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PubMed2003

On the trail of a cereal killer: Exploring the biology of Magnaporthe grisea.

The blast fungus Magnaporthe grisea causes a serious disease on a wide variety of grasses including rice, wheat, and barley. Rice blast is the most serious disease of cultivated rice and therefore poses a threat to the world's most important food security crop. Here, I review recent progress toward understanding the molecular biology of plant infection by M. grisea, which involves development of a specialized cell, the appressorium. This dome-shaped cell generates enormous turgor pressure and physical force, allowing the fungus to breach the host cuticle and invade plant tissue. The review also considers the role of avirulence genes in M. grisea and the mechanisms by which resistant rice cultivars are able to perceive the fungus and defend themselves. Finally, the likely mechanisms that promote genetic diversity in M. grisea and our current understanding of the population structure of the blast fungus are evaluated.

Genetic Variation↗

PubMed2005

A second-site suppressor strategy for chemical genetic analysis of diverse protein kinases.

Chemical genetic analysis of protein kinases involves engineering kinases to be uniquely sensitive to inhibitors and ATP analogs that are not recognized by wild-type kinases. Despite the successful application of this approach to over two dozen kinases, several kinases do not tolerate the necessary modification to the ATP binding pocket, as they lose catalytic activity or cellular function upon mutation of the 'gatekeeper' residue that governs inhibitor and nucleotide substrate specificity. Here we describe the identification of second-site suppressor mutations to rescue the activity of 'intolerant' kinases. A bacterial genetic selection for second-site suppressors using an aminoglycoside kinase APH(3')-IIIa revealed several suppressor hotspots in the kinase domain. Informed by results from this selection, we focused on the beta sheet in the N-terminal subdomain and generated a structure-based sequence alignment of protein kinases in this region. From this alignment, we identified second-site suppressors for several divergent kinases including Cdc5, MEKK1, GRK2 and Pto. The ability to identify second-site suppressors to rescue the activity of intolerant kinases should facilitate chemical genetic analysis of the majority of protein kinases in the genome.

Amino Acid Substitution↗

PubMed1991

Influence of genome imprinting on gene expression, phenotypic variations and development.

Genome imprinting confers functional differences on parental chromosomes as a result of the differences in epigenetic inheritance from parental germlines. Repressed and derepressed chromatin structures probably constitute the initial germline-dependent 'imprints'. Any subsequent modifications, such as DNA methylation, will be influenced by these initial epigenetic modifications. Hence, epigenetic modifications of parental alleles probably occur progressively and this will affect their potential for expression. It appears that imprinting of some parental alleles is critical for their dosage, affecting embryonic growth, cell proliferation and differentiation. Genetic studies highlight the influence of subsets of imprinted genes and identify those which are crucial for development. Genomic imprinting also affects some transgene loci and dominant mutations with accompanying variable penetrance and expressivity. The response of transgenes can be influenced by modifier genes whose presence is most readily detected in different inbred backgrounds. The influence of modifier genes can in turn be affected by their parental origin, perhaps partly by the maternally inherited oocyte cytoplasmic factors, as well as by complex interactions between some parental alleles and oocyte cytoplasmic factors. The resulting epigenetic modifications of unlinked loci can result in substantial phenotypic variations.

Animals↗

PubMed1989

Structure of rDNA in the mosquito Anopheles gambiae and rDNA sequence variation within and between species of the A. gambiae complex.

The structure of the rDNA repeating unit of Anopheles gambiae (Diptera: Culicidae) was determined by restriction endonuclease mapping and hybridization analyses on four independent clones obtained from a genomic library of a colony (G3) from the Gambia (West Africa). rDNA gene coding sequences are conserved, but much intragenomic and intraspecific (geographic) variation occurs in the intergenic spacer. Hybridization of subclones from spacer and coding sequences to genomic DNA that was isolated from single mosquitoes from laboratory colonies of four other A. gambiae complex species reveals conservation of coding sequences but concerted evolution in the intergenic spacers.

Africa, Western↗

PubMed2025

In silico generation of synthetic cancer genomes using generative AI.

Understanding how genomic alterations drive cancer is key to advancing precision oncology. To detect these alterations, accurate algorithms are used; however, due to privacy concerns, few deeply sequenced cancer genomes can be shared, limiting benchmarking and representing a major obstacle to the improvement of analytic tools. To address this, we developed OncoGAN, a generative AI model combining adversarial networks and variational autoencoders to create realistic synthetic cancer genomes. Trained on large-scale genomic datasets, OncoGAN accurately reproduces somatic mutations, copy number alterations, and structural variants across cancer types while preserving donors' privacy. The synthetic genomes reflect tumor-specific mutational signatures and positional mutation patterns. Using DeepTumour, we validated the synthetic data's fidelity, showing high concordance between generated and predicted tumors. Moreover, augmenting the training data with synthetic genomes improved DeepTumour's accuracy, underscoring OncoGAN's potential to generate shareable datasets with known ground truths for benchmarking and enhancement of cancer genome analysis tools.

Humans↗

PubMed2026

A De Novo 16p13.3 Triplication Underlying Early-Onset Complex Neurodegeneration.

BACKGROUND: Neurodegenerative disorders are clinically and genetically heterogeneous, characterized by progressive neuronal loss and multidomain functional decline. Despite a presumed genetic etiology, a substantial proportion of cases remain molecularly undiagnosed. OBJECTIVE: The aim was to identify the genetic cause of an early-onset neurodegenerative disorder presenting with ataxia and cognitive impairment. METHODS: Rare copy-number variants were detected via short-read whole-genome sequencing (WGS), with candidate structural models inferred using long-read WGS. We performed transcriptomic profiling of peripheral blood leukocytes by RNA sequencing, with validation using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: We identified a de novo copy-number gain at 16p13.3. Combined copy-number profiling and long-read WGS suggested a candidate model comprising a triplicated segment in tandem with a proximal duplication, joined to a distal duplication via an inverted junction. Transcriptomic analysis demonstrated significant upregulation of ATP6V0C, AMDHD2, and PDPK1. CONCLUSIONS: These findings support a role for structural variation in early-onset neurodegeneration and highlight the value of combining short-read copy-number profiling with long-read WGS to detect and characterize complex genomic rearrangements. © 2026 International Parkinson and Movement Disorder Society.

16p13.3↗

PubMed1999

Characterization of the structural-protein-coding region of SAT 2 type foot-and-mouth disease virus.

The South African Territories (SAT) types of foot-and-mouth disease (FMD) virus show marked genomic and antigenic variation in sub-Saharan Africa that is to a large extent geographically determined. This has implications for selection of appropriate vaccine strains as well as the accuracy of laboratory diagnosis. However, adaptation of field isolates as vaccine strains is cumbersome, time consuming and expensive. We propose the construction of recombinant viruses in which specific antigenic determinants can be manipulated. To achieve this goal, the structural-protein-coding region of a SAT 2 vaccine strain, ZIM 7/83/2, was determined and compared with two other known SAT 2 P1 regions. Five hypervariable regions were identified of which four are situated within VP1. The cleavage sites for proteolytic processing differs from serotype A, while the junction between P1/2A is variable within the SAT 2 serotype. These differences could influence the construction of recombinant vaccines.

Amino Acid Sequence↗

PubMed2026

Signals of Natural Selection Across Regions of Low Recombination in Wild Populations of the Purple Sea Urchin, Strongylocentrotus purpuratus.

Structural variants (SVs) are increasingly recognized as important components of genetic architecture. Yet our understanding of the evolutionary forces maintaining SVs in natural populations is limited. Chromosomal inversions in particular can facilitate local adaptation in populations with high gene flow, including many marine species. The purple sea urchin (Strongylocentrotus purpuratus) is a powerful system to study these dynamics due to its high gene flow, lack of population structure, and broad latitudinal range. We analyzed whole genome sequence data from 137 individuals sampled across seven populations to identify regions of low recombination using scans for elevated linkage disequilibrium and genetic differentiation. Such regions may arise from structural variants, including chromosomal inversions. We identified nine regions showing signatures of reduced recombination, including three way genotype clustering, long range linkage, and hanging bridge patterns frequently associated with inversion polymorphisms. The regions were polymorphic within locations and along the species range with three loci showing concordant signatures of balancing and spatially heterogeneous selection based on enrichment of outliers and distinct patterns of allelic age. Additionally, these loci showed enrichment for genes associated with biomineralization and development. Our results provide the first evidence for regions of low recombination in the purple sea urchin genome, several of which display genomic signatures consistent with structural variants such as chromosomal inversions. These findings add to growing evidence that regions of reduced recombination constitute an important component of standing genetic variation in natural populations and may play a key role in adaptation to heterogeneous environments.

Strongylocentrotus purpuratus↗

PubMed2003

Impact of alternative initiation, splicing, and termination on the diversity of the mRNA transcripts encoded by the mouse transcriptome.

We analyzed the FANTOM2 clone set of 60,770 RIKEN full-length mouse cDNA sequences and 44,122 public mRNA sequences. We developed a new computational procedure to identify and classify the forms of splice variation evident in this data set and organized the results into a publicly accessible database that can be used for future expression array construction, structural genomics, and analyses of the mechanism and regulation of alternative splicing. Statistical analysis shows that at least 41% and possibly as much as 60% of multiexon genes in mouse have multiple splice forms. Of the transcription units with multiple splice forms, 49% contain transcripts in which the apparent use of an alternative transcription start (stop) is accompanied by alternative splicing of the initial (terminal) exon. This implies that alternative transcription may frequently induce alternative splicing. The fact that 73% of all exons with splice variation fall within the annotated coding region indicates that most splice variation is likely to affect the protein form. Finally, we compared the set of constitutive (present in all transcripts) exons with the set of cryptic (present only in some transcripts) exons and found statistically significant differences in their length distributions, the nucleotide distributions around their splice junctions, and the frequencies of occurrence of several short sequence motifs.

Alternative Splicing↗

PubMed1991

Structure of the human gene for monoamine oxidase type A.

Monoamine oxidases, type A and type B, are principal enzymes for the degradation of biogenic amines, including catecholamines and serotonin. These isozymes have been implicated in neuropsychiatric disorders. Previously, cDNA clones for both MAO-A and MAO-B have been sequenced and the genes encoding them have been localized to human chromosome Xp11.23-Xp11.4. In this work, we isolated human genomic clones spanning almost all the MAOA gene from cosmid and phage libraries using a cDNA probe for MAO-A. Restriction mapping and sequencing show that the human MAOA gene extends over 70 kb and is composed of 15 exons. The exon structure of human MAOA is similar to that described by others for human MAOB. Exon 12 (bearing the codon for cysteine, which carries the covalently bound FAD cofactor) and exon 13 are highly conserved between human MAOA and MAOB genes (92% at the amino acid level). Earlier work revealed two species of MAO-A mRNA, 2.1 kb and 4.5-5.5 kb. We now report on further cDNA isolation and sequencing, which demonstrates that the longer message has an extension of 2.2 kb in the 3' noncoding region. This extended region is contained entirely within exon 15. The two messages therefore appear to be generated by the use of two alternative polyadenylation sites. Results from the present work should facilitate the mutational analysis of functional domains of MAO-A and MAO-B. Knowledge of the gene structure will also help in evaluating the role of genetic variations in MAO-A in human disease through the use of genomic DNA, which is more accessible than the RNA, as a template for PCR-amplification and sequencing.

Amino Acid Sequence↗

PubMed1987

Impact of plasmids and genetic change on the numerical classification of staphylococci.

Newly isolated bacterial strains often contain extrachromosomal DNA as plasmid DNA. These accessory components of the DNA gene pool confer additional phenotypic properties on their host but, despite this, little attention has been paid to the impact of plasmid-mediated characters on bacterial classification. In the present study, the effect of antibiotic resistance plasmids on the classification of representative staphylococci was determined using numerical phenetic techniques. Over sixty percent of the eighty-one test strains contained one or more plasmids which varied in molecular weight from 1.4 to 36 Mdal. Antibiotic resistance phenotypes were eliminated from strains of S. aureus, S. chromogenes, S. cohnii, S. hyicus and S. xylosus, and from a laboratory isolate, to give sixteen derivative strains. Fourteen had lost one or more plasmids and two had deleted plasmids. In addition three further derivative strains were isolated which showed no plasmid loss but exhibited gross phenotypic changes. The test and derivative strains were the subject of numerical phenetic analyses based on seventy-eight unit characters. Data were examined using the simple matching, Jaccard and pattern coefficients and clustering achieved using the unweighted pair group method with arithmetic averages algorithm. Cluster composition was not markedly affected by the statistics used or by test error, estimated at 1.02%. Numerically circumscribed clusters and subclusters were equated with the established species S. aureus, S. chromogenes, S. cohnii, S. hyicus, S. lentus, S. intermedius, S. sciuri and S. xylosus. The sixteen derivative strains with either lost or delected plasmids were recovered in the same cluster or subcluster as their corresponding parent indicating that the removal of plasmid-expressed characters had little effect on the structure of the numerical classification. In contrast, two of the three strains of S. xylosus with genomically-derived phenotypic variation formed a cluster that separated from their parent strain at the 70% similarity level in the SSM, UPGMA analysis.

Animals↗

PubMed1986

Repetitive DNA and chromosome evolution in plants.

Most higher plant genomes contain a high proportion of repeated sequences. Thus repetitive DNA is a major contributor to plant chromosome structure. The variation in total DNA content between species is due mostly to variation in repeated DNA content. Some repeats of the same family are arranged in tandem arrays, at the sites of heterochromatin. Examples from the Secale genus are described. Arrays of the same sequence are often present at many chromosomal sites. Heterochromatin often contains arrays of several unrelated sequences. The evolution of such arrays in populations is discussed. Other repeats are dispersed at many locations in the chromosomes. Many are likely to be or have evolved from transposable elements. The structures of some plant transposable elements, in particular the sequences of the terminal inverted repeats, are described. Some elements in soybean, antirrhinum and maize have the same inverted terminal repeat sequences. Other elements of maize and wheat share terminal homology with elements from yeast, Drosophila, man and mouse. The evolution of transposable elements in plant populations is discussed. The amplification, deletion and transposition of different repeated DNA sequences and the spread of the mutations in populations produces a turnover of repetitive DNA during evolution. This turnover process and the molecular mechanisms involved are discussed and shown to be responsible for divergence of chromosome structure between species. Turnover of repeated genes also occurs. The molecular processes affecting repeats imply that the older a repetitive DNA family the more likely it is to exist in different forms and in many locations within a species. Examples to support this hypothesis are provided from the Secale genus.

Animals↗

PubMed2005

Major structural differences and novel potential virulence mechanisms from the genomes of multiple campylobacter species.

Sequencing and comparative genome analysis of four strains of Campylobacter including C. lari RM2100, C. upsaliensis RM3195, and C. coli RM2228 has revealed major structural differences that are associated with the insertion of phage- and plasmid-like genomic islands, as well as major variations in the lipooligosaccharide complex. Poly G tracts are longer, are greater in number, and show greater variability in C. upsaliensis than in the other species. Many genes involved in host colonization, including racR/S, cadF, cdt, ciaB, and flagellin genes, are conserved across the species, but variations that appear to be species specific are evident for a lipooligosaccharide locus, a capsular (extracellular) polysaccharide locus, and a novel Campylobacter putative licABCD virulence locus. The strains also vary in their metabolic profiles, as well as their resistance profiles to a range of antibiotics. It is evident that the newly identified hypothetical and conserved hypothetical proteins, as well as uncharacterized two-component regulatory systems and membrane proteins, may hold additional significant information on the major differences in virulence among the species, as well as the specificity of the strains for particular hosts.

Animals↗

PubMed2000

Epidemiology: surveillance of fungal infections.

Surveillance for fungal diseases is essential to improve our understanding of their epidemiology and to enable research and prevention efforts to be prioritized. In order to conduct better surveillance for fungal diseases, it is important to develop more accurate and timely diagnostic tests, to follow rigorous epidemiological methods and to have adequate support from public health agencies and the pharmaceutical industry. Investigations of nosocomial and community outbreaks of fungal infection have also resulted in a better understanding of the sources and routes of transmission of these diseases, and of the risk factors for infection. This has led to more effective prevention and control strategies. In addition, outbreak investigations have offered excellent opportunities to develop new molecular sub-typing methods, and to evaluate and validate older ones. For example, results obtained from a global epidemiological study of the genomic structure of Cryptococcus neoformans have led to a better understanding of the epidemiology of cryptococcosis. Similarly, a study of variations in the genotype of Trichophyton rubrum has found that patients may become infected with multiple strains, which has important implications for study design when looking at the epidemiology of dermatophyte infections.

Arthrodermataceae↗

PubMed2002

Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains.

Several human pathogens (e.g., Bacillus anthracis, Yersinia pestis, Bordetella pertussis, Plasmodium falciparum, and Mycobacterium tuberculosis) have very restricted unselected allelic variation in structural genes, which hinders study of the genetic relationships among strains and strain-trait correlations. To address this problem in a representative pathogen, 432 M. tuberculosis complex strains from global sources were genotyped on the basis of 230 synonymous (silent) single nucleotide polymorphisms (sSNPs) identified by comparison of four genome sequences. Eight major clusters of related genotypes were identified in M. tuberculosis sensu stricto, including a single cluster representing organisms responsible for several large outbreaks in the United States and Asia. All M. tuberculosis sensu stricto isolates of previously unknown phylogenetic position could be rapidly and unambiguously assigned to one of the eight major clusters, thus providing a facile strategy for identifying organisms that are clonally related by descent. Common clones of M. tuberculosis sensu stricto and M. bovis are distinct, deeply branching genotypic complexes whose extant members did not emerge directly from one another in the recent past. sSNP genotyping rapidly delineates relationships among closely related strains of pathogenic microbes and allows construction of genetic frameworks for examining the distribution of biomedically relevant traits such as virulence, transmissibility, and host range.

Alleles↗

PubMed1990

Polyploidy in differentiation and evolution.

Somatic and generative (germ-line) polyploidy are more widely spread phenomena among living organisms than generally thought. The occurrence of polyploidization and related events in normal and pathological differentiation, their recognized main functions, as well as the structural specificities of polyploid nuclei are reviewed, and the relationship between ontogenetic and phylogenetic events is discussed. The mechanisms leading to the polyploid state, as well as other processes resulting in a genomic condition different from the diploid one (such as DNA under-replication, gene amplification, and chromatin elimination), are briefly sketched. The various changes in chromosomal DNA described are, in conclusion, seen as evidence supporting the paradigm of a "fluid" or dynamic organization of the eukaryotic genome, as being part of a cybernetic feedback regulation system of gene expression. A model is proposed that unifies the aspects of DNA variation, chromatin structure, and diversification in ontogenesis and phylogenesis.

Animals↗

PubMed2006

Population structure and gene evolution in Saccharomyces cerevisiae.

The fully sequenced genomes of four species within the Saccharomyces sensu stricto complex provide a wealth of information for molecular-evolutionary inference. Yet virtually nothing is known about population-genetic variation within these species, including the molecular-biological and genetic-model organism S. cerevisiae. Here we investigate the population-genetic variation and population structure of S. cerevisiae by sequencing the four loci CDC19, PHD1, FZF1 and SSU1 in 27 strains. Sequence analysis demonstrates a distinct population structure in S. cerevisiae, distinguishing strains collected from a Pennsylvanian oak forest and strains collected from vineyards, perhaps due to ecological rather than geographic factors. The low level of conflict observed between the gene trees estimated for each locus implies moderate recombination in nature. High polymorphism in the gene SSU1 provides evidence of diversifying selection on its protein product, a sulfite exporter, perhaps associated with the use of sulfur-based fungicides in vineyards. FZF1, encoding a transcription factor regulating the expression level of SSU1, displays even greater polymorphism. This, the first multilocus sequence study of population structure in natural isolates of S. cerevisiae, is the first study to demonstrate population structure within S. cerevisiae, and the first study to detect historical selection on a locus important to the natural history of wine yeast.

Cloning, Molecular↗

PubMed2026

Response to divergent selection on meiotic recombination in Saccharomyces cerevisiae.

Meiotic recombination is a key driver of evolution in sexually reproducing species, reshaping genetic diversity by generating novel allelic combinations. The rate of recombination varies substantially across living organisms depending on cis- or trans-acting genetic elements, as seen in many species, including the yeast Saccharomyces cerevisiae. Here, we report on an experimental evolution-based study to better understand the factors shaping this natural variation. Starting with a genetically diverse population of S. cerevisiae, we have carried out recurrent divergent selection on recombination rate using a fluorescence-based sorting approach in four independent lineages. After ten generations, we observed an average response of recombination rate of +28% after positive selection and -24% after negative selection, within the interval used for selection. In the adjacent region, however, we observed a weaker response in the opposite direction, and no response in four other unlinked genomic regions. Whole-genome sequencing of individuals selected for high recombination revealed mixed outcomes in the four independently evolved lineages for high genome-wide recombination rates. However, all four lineages showed selection for high recombination locally, with particular haplotypes heavily favored and sequence- or structural variation-based heterozygosity selected against within the selection interval. Overall, this experimental evolution approach provides original and useful insights into the evolvability of the meiotic recombination rate and the associated genetic determinants.

Meiotic recombination↗