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PubMed2025

Comparative Analysis of Mammalian Adaptive Immune Loci Revealed Spectacular Divergence and Common Genetic Patterns.

Adaptive immune responses are mediated by the production of adaptive immune receptors, antibodies, and T-cell receptors, which bind antigens, thus causing their neutralization. Unlike other proteins, adaptive immune receptors are not fully encoded in the germline genome and result from a complex of somatic processes collectively called V(D)J recombination affecting germline immunoglobulin (IG) and T-cell receptor (TR) loci consisting of template genes. While various existing studies report extreme diversity of antibodies and T-cell receptors, little is known about the diversity of germline IG and TR loci. To overcome this gap, the first comparative analysis of full-length sequences of IG/TR loci across 46 mammalian species from 13 taxonomic orders was performed. First, germline gene counts were shown to correlate in immunoglobulin heavy chain immunoglobulin heavy chain (IGH)/immunoglobulin lambda (IGL) loci and T-cell receptor alpha (TRA)/T-cell receptor beta (TRB) and anticorrelate in immunoglobulin kappa (IGK)/IGL, possibly indicating coevolution between corresponding chains. Second, structures of IG/TR loci were analyzed, and it was shown that IG/TR loci formed by long arrays of high multiplicity repeats are more common for species that have experienced population bottlenecks. Finally, haplotypes of IG/TR loci with little or no sequence similarity within a species were found, suggesting that they may have a limited potential for homologous recombination. These results demonstrate that IG/TR loci are rapidly evolving genomic regions whose structural variation is shaped by the population history of the species and open new perspectives for immunogenomics studies.

Animals↗
PubMed2025

PARTAGE: Parallel analysis of replication timing and gene expression.

The human genome is partitioned into functional compartments that replicate at specific times during the S-phase. This temporal program, referred to as replication timing (RT), is co-regulated with the 3D genome organization, is cell type-specific, and changes during development in coordination with gene expression. Moreover, RT alterations are linked to abnormal gene expression, genome instability, and structural variation in multiple diseases, including cancer. However, mechanistic links between RT, large-scale 3D genome architecture, and transcriptional regulation remain poorly understood. A major limitation is that current approaches require the separate profiling of RT and transcriptomes from independent batches of samples, obscuring the complex co-regulation between the epigenome and transcriptome. Here, we developed PARTAGE, a multiomics approach that enables joint profiling of copy number variation (CNV), RT, and gene expression from the same sample, providing a more accurate integrative view of the complex relationships between RT and gene regulation.

Journal Article↗
PubMed1988

Global variation in G+C content along vertebrate genome DNA. Possible correlation with chromosome band structures.

The global, rather than local, variation in G+C content along the nuclear DNA sequences of various organisms was studied using GenBank sequence data. When long DNA sequences of the genomes of Escherichia coli and Saccharomyces cerevisiae were examined, the levels of their G+C content (G+C%) were found to be within a narrow range around that of the whole genome. The G+C% levels for sequences of vertebrate genomes, however, were found to cover a wide range, showing that their genome is a mosaic of sequences with different G+C% levels, in each of which the sequence is fairly homogeneous in its G+C% for a very long distance. Through surveying a human genetic map and GenBank DNA sequences, the global variations in G+C% along the human genome DNA were found to be correlated with chromosome band structures.

Animals↗
PubMed2004

Genomic organization and sequence variation of the human integrin subunit alpha8 gene (ITGA8).

The integrin alpha8 is highly expressed during kidney and lung development. alpha8-deficient mice display abnormal renal development suggesting that alpha8 plays a critical role in organogenesis. Therefore, it would be of considerable interest to understand the genomic structure, localization and sequence variation of the alpha8 gene. Using FISH and genomic database analysis, we show that alpha8 gene maps to chromosome 10p13 and consists of >200 kbp organized into 30 exons. Examination of 47 individuals from two different ethnic groups (European and African descent) identified 286 varying sites. The diversity of alpha8 is comparable to that of other regions within the human genome. Eight of the varying sites were located in the coding regions: six resulted in nonsynonymous substitutions of which two lead to non-conservative changes in protein. None of the sites showed significant deviation from Hardy-Weinberg equilibrium. We mapped the coding region single nucleotide polymorphisms (SNPs) onto a model of the predicted alpha8 structure and found all the SNPs were located in the "calf" of the extracellular domain. In the European population, the linkage disequilibrium statistic D' showed three blocks of relatively non-recombinant regions in the alpha8 gene while the African population showed more evidence of recombination. The observed patterns of the linkage disequilibrium statistic R2 suggest that a large number of sites will need to be genotyped to ensure coverage of the entire gene for genetic association studies. Identification of the sequence variation will allow genetic association studies of alpha8 in kidney and lung disease.

Base Sequence↗
PubMed2006

Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome.

The discovery of an abundance of copy number variants (CNVs; gains and losses of DNA sequences >1 kb) and other structural variants in the human genome is influencing the way research and diagnostic analyses are being designed and interpreted. As such, comprehensive databases with the most relevant information will be critical to fully understand the results and have impact in a diverse range of disciplines ranging from molecular biology to clinical genetics. Here, we describe the development of bioinformatics resources to facilitate these studies. The Database of Genomic Variants (http://projects.tcag.ca/variation/) is a comprehensive catalogue of structural variation in the human genome. The database currently contains 1,267 regions reported to contain copy number variation or inversions in apparently healthy human cases. We describe the current contents of the database and how it can serve as a resource for interpretation of array comparative genomic hybridization (array CGH) and other DNA copy imbalance data. We also present the structure of the database, which was built using a new data modeling methodology termed Cross-Referenced Tables (XRT). This is a generic and easy-to-use platform, which is strong in handling textual data and complex relationships. Web-based presentation tools have been built allowing publication of XRT data to the web immediately along with rapid sharing of files with other databases and genome browsers. We also describe a novel tool named eFISH (electronic fluorescence in situ hybridization) (http://projects.tcag.ca/efish/), a BLAST-based program that was developed to facilitate the choice of appropriate clones for FISH and CGH experiments, as well as interpretation of results in which genomic DNA probes are used in hybridization-based experiments.

Algorithms↗
PubMed2006

TAR cloning: insights into gene function, long-range haplotypes and genome structure and evolution.

The structural and functional analysis of mammalian genomes would benefit from the ability to isolate from multiple DNA samples any targeted chromosomal segment that is the size of an average human gene. A cloning technique that is based on transformation-associated recombination (TAR) in the yeast Saccharomyces cerevisiae satisfies this need. It is a unique tool to selectively recover chromosome segments that are up to 250 kb in length from complex genomes. In addition, TAR cloning can be used to characterize gene function and genome variation, including polymorphic structural rearrangements, mutations and the evolution of gene families, and for long-range haplotyping.

Animals↗
PubMed2026

Graph-based pan-genome reveals structural and functional diversity across oil palm domestication gradients.

BACKGROUND: Oil palm (Elaeis guineensis Jacq.), the world's most land-efficient oil crop, underpins global vegetable oil supply yet faces mounting constraints from limited expansion, climate stress, and disease pressure. These challenges highlight the urgent need for genomic resources that capture species-wide diversity to support sustainable improvement. While recent reference assemblies have advanced trait discovery, single linear genomes fail to represent the full spectrum of structural and gene-content variation, limiting resolution of agronomic alleles. RESULTS: Here, we constructed a graph-based pan-genome from 30 diverse oil palm assemblies representing wild, semi-domesticated, and commercial accessions. We characterized structural variants, gene presence-absence variation, and copy-number gains, with focusing on functional stratification and resistance gene dynamics. The graph-based pan-genome revealed extensive structural and gene-content variation, including a large conserved core, complemented by shell and unique fractions enriched or biased toward regulatory, stress-responsive, and defense-related functions. Structural variation and duplication-derived copy-number gains contributed substantially to gene-content diversity, with semi-domesticated accessions exhibiting the greatest variability. Resistance gene repertoires showed contrasting patterns: receptor-like kinases remained comparatively stable, whereas the CNL subclass of NLR genes contributed disproportionately to shell-genome variation and duplication-associated turnover. CONCLUSIONS: This graph-based pan-genome provides a curated multi-assembly reference and comparative framework for oil palm genomics. By capturing structural variants, gene-content variations, copy-number gains, and resistance gene dynamics across domestication gradients, it establishes a foundation for future pan-GWAS analysis, functional genomics, and molecular breeding strategies aimed at improving resilience and productivity in this globally important crop.

Arecaceae↗
PubMed2026

Genome-wide SNP data reveal geographic structure and landscape-associated genomic differentiation in a widespread lizard in arid Eastern Central Asia.

Arid landscapes provide important systems for examining how geographic structure and environmental heterogeneity shape genomic differentiation. In topographically complex desert regions, however, it remains challenging to determine whether population structure primarily reflects landscape resistance, geographic distance, or contemporary environmental variation. Here, we use genome-wide SNP data to investigate population structure, phylogenetic relationships, historical gene flow, demographic history, and landscape correlates of genomic differentiation in the variegated racerunner (Eremias vermiculata), a widespread lacertid lizard across arid Eastern Central Asia. Analyses of 164 individuals recovered six geographically structured nuclear clusters associated with major desert basins and mountain-bounded regions. Nuclear phylogenies resolved two broad regional clades corresponding to northeastern and southwestern parts of the species' range, while PCA and ADMIXTURE analyses recovered six finer-scale genetic clusters. Mitochondrial phylogenies, based on combined NCBI-derived Cyt b and COI sequences from the same individuals, recovered four deeper maternal lineages. These patterns indicate overall phylogeographic agreement between nuclear and mitochondrial datasets, with genome-wide SNPs providing finer-scale resolution of population structure. Demographic reconstructions further uncovered regionally heterogeneous Late Pleistocene histories among clusters, including signals of expansion, stability, and decline. Landscape genomic analyses revealed that genomic differentiation is primarily associated with landscape resistance, particularly elevation and land cover, as well as geographic distance, whereas contemporary environmental variables explained comparatively little variation after controlling for spatial structure. Together, our results suggest that genomic differentiation in E. vermiculata reflects the interplay of persistent landscape configuration, historical connectivity, and region-specific demographic histories across arid Eastern Central Asia. More broadly, this study highlights the value of integrating phylogeographic and landscape genomic approaches for understanding population differentiation and evolutionary history in topographically heterogeneous desert ecosystems.

Arid Eastern Central Asia↗
PubMed2004

The fine-scale structure of recombination rate variation in the human genome.

The nature and scale of recombination rate variation are largely unknown for most species. In humans, pedigree analysis has documented variation at the chromosomal level, and sperm studies have identified specific hotspots in which crossing-over events cluster. To address whether this picture is representative of the genome as a whole, we have developed and validated a method for estimating recombination rates from patterns of genetic variation. From extensive single-nucleotide polymorphism surveys in European and African populations, we find evidence for extreme local rate variation spanning four orders in magnitude, in which 50% of all recombination events take place in less than 10% of the sequence. We demonstrate that recombination hotspots are a ubiquitous feature of the human genome, occurring on average every 200 kilobases or less, but recombination occurs preferentially outside genes.

Base Composition↗
PubMed2025

Genetic Differentiation is Constrained to Chromosomal Inversions and Putative Centromeres in Locally Adapted Populations With Higher Gene Flow.

The impact of genome structure on adaptation is a growing focus in evolutionary biology, revealing an important role for structural variation and recombination landscapes in shaping genetic diversity across genomes and among populations. This is particularly relevant when local adaptation occurs despite gene flow, where clustering of differentiated loci can maintain locally adapted variants by reducing recombination between them. However, the limited genomic resources for nonmodel species, including reference genomes and recombination maps, have constrained our understanding of these patterns. In this study, we leverage the Atlantic silverside-a nonmodel fish with extensive local adaptation across a steep latitudinal gradient-as an ideal system to explore how genome structure influences adaptation under varying levels of gene flow, using a newly available reference genome and multiple recombination maps. Analyzing 168 genomes from four populations, we found a continuum of genome-wide differentiation increasing from south to north, reflecting higher connectivity among southern populations and reduced gene flow at northern latitudes. With increasing gene flow, the number and clustering of FST outlier loci also increased, with differentiated loci found exclusively within large haploblocks harboring inversions and smaller peaks overlapping putative centromeric regions. Notably, sequence divergence was only evident in inversions, supporting their role in adaptive divergence with gene flow, whereas centromeric regions appeared differentiated because of low recombination and diversity, with no indication of elevated divergence. Our results support the hypothesis that clustered genomic architectures evolve with high gene flow and enhance our understanding of how inversions and centromeres are linked to different evolutionary processes.

Gene Flow↗
PubMedDate not supplied

Comparisons of genetic variability and genome structure among mosquito strains selected for refractoriness to a malaria parasite.

Restriction fragment length polymorphism (RFLP) markers were used to evaluate Aedes aegypti genome structure and genetic variability within and between substrains selected for different levels of refractoriness to the malaria parasite, Plasmodium gallinaceum. The MOYO-R substrain was previously selected for complete refractoriness and the MOYO-IS substrain for intermediate susceptibility from the Moyo-In-Dry (MOYO) strain by selective inbreeding (F = 0.5). Eighteen mapped RFLP markers were used to provide coverage of the mosquito genome. The two substrains showed reduced genetic diversity compared with the MOYO strain, including significant reductions in mean heterozygosity, number of alleles per locus, and proportion of polymorphic loci. Genetic differentiation between the two substrains was statistically significant, as reflected by differences in allele frequencies. Significant pairwise linkage disequillbrium among the RFLP loci was detected in all three strains, most evidently in the MOYO strain. This is surprising because the RFLP loci examined are separated by large map distances, and therefore linkage disequilibrium should decay to zero after many generations of laboratory culture. Our hypothesis to explain this phenomena is that lack of recombination, or low recombination rates in some regions of the A. aegypti genome, is a result of chromosome inversions. Finally, we used graphical genotyping, wherein whole genome genotypic information for individual mosquitoes is represented in a simple graphic format, to illustrate genome structure and allelic variation within and among the mosquito strains. Our analysis revealed an apparent chromosomal deletion on chromosome 3 for some individuals in the MOYO strain and MOYO-IS substrain.

Aedes↗
PubMed1999

Evolutionary instability of operon structures disclosed by sequence comparisons of complete microbial genomes.

Gene orders have been shown to be generally unstable by comprehensive analyses in several complete genomes. In this study, we examined instability of genome structures within operons, where functionally related genes are clustered. We compared gene orders of known operons obtained from Escherichia coli and Bacillus subtilis with corresponding those of operons in 11 complete genome sequences. We found that in many cases, gene orders within operons could be shuffled frequently during evolution, although several operon structures, such as ribosomal protein operons, were well conserved. This suggests that shuffling of a genome structure is virtually neutral in long-term evolution. Moreover, degrees of instability of the operon structures depended on the genomes examined. Variation in degrees of instability of the genome structures was likely to be related to differences in amounts of insertion sequences. Effects on transcription regulation are also discussed in association with operon destruction.

Bacillus subtilis↗
PubMed1986

Rapid emergence of novel antigenic and genetic variants of equine infectious anemia virus during persistent infection.

Previous results from our laboratory have demonstrated that equine infectious anemia virus displays structural variations in its surface glycoproteins and RNA genome during passage and chronic infections in experimentally infected Shetland ponies (Montelaro et al., J. Biol. Chem. 259:10539-10544, 1984; Payne et al., J. Gen. Virol. 65:1395-1399, 1984). The present study was undertaken to obtain an antigenic and biochemical characterization of equine infectious anemia virus isolates recovered from an experimentally infected pony during sequential disease episodes, each separated by intervals of only 4 to 8 weeks. The virus isolates could be distinguished antigenically by neutralization assays with serum from the infected pony and by Western blot analysis with a monoclonal antibody against the major surface glycoprotein gp90, thus demonstrating that novel antigenic variants of equine infectious anemia virus predominate during each clinical episode. The respective virion glycoproteins displayed different electrophoretic mobilities on sodium dodecyl sulfate-polyacrylamide gels, indicating structural variation. Tryptic peptide and glycopeptide maps of the viral proteins of each virus isolate revealed biochemical alterations involving amino acid sequence and glycosylation patterns in the virion surface glycoproteins gp90 and gp45. In contrast, no structural variation was observed in the internal viral proteins pp15, p26, and p9 from any of the four virus isolates. Oligonucleotide mapping experiments revealed similar but unique RNase T1-resistant oligonucleotide fingerprints of the RNA genomes of each of the virus isolates. Localization of altered oligonucleotides for one virus isolate placed two of three unique oligonucleotides within the predicted env gene region of the genome, perhaps correlating with the structural variation observed in the envelope glycoproteins. Thus these results support the concept that equine infectious anemia virus is indeed capable of relatively rapid genomic variations during replication, some of which result in altered glycoprotein structures and antigenic variants which are responsible for the unique periodic disease nature observed in persistently infected animals. The findings of envelope specific differences in isolates of visna virus and of human T-cell lymphotropic virus III (acquired immune deficiency syndrome-related virus) suggest that this variation may be a common characteristic of the subfamily Lentivirinae.

Animals↗
PubMed2005

Identification of novel non-autonomous CemaT transposable elements and evidence of their mobility within the C. elegans genome.

We describe here two new transposable elements, CemaT4 and CemaT5, that were identified within the sequenced genome of Caenorhabditis elegans using homology based searches. Five variants of CemaT4 were found, all non-autonomous and sharing 26 bp inverted terminal repeats (ITRs) and segments (152-367 bp) of sequence with similarity to the CemaT1 transposon of C. elegans. Sixteen copies of a short, 30 bp repetitive sequence, comprised entirely of an inverted repeat of the first 15 bp of CemaT4's ITR, were also found, each flanked by TA dinucleotide duplications, which are hallmarks of target site duplications of mariner-Tc transposon transpositions. The CemaT5 transposable element had no similarity to maT elements, except for sharing identical ITR sequences with CemaT3. We provide evidence that CemaT5 and CemaT3 are capable of excising from the C. elegans genome, despite neither transposon being capable of encoding a functional transposase enzyme. Presumably, these two transposons are cross-mobilised by an autonomous transposon that recognises their shared ITRs. The excisions of these and other non-autonomous elements may provide opportunities for abortive gap repair to create internal deletions and/or insert novel sequence within these transposons. The influence of non-autonomous element mobility and structural diversity on genome variation is discussed.

Animals↗
PubMed2000

HCV genotypes--role in pathogenesis of disease and response to therapy.

Hepatitis C virus (HCV) shows considerable variation in its genomic structure, allowing classification into six main genotypes. Epidemiological studies have shown marked differences in genotype distribution by geographical region, and between patient groups. Improved understanding of the rate of nucleotide sequence mutation in HCV has allowed the approximate time of divergence of major genotypes to be estimated, and the origin and spread of the present epidemic of hepatitis C to be better defined. Improved methods of genotype definition over the last few years have enabled the importance of genotype in the progression of HCV-related disease and response to anti-viral therapy to be studied. Present data strongly indicates that HCV genotype is an important determinant of response to treatment, but the effect of genotype on disease progression has been harder to clarify. This is largely due to the absence of model systems of HCV infection, the epidemiological differences in patient groups infected with the different genotypes, and the lack of good prospective longitudinal clinical data. As a result of advances in methodology, and recent results of large clinical trials of combination therapy, a knowledge of HCV genotype is now central to the clinician in the management of patients with chronic hepatitis C.

Antiviral Agents↗
PubMed1987

Globin gene structure and the nature of mutation.

In this chapter I have tried to relate the salient features of globin gene structure, genomic organization, normal variation, and mutations affecting gene expression. The lessons learned from the normal beta-globin gene cluster and mutations producing beta-thalassemia should be highly applicable to studies of other inherited diseases. As more and more gene probes become available, which have relevance to the study of human disease, the striking extent of genetic heterogeneity producing single gene disorders of man will be illuminated.

Gene Expression Regulation↗
PubMed1983

Gene structure and the nature of mutation.

In this paper we have tried to relate the salient features of gene structure, genomic organization, normal variation, and mutations affecting gene expression. The lessons learned from the normal beta-globin gene cluster and mutations producing beta-thalassemia should be greatly applicable to studies of other inherited diseases. As more and more gene probes become available which have relevance to the study of human disease, the striking extent of genetic heterogeneity producing single gene disorders of man will be illuminated.

Animals↗
PubMed2026

Low-pass whole-genome sequencing reveals genomic diversity and ecotype-specific adaptation in indigenous Tigrayan chickens.

Indigenous chickens play a critical role in food security and climate resilience in smallholder systems, yet their genomic diversity and adaptive potential remain insufficiently characterised. This study employed low-pass whole-genome sequencing (LP-WGS; 0.2-1.99×) to investigate genomic diversity, population structure, inbreeding and candidate environment-associated genomic variation in 33 chickens from highland, midland, and lowland agroecologies in the Tigray region of northern Ethiopia. After imputation and stringent filtering, 23.4 million high-confidence SNPs were retained, including ~ 17% novel variants, indicating substantial uncharacterised genetic diversity in these populations. SNP density (13.8 ± 8.6 SNPs/kb) was comparable to values reported from high-coverage Ethiopian chicken datasets, demonstrating the suitability of LP-WGS for population genomics in resource-limited settings. Marked differences in genomic diversity were observed among ecotypes: midland chickens showed the highest nucleotide diversity (π = 0.00267), followed by lowland (π = 0.00233), whereas highland chickens showed the lowest diversity (π = 0.00203) and elevated genomic inbreeding (FROH and FHOM ≈ 0.18). Population structure analyses revealed clear genetic separation among ecotypes. PCA (13.91% variation explained) distinguished lowland chickens along PC1 and separated highland from midland along PC2, while ADMIXTURE and FST patterns supported three major ancestral genomic backgrounds. Functional annotation of private missense variants uncovered distinct adaptive signatures reflecting the contrasting agroecological conditions. Highland chickens showed enrichment of candidate genes potentially involved in physiological processes relevant to high-altitude environments, including cold response, angiogenesis, cardiovascular regulation and metabolic homeostasis (eg., PARP1, ACOX2, ITGB3, EDNRB, SOX8, and SOX10). Midland chickens exhibited candidate signals of selection in genes with known roles in innate antiviral immunity, bacterial defence and inflammatory regulation (eg., BAK1, CLSTN1, CYSLTR1, CYSLTR2, CXCR7, GIPR, DSCAM, GDAP1, TLR3, TLR4, TLR7, IFIH1, ADORA1, EPHB1, and TMPRSS2). Lowland chickens displayed candidate variants associated with heat-stress response, DNA damage repair, oxidative balance and cardiovascular support under extreme temperatures (e.g., MLH1, BDKRB1, GPR19, FLT1, CCL18, TGM2, and RAMP3). Overall, the results indicate substantial genomic differentiation among ecotypes and suggest candidate environment-associated genetic divergence across Tigray's diverse agroecological zones. These populations may represent important reservoirs of adaptive genetic variation for climate-resilient poultry breeding, warranting further functional validation and conservation-oriented management.

Animals↗