Corrigendum: Genome-wide genetic changes during modern breeding of maize

ABSTRACTBackgroundTreatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana - exposed to more than a decade of regular ivermectin treatment - have raised concern that sub-optimal responses to ivermectin’s anti-fecundity effect are becoming more frequent and may spread.Methodology/Principal FindingsPooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.Conclusions/SignificanceThis study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait in which identical or related molecular pathways but not necessarily individual genes likely determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations.Author summaryOnchocerciasis is a human parasitic disease endemic across large areas of Sub-Saharan Africa, where more that 99% of the estimated 100 million people globally at-risk live. The microfilarial stage of Onchocerca volvulus causes pathologies ranging from mild itching to visual impairment and ultimately, irreversible blindness. Mass administration of ivermectin kills microfilariae and has an anti-fecundity effect on adult worms by temporarily inhibiting the development in utero and/or release into the skin of new microfilariae, thereby reducing morbidity and transmission. Phenotypic and genetic changes in some parasite populations that have undergone multiple ivermectin treatments in Cameroon and Ghana have raised concern that sub-optimal response to ivermectin’s anti-fecundity effect may increase in frequency, reducing the impact of ivermectin-based control measures. We used next generation sequencing of small pools of parasites to define genome-wide genetic differences between phenotypically characterised good and sub-optimal responder parasites from Cameroon and Ghana, and identified multiple genomic regions differentiating the response types. These regions were largely different between parasites from both countries but revealed common molecular pathways that might be involved in determining the extent of response to ivermectin’s anti-fecundity effect. These data reveal a more complex than previously described pattern of genetic diversity among O. volvulus populations that differ in their geography and response to ivermectin treatment.

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High Resolution Genomic Profiling in CLL Using SNP Oligonucleotide Microarrays.

Blood ◽

10.1182/blood.v106.11.2946.2946 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2946-2946

Author(s):

Justyna Rawluk ◽

Dietmar Pfeifer ◽

Milena Pantic ◽

Hendrik Veelken

Keyword(s):

High Resolution ◽

Copy Number ◽

Fish Analysis ◽

Genomic Profiling ◽

Genetic Changes ◽

Genome Wide ◽

Custom Made ◽

Wide Range ◽

The Common ◽

Regions Of Homozygosity

Abstract Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by different recurrent chromosomal aberrations with prognostic significance. Therefore, convenient genome-wide assays to identify genetic changes with high accuracy are required to assess the risk category of an individual patient, and to identify genetic mechanisms underlying the malignant transformation. Array-based CGH with custom-made chips has been proposed for this purpose (Schwaenen et al., 2004). We analyzed unselected peripheral blood cells from 50 consecutive CLL patients (33 with mutated IgVH genes) for the presence of genetic changes using Affymetrix 10k and 50k SNP mapping arrays that allow copy number analysis with a mean intermarker distance 300 kb and 60 kb, respectively. The detection limit of the assay with respect to tumor cell content was 25 to 40 % as assessed by validation experiments with a commercially available panel of FISH probes for typical recurrent CLL aberrations. 14 cases (28%) failed to show any detectable abnormalities. Among the common prognostically important aberrations, we readily identified del13q14 in 26 (52%), trisomy 12 in 9 (18%), del11q22 in 6 (12%), and del17p13 in 3 cases (6%). In 9 cases, additional losses in 17q (3 cases), 14q (2 cases), 5q (2 cases), 1q, 18p and 20q were detected. Likewise, multiple gains like trisomy 3, dup17q and dup2p (2 cases) were diagnosed. In addition to their convenient detection, size and extent of genomic aberrations can be defined with high resolution due to the precise positional information of the SNPs: In 2 out of 6 patients with a del11q22, in which deletion of the ATM (ataxia-telangiectasia mutated) gene is thought to represent the critical event, the ATM gene was present, but a 1Mb deletion around the RDX (radixin) gene was revealed. These deletions were missed by FISH analysis with ATM-spanning probes. Similarly, TP53 was still present in 1 of 3 patients with del17p13, despite the common assumption that this deletion causes the loss of a TP53 allele. An observed gain of 2p16 could be narrowed down to a 3Mb region containing the REL gene. Overexpression of REL may contribute to resistance to DNA-damage-induced apoptosis in CLL cells in vitro (Vallat et al., 2003). Finally, both the 10k and 50k SNP arrays showed the extent of the most frequent del13q14 in a wide range with a size distribution of 500kb to over 30Mb. However, for a more reliable detection of the del13q14 core region, the 50k array may be preferable to the 10k version, since this region is covered by 34 compared to 4 SNPs, respectively. Unexpectedly, 3 of 6 cases with a homozygous del13q14 showed loss of heterozygosity (LOH) associated with a normal copy number distal to the del13q14 extending to the telomere. A similar phenomenon has recently been described in AML patients (Raghavan et al., 2005) and can be explained by a somatic recombination event. Preliminary analyses demonstrated additional large regions of homozygosity ranging from 3 to over 20Mb on various chromosomes in at least 12 CLL cases. In conclusion, genomic profiling with Affymetrix SNP microarrays is an efficient screening method for simultaneous genome-wide detection of submicroscopic aberrations. Information on genotype with dosis information reveals hitherto undetected regions of homozygosity that may harbor imprinted genes or loss-of-function alleles with importance for the pathogenesis of CLL.

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Genetic Profile of Adenoid Cystic Carcinomas (ACC) with High-Grade Transformation versus Solid Type

Analytical Cellular Pathology ◽

10.1155/2010/706205 ◽

2010 ◽

Vol 33 (5-6) ◽

pp. 217-228 ◽

Cited By ~ 5

Author(s):

Ana Flávia Costa ◽

Albina Altemani ◽

Hedy Vékony ◽

Elisabeth Bloemena ◽

Florentino Fresno ◽

...

Keyword(s):

Copy Number ◽

Genetic Profile ◽

High Grade ◽

Ki 67 ◽

Genetic Changes ◽

Genome Wide ◽

Genetic Complexity ◽

Poorly Differentiated ◽

High Grade Transformation ◽

Copy Number Changes

Background: ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features and to compare results to solid ACC.Methods: Genome-wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, 4 with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), 5 solid ACC. In addition, Ki-67 index and p53 immunopositivity was assessed.Results: ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component.Conclusion: ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC.

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PfGCN5, a global regulator of stress responsive genes, modulates artemisinin resistance inPlasmodium falciparum

10.1101/679100 ◽

2019 ◽

Cited By ~ 1

Author(s):

Mukul Rawat ◽

Abhishek Kanyal ◽

Aishwarya Sahasrabudhe ◽

Shruthi S. Vembar ◽

Jose-Juan Lopez-Rubio ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Stress Responses ◽

Artemisinin Resistance ◽

Genetic Changes ◽

Important Target ◽

Genome Wide ◽

Chromatin Regulator ◽

Stress Responsive Genes ◽

Almost All

AbstractPlasmodium falciparumhas evolved resistance to almost all front-line drugs including artemisinins, which threatens malaria control and elimination strategies. Oxidative stress and protein damage responses have emerged as key players in the generation of artemisinin resistance. In this study, we show that PfGCN5, a histone acetyltransferase, binds to the stress responsive and multi-variant family genes in poised state and regulates their expression under stress conditions. We have also provided biochemical and cellular evidences that PfGCN5 regulates stress responsive genes by acetylation of PfAlba3. Furthermore, we show that upon artemisinin exposure, genome-wide binding sites for PfGCN5 are increased and it is directly associated with the genes implicated in artemisinin resistance generation like BiP and TRiC chaperone. Moreover, inhibition of PfGCN5 in artemisinin resistant parasites, Kelch13 mutant, K13I543T and K13C580Y (RSA∼ 25% and 6%, respectively) reverses the sensitivity of the parasites to artemisinin treatment indicating its role in drug resistance generation. Together, these findings elucidate the role of PfGCN5 as a global chromatin regulator of stress-responses with potential role in modulating artemisinin drug resistance, and identify PfGCN5 as an important target against artemisinin resistant parasites.Author SummaryMalaria parasites are constantly adapting to the drugs we used to eliminate them. Thus, when we use the drugs to kill parasites; with time, we select the parasites with the favourable genetic changes. Parasites develop various strategies to overcome exposure to the drugs by exhibiting the stress responses. The changes specific to the drug adapted parasites can be used to understand the mechanism of drug resistance generation. In this study, we have identified PfGCN5 as a global transcriptional regulator of stress responses inPlasmodium falciparum. Inhibition of PfGCN5 reverses the sensitivity of the parasites to the artemisinin drug and identify PfGCN5 as an important target against artemisinin resistant parasites.

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A chromosome-level genome of a Kordofan melon illuminates the origin of domesticated watermelons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2101486118 ◽

2021 ◽

Vol 118 (23) ◽

pp. e2101486118

Author(s):

Susanne S. Renner ◽

Shan Wu ◽

Oscar A. Pérez-Escobar ◽

Martina V. Silber ◽

Zhangjun Fei ◽

...

Keyword(s):

Citrullus Lanatus ◽

Wild Relatives ◽

Nile Valley ◽

Structural Variants ◽

Flesh Color ◽

Genetic Changes ◽

Modern Cultivar ◽

Melon Genome ◽

Modern Breeding ◽

Chromosome Level

Wild relatives or progenitors of crops are important resources for breeding and for understanding domestication. Identifying them, however, is difficult because of extinction, hybridization, and the challenge of distinguishing them from feral forms. Here, we use collection-based systematics, iconography, and resequenced accessions of Citrullus lanatus and other species of Citrullus to search for the potential progenitor of the domesticated watermelon. A Sudanese form with nonbitter whitish pulp, known as the Kordofan melon (C. lanatus subsp. cordophanus), appears to be the closest relative of domesticated watermelons and a possible progenitor, consistent with newly interpreted Egyptian tomb paintings that suggest that the watermelon may have been consumed in the Nile Valley as a dessert by 4360 BP. To gain insights into the genetic changes that occurred from the progenitor to the domesticated watermelon, we assembled and annotated the genome of a Kordofan melon at the chromosome level, using a combination of Pacific Biosciences and Illumina sequencing as well as Hi-C mapping technologies. The genetic signature of bitterness loss is present in the Kordofan melon genome, but the red fruit flesh color only became fixed in the domesticated watermelon. We detected 15,824 genome structural variants (SVs) between the Kordofan melon and a typical modern cultivar, “97103,” and mapping the SVs in over 400 Citrullus accessions revealed shifts in allelic frequencies, suggesting that fruit sweetness has gradually increased over the course of watermelon domestication. That a likely progenitor of the watermelon still exists in Sudan has implications for targeted modern breeding efforts.

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Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice

Science ◽

10.1126/science.aaw7166 ◽

2019 ◽

pp. eaaw7166 ◽

Cited By ~ 77

Author(s):

Shuai Jin ◽

Yuan Zong ◽

Qiang Gao ◽

Zixu Zhu ◽

Yanpeng Wang ◽

...

Keyword(s):

High Fidelity ◽

Single Nucleotide Variants ◽

Disease Treatment ◽

Single Nucleotide ◽

Genetic Changes ◽

Base Editing ◽

Guide Rna ◽

Genome Wide ◽

Adenine Base

Cytosine and adenine base editors (CBEs and ABEs) are promising new tools for achieving the precise genetic changes required for disease treatment and trait improvement. However, genome-wide and unbiased analyses of their off-target effects in vivo are still lacking. Our whole genome sequencing (WGS) analysis of rice plants treated with BE3, high-fidelity BE3 (HF1-BE3), or ABE revealed that BE3 and HF1-BE3, but not ABE, induce substantial genome-wide off-target mutations, which are mostly the C→T type of single nucleotide variants (SNVs) and appear to be enriched in genic regions. Notably, treatment of rice with BE3 or HF1-BE3 in the absence of single-guide RNA also results in the rise of genome-wide SNVs. Thus, the base editing unit of BE3 or HF1-BE3 needs to be optimized in order to attain high fidelity.

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Genome Wide Analysis Reveals the Role of VadA in Stress Response, Germination, and Sterigmatocystin Production in Aspergillus nidulans Conidia

Microorganisms ◽

10.3390/microorganisms8091319 ◽

2020 ◽

Vol 8 (9) ◽

pp. 1319 ◽

Cited By ~ 1

Author(s):

Ye-Eun Son ◽

Hee-Soo Park

Keyword(s):

Stress Response ◽

Secondary Metabolism ◽

Aspergillus Nidulans ◽

Gene Clusters ◽

Tube Formation ◽

Spore Viability ◽

Genetic Changes ◽

Genome Wide ◽

Trehalose Biosynthesis

In the Aspergillus species, conidia are asexual spores that are infectious particles responsible for propagation. Conidia contain various mycotoxins that can have detrimental effects in humans. Previous study demonstrated that VadA is required for fungal development and spore viability in the model fungus Aspergillus nidulans. In the present study, vadA transcriptomic analysis revealed that VadA affects the mRNA expression of a variety of genes in A. nidulans conidia. The genes that were primarily affected in conidia were associated with trehalose biosynthesis, cell-wall integrity, stress response, and secondary metabolism. Genetic changes caused by deletion of vadA were related to phenotypes of the vadA deletion mutant conidia. The deletion of vadA resulted in increased conidial sensitivity against ultraviolet stress and induced germ tube formation in the presence and absence of glucose. In addition, most genes in the secondary metabolism gene clusters of sterigmatocystin, asperfuranone, monodictyphenone, and asperthecin were upregulated in the mutant conidia with vadA deletion. The deletion of vadA led to an increase in the amount of sterigmatocystin in the conidia, suggesting that VadA is essential for the repression of sterigmatocystin production in conidia. These results suggest that VadA coordinates conidia maturation, stress response, and secondary metabolism in A. nidulans conidia.

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Genomic Analysis of Vavilov’s Historic Chickpea Landraces Reveals Footprints of Environmental and Human Selection

International Journal of Molecular Sciences ◽

10.3390/ijms21113952 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3952 ◽

Cited By ~ 1

Author(s):

Alena Sokolkova ◽

Sergey V. Bulyntsev ◽

Peter L. Chang ◽

Noelia Carrasquilla-Garcia ◽

Anna A. Igolkina ◽

...

Keyword(s):

Association Studies ◽

Genomic Analysis ◽

Phenotypic Traits ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Multiple Traits ◽

Phenotypic Data ◽

Genome Wide ◽

Bioclimatic Variables ◽

Modern Breeding

A defining challenge of the 21st century is meeting the nutritional demands of the growing human population, under a scenario of limited land and water resources and under the specter of climate change. The Vavilov seed bank contains numerous landraces collected nearly a hundred years ago, and thus may contain ‘genetic gems’ with the potential to enhance modern breeding efforts. Here, we analyze 407 landraces, sampled from major historic centers of chickpea cultivation and secondary diversification. Genome-Wide Association Studies (GWAS) conducted on both phenotypic traits and bioclimatic variables at landraces sampling sites as extended phenotypes resulted in 84 GWAS hits associated to various regions. The novel haploblock-based test identified haploblocks enriched for single nucleotide polymorphisms (SNPs) associated with phenotypes and bioclimatic variables. Subsequent bi-clustering of traits sharing enriched haploblocks underscored both non-random distribution of SNPs among several haploblocks and their association with multiple traits. We hypothesize that these clusters of pleiotropic SNPs represent co-adapted genetic complexes to a range of environmental conditions that chickpea experienced during domestication and subsequent geographic radiation. Linking genetic variation to phenotypic data and a wealth of historic information preserved in historic seed banks are the keys for genome-based and environment-informed breeding intensification.

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