
Potato Crop ◽  
Abiotic Factors ◽  
Review Article ◽  
Pivotal Role ◽  
Yield Reduction ◽  
Human Consumption ◽  
Yield Losses ◽  
Food Crop ◽  
Potato Viruses ◽  
Significant Yield

Potato is ranked fourth among the food crop and fifth for human consumption. It provides more yield and calories production as compare to cereals. Fungal, viral, viroid, bacteria, nematode, phytoplasmas and abiotic factors play a pivotal role for yield reduction of potato crop. Viruses known to infect potato in Pakistan include PVA, PVM, PVS, PVX, PVY, PLRV and PMTV. Increasing incidence of PVX and PVY in main potato growing areas of Pakistan is getting an alarming position and PLRV has caused significant yield losses. Present review article demonstrate different techniques for diagnostics of major potato viruses.

scholarly journals Genetic sex determination and sex-specific lifespan in tetrapods – evidence of a toxic Y effect

2020 ◽  
Author(s):  
Zahida Sultanova ◽  
Philip A. Downing ◽  
Pau Carazo
Keyword(s):  
Sex Chromosomes ◽  
Alternative Hypothesis ◽  
Z Chromosome ◽  
W Chromosome ◽  
Deleterious Mutations ◽  
Recessive Mutations ◽  
Y Chromosomes ◽  
Heterogametic Sex ◽  
Taxonomic Patterns

ABSTRACTSex-specific lifespans are ubiquitous across the tree of life and exhibit broad taxonomic patterns that remain a puzzle, such as males living longer than females in birds and vice versa in mammals. The prevailing “unguarded-X” hypothesis (UXh) explains this by differential expression of recessive mutations in the X/Z chromosome of the heterogametic sex (e.g., females in birds and males in mammals), but has only received indirect support to date. An alternative hypothesis is that the accumulation of deleterious mutations and repetitive elements on the Y/W chromosome might lower the survival of the heterogametic sex (“toxic Y” hypothesis). Here, we report lower survival of the heterogametic relative to the homogametic sex across 138 species of birds, mammals, reptiles and amphibians, as expected if sex chromosomes shape sex-specific lifespans. We then analysed bird and mammal karyotypes and found that the relative sizes of the X and Z chromosomes are not associated with sex-specific lifespans, contrary to UXh predictions. In contrast, we found that Y size correlates negatively with male survival in mammals, where toxic Y effects are expected to be particularly strong. This suggests that small Y chromosomes benefit male lifespans. Our results confirm the role of sex chromosomes in explaining sex differences in lifespan, but indicate that, at least in mammals, this is better explained by “toxic Y” rather than UXh effects.

Sustainability of cassava ( Manihot esculenta Crantz ) as industrial feedstock, energy and food crop in Nigeria

2015 ◽  
Vol 81 ◽  
pp. 745-752 ◽  
Author(s):  
C.N. Anyanwu ◽  
C.N. Ibeto ◽  
S.L. Ezeoha ◽  
N.J. Ogbuagu
Keyword(s):  
Manihot Esculenta ◽  
Food Crop ◽  
Manihot Esculenta Crantz

scholarly journals Most cancers carry a substantial deleterious load due to Hill-Robertson interference

2019 ◽  
Author(s):  
Susanne Tilk ◽  
Christina Curtis ◽  
Dmitri A Petrov ◽  
Christopher D McFarland
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Selection Model ◽  
Fitness Cost ◽  
Deleterious Mutations ◽  
Weak Selection ◽  
Selective Pressures ◽  
Mutational Burden ◽  
Genome Wide ◽  
Average Fitness

AbstractCancer genomes exhibit surprisingly weak signatures of negative selection1,2. This may be because tumors evolve under weak selective pressures (‘weak selection’) or because genome-wide linkage in cancer prevents most deleterious mutations from being removed due to Hill-Robertson interference3 (‘inefficient selection’). The weak selection model argues that most genes are only important for multicellular function and that selection acts only on a subset of essential genes. In contrast, the inefficient selection model predicts that only cancers with low mutational burdens, where linkage effects are minimal, will exhibit strong signals of negative selection against deleterious passengers and positive selection for beneficial drivers. We leverage the 10,000-fold variation in mutational burden across cancer subtypes to stratify tumors by their genome-wide mutational burden and used a normalized ratio of nonsynonymous to synonymous substitutions (dN/dS) to quantify the extent that selection varies with mutation rate. We find that appreciable negative selection (dN/dS ~ 0.4) is present in tumors with a low mutational burden, while the remaining cancers (96%) exhibit dN/dS ratios approaching 1, suggesting that the majority of tumors do not remove deleterious passengers. A parallel pattern is seen in drivers, where positive selection attenuates as the mutational burden of cancers increases. Both trends persist across tumor-types, are not exclusive to essential or housekeeping genes, are present in clonal and subclonal mutations, and persist in Copy Number Alterations. A consequence of this inability to remove deleterious passengers is that tumors with elevated mutational burdens, which are expected to harbor substantial protein folding stress, upregulate heat shock pathways. Finally, using evolutionary modeling, we find that Hill-Robertson interference alone can reproduce the patterns of attenuated selection observed in both drivers and passengers if the average fitness cost of passengers is 1.0% and the average fitness benefit of drivers is 19%. As a result, despite the weak individual fitness effects of passengers, most cancers harbor a large mutational load (median ~40% total fitness cost). Collectively, our findings suggest that the lack of observed negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove individual deleterious mutations in the presence of genome-wide linkage.

scholarly journals DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244558
Author(s):  
McKayla J. Riggs ◽  
Nan Lin ◽  
Chi Wang ◽  
Dava W. Piecoro ◽  
Rachel W. Miller ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Microsatellite Instability ◽  
Information Exchange ◽  
P Value ◽  
Tumor Mutation Burden ◽  
Prognostic Features ◽  
Oncology Research ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden

Objective DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population. Methods We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). Conclusions DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.

scholarly journals Prolonged Response to Anti–PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden

2019 ◽  
Vol 17 (6) ◽  
pp. 644-648 ◽  
Author(s):  
Olumide Gbolahan ◽  
Neda Hashemi-Sadraei ◽  
Bert O’Neil
Keyword(s):  
Overall Survival ◽  
Clinical Symptoms ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Tumor Genome ◽  
Prolonged Response

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

PD-L1 expression landscape and its relationship with tumor mutation burden in Chinese cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15267-e15267
Author(s):  
Haihua Yang ◽  
Longgang Cui ◽  
Yuzi Zhang ◽  
Zhengyi Zhao ◽  
Yuezong Bai ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Expression Profiles ◽  
Chinese Patients ◽  
Cancer Type ◽  
Tissue Samples ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Chinese Cancer Patients

e15267 Background: Little is known about the pan-cancer PD-L1 expression landscape in Chinese patients although PD-L1 expression has been approved by FDA as a diagnosis for anti-PD-(L)1 therapy in several types of cancer. We did a cross-sectional analysis to assess the PD-L1 expression landscape in Chinese patients and its relationship with Tumor mutation burden (TMB). Methods: Tissue samples were collected from more than 8,000 consecutive cases in China between January, 2017, and August, 2019 and were analyzed by 3D Medicines, a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The method for NGS sequencing and tumor mutational burden (TMB) measurement were described previously. Clinical data and PD-L1 expression profiles were obtained from 8,063 patients whose tissue samples assed quality control. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay (Dako North America, Carpentaria, CA, U.S.) or Ventana PD-L1 SP263 assay (Ventana Medical Systems, Tucson, AZ, U.S.). PD-L1 expression was determined using Tumor Proportion Score (TPS), the percentage of viable tumor cells stained. Results: PD-L1 expression was examined for 8,063 tissue samples collected from more than 18 different types of solid tumors. There were 4,866 (60%) male and 3,197 (40%) female patients. Their median age was 59 (IQR range, 50-66) years. Given the significance of different cut-points of PD-L1 expression in predicting clinical outcomes, expression levels of PD-L1 were arranged into the following intervals: < 1%, 1%-5%, 5%-50% and ≥50% for each cancer type. Small cell lung cancer (SCLC) had the lowest and Squamous Carcinoma of Head and Neck (HNSC) had the highest levels of PD-L1 expression. Spearman correlation analysis indicated no correlation between PD-L1 and tumor mutational burden (TMB) for Chinese cancer patients (R = 0.1, P < 0.01), which is in line with the previous reports that PD-L1 and TMB were two independent predictors in immunotherapy. Conclusions: The landscape of PD-L1 expression among Chinese cancer population in this study will further assist the utilization of PD-L1 as a predictive biomarker in clinical practice.

Real-world patterns on tumor mutation burden testing in a pan-tumor population

2021 ◽  
Author(s):  
Santosh Gautam ◽  
Sumesh Kachroo ◽  
Richard W DeClue ◽  
Maxine D Fisher ◽  
Anirban Basu
Keyword(s):  
Real World ◽  
Clinical Characteristics ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Black Patients ◽  
Study Results ◽  
Tumor Mutational Burden ◽  
Anticancer Treatment ◽  
World Information

Background: There is limited real-world information on use of tumor mutational burden (TMB) testing and characteristics of patients receiving it. Materials & methods: Patients ≥18 years old and diagnosed with advanced solid tumors between 1 January 2015 and 31 January 2019 with TMB testing (TMB cohort) and without it (non-TMB) were included in this retrospective, observational study. Results: The TMB cohort (n = 202) was younger than non-TMB (n = 212) (mean age 62.1 vs 65.6 at diagnosis; p = 0.005). There were more Black patients in the TMB cohort (21.3 vs 11.8% in non-TMB; p = 0.004). Clinical characteristics were comparable between the two cohorts; however, systemic anticancer treatment was higher among TMB cohort (91.6 vs 77.8% in non-TMB). Conclusion: Notable differences were observed between patients receiving TMB test and those not receiving it.

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