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PubMed2002

HLA and sarcoidosis: new pathogenetic insights.

Many theories have been presented to account for the immunological and epidemiological features of sarcoidosis; several lines of study support the prevailing opinion that an environmental agent, possibly microbial in origin, may cause sarcoidosis in a genetically predisposed host. Many polymorphic genes have been suggested to contribute to this genetic susceptibility: genes encoding angiotensin converting enzyme, vitamin D receptor, and interleukin-1, T-cell receptor genes, Gm and Km immunoglobulin genes and, most relevant, HLA genes (classical and non classical). There is also some evidence of an HLA-associated protection against sarcoidosis. The main action of disease-associated HLA molecules is to present specific antigenic peptides in such a way that the recognizing T-lymphocytes initiate an inflammatory response with peculiar pathological consequences. Other, so-called, non-classical HLA genes coding for proteins involved in antigen processing and presentation, namely TAP, LMP and DM, seem to contribute. Particular alleles of the tumor necrosis factor gene cluster (TNFA, LTA, LTB) are known to be associated with peculiar clinical forms of sarcoidosis. For instance, Löfgren's syndrome, which is an acute form of pulmonary sarcoidosis with frequent spontaneous remission, is marked by the TNFA*2, HLA-DR3 haplotype. How many HLA genes are involved is still unknown, but it is now clear that the HLA region is strongly implicated in the development of sarcoidosis. Probably, the future lies in isolating and sequencing the putative peptide bound to susceptible MHC molecules which, activating reactive T-cells, is responsible for disease initiation and/or exacerbation. However, the investigative approach should not be confined only to genomic sequences: the temporal and spatial expression of gene products, the post-transcriptional modification of the protein products will be fundamental in determining the basic functional context of developing sarcoidosis.

Genes, MHC Class I↗
PubMed2026

Experimental evolution reveals contrasting adaptive landscapes in lab and field environments.

Experimental evolution is widely used to infer microbial responses to environmental change, yet most laboratory studies impose constant, well-mixed conditions that differ fundamentally from fluctuating, spatially structured field environments. We compared genomic evolution in the leaf litter-associated bacterium Curtobacterium strain MMLR14_002 under control and warming treatments in laboratory culture and in a complementary field experiment. Laboratory-derived isolates accumulated more mutations per genome and exhibited stronger locus-level parallelism, with mutations recurring in a small number of coding loci. Field-derived isolates accumulated fewer mutations per genome, and these mutations rarely occurred in the same coding loci across replicate populations. Instead, field isolates exhibited a higher proportion of intergenic mutations, with mutations recurring in the same intergenic regions across independent field deployments. When coding mutations were detected in the field, they were distributed across functionally diffuse targets and more often involved metabolic pathways than the core cellular processes repeatedly targeted during laboratory evolution. Warming itself did not consistently influence mutation accumulation or the genomic distribution of mutations; instead, laboratory and field contexts primarily shaped the accumulation, targets, and repeatability of genomic change. These results suggest that laboratory thermal evolution identifies adaptive routes favored under sustained selection but may overestimate coding-level parallelism under heterogeneous field conditions. Bridging laboratory and field evolution will likely require experimental designs that incorporate temporal variability and spatial heterogeneity characteristic of natural systems.IMPORTANCEA central goal of experimental evolution is to infer how microbes evolve in nature from laboratory studies. Here, we evaluate this assumption by comparing genomic evolution of a leaf litter-associated Curtobacterium strain in laboratory and field warming experiments to identify broad patterns rather than isolate the contribution of any single environmental factor. We find that the strong parallelism at coding loci observed under laboratory conditions is reduced in the field, while mutations recurring in the same intergenic regions across field deployments suggest that parallel evolution in nature may more often involve regulatory noncoding regions rather than coding targets. These results show that environmental context reshapes adaptive landscapes and may limit the parallelism of coding-level genomic responses inferred from homogeneous laboratory conditions.

experimental evolution↗
PubMed2001

Comprehensive comparison between locations of orthologous genes on archaeal and bacterial genomes.

MOTIVATION: Following an extensive search for orthologous genes between the complete genomes from archaea and bacteria, the spatial association of the orthologs has been investigated in terms of synteny, the conservation of the order of neighboring genes. However, the relationships between the relative locations of remote orthologs over entire genomes have not been shown. RESULTS: Comprehensive comparisons between the locations of orthologs on nineteen archaeal and bacterial genomes are presented by the location to location correspondence based on the gene-location distance. When the two genomes are rotated such that a pair of orthologs with the shortest distance is set in the same angle, a statistically significant number of orthologs maintain their relative locations between the genomes. Even by the short distances at the 5% significance level, the rotations are restricted within a narrow range, suggesting an intrinsic angle for realizing similar locations between the orthologs in each genome pair. Furthermore, the rotations in the restricted range agree with the replication origin and terminus sites for the analyzed genomes where such sites are known. The relationship between location-maintained orthologs and gene function is also discussed.

Chromosome Mapping↗
PubMed2002

Two QTLs located on chromosomes 1 and 5 modulate different aspects of the performance of mice of the B x D Ty RI strain series in the Morris navigation task.

The Morris navigation task is widely used to study spatial abilities in rodents; namely, to analyze the effects of mutations in genetically engineered mice. Although quantitative and Mendelian genetic studies have shown that the variation of these abilities is partly under genetic control, little is known about these genetic factors. In order to analyze the genetic architecture of spatial navigation in mice, a wide genome scan was performed to map the QTLs that control various aspects of the performance, using the RI strain methodology. Latencies to locate the submerged platform across learning sessions and performance to the spatial probe test were analyzed in the 26 strains of the B x D RI series. Both cluster analysis of behavioral measurements and QTL mapping confirmed previous data showing that the escape latencies and the spatial bias rely on two distinct components of the task, controlled by different loci. A QTL on chromosome 1 influenced escape latencies during the four training sessions, whereas another QTL, located on chromosome 5, was shown to control spatial performance at the probe trial and also exhibited epistatic interactions with two other QTLs on chromosomes 2 and 13. The function of these QTLs is examined in the broader context of hippocampal-dependent learning processes and in relation to QTLs already found in similar positions in other behavioral traits.

Animals↗
PubMed2005

The role of geographic analysis in locating, understanding, and using plant genetic diversity.

The genetic structure of an organism is shaped by various factors, many of which vary significantly over space. In this chapter, we provide insight on how studying geographic patterns may contribute to an improved understanding of variability in genetic structure. We first review the theoretical background on how differences in genetic structure may be generated through processes that are inherently variable over space. We then present novices with some basics on how geographic information systems (GIS) may be adopted to study this variation, including advice on software, data, and the type of research questions that might be addressed. The chapter finishes with a brief review of how spatial analysis has contributed to the conservation and use of plant genetic resources, through an understanding of spatial patterns in species distribution and genetic structure. We conclude that spatial variation is a factor often overlooked in genetic studies and one that merits greater consideration. With the advent of functional genomics and improved quantification of adaptive traits, spatial analysis may be key in understanding variation in genetic structure through careful analysis of genotype-environment interactions.

Algorithms↗
PubMed2004

Functional bias and spatial organization of genes in mutational hot and cold regions in the human genome.

The neutral mutation rate is known to vary widely along human chromosomes, leading to mutational hot and cold regions. We provide evidence that categories of functionally related genes reside preferentially in mutationally hot or cold regions, the size of which we have measured. Genes in hot regions are biased toward extracellular communication (surface receptors, cell adhesion, immune response, etc.), while those in cold regions are biased toward essential cellular processes (gene regulation, RNA processing, protein modification, etc.). From a selective perspective, this organization of genes could minimize the mutational load on genes that need to be conserved and allow fast evolution for genes that must frequently adapt. We also analyze the effect of gene duplication and chromosomal recombination, which contribute significantly to these biases for certain categories of hot genes. Overall, our results show that genes are located nonrandomly with respect to hot and cold regions, offering the possibility that selection acts at the level of gene location in the human genome.

Chromosome Mapping↗
PubMed2004

Identification of sparsely distributed clusters of cis-regulatory elements in sets of co-expressed genes.

Sequence information and high-throughput methods to measure gene expression levels open the door to explore transcriptional regulation using computational tools. Combinatorial regulation and sparseness of regulatory elements throughout the genome allow organisms to control the spatial and temporal patterns of gene expression. Here we study the organization of cis-regulatory elements in sets of co-regulated genes. We build an algorithm to search for combinations of transcription factor binding sites that are enriched in a set of potentially co-regulated genes with respect to the whole genome. No knowledge is assumed about involvement of specific sets of transcription factors. Instead, the search is exhaustively conducted over combinations of up to four binding sites obtained from databases or motif search algorithms. We evaluate the performance on random sets of genes as a negative control and on three biologically validated sets of co-regulated genes in yeasts, flies and humans. We show that we can detect DNA regions that play a role in the control of transcription. These results shed light on the structure of transcription regulatory regions in eukaryotes and can be directly applied to clusters of co-expressed genes obtained in gene expression studies. Supplementary information is available at http://www.mit.edu/ approximately kreiman/resources/cisregul/.

Algorithms↗
PubMed1999

Spatial patterning via PTP adhesive phosphatases.

Signaling pathways to the genome are a common way by which cells communicate with each other and their environment, and are often kineases or phosphatases. Patter formation is the differential spatial specification of gene activity necessary for multicellularity. It has been suspected that signaling pathways are crucial players in pattern formation in metazoans, but exactly how the pattern arise from the signaling systems has not been shown. The model discussed here is based on the protein tyrosine phosphatases, and it is shown how this important signaling system may straightforwardly produce patterns typical of early development. The protein tyrosine phosphatases have architectural characteristics basically different from those of the kinases, with the receptor tyrosine phosphatases displaying structural motifs of cell adhesion molecules. These membrane-spanning phosphatases then have a unique mission in cell growth, cell shape, and differentiation quite apart from that of the kineases. The complex intracellular biochemistry involved is modeled in the simplest way, with the intent that concepts be emphasized over biochemical detail.

Animals↗
PubMed1998

Conditional genome alteration in mice.

The recent ability to inactivate specific genes in mice has significantly accelerated our understanding of molecular, cellular, and even behavioral aspects of normal and disease processes. However, this ability has also demonstrated the extreme complexity of genetic determination in mammals, in particular, that genes in the same family or pathway can be functionally redundant and that a given gene often has multiple roles. Thus, inactivation of a gene often does not indicate its complete spectrum of functions. To circumvent this problem, many new tools and novel applications of classic techniques have been developed to place spatial and temporal restrictions on the genomic alterations. These approaches include chimera and mosaic studies, organ transplantation, complementation assays, dominant negative mutants, conditional gene knockouts, and lineage-specific gene rescue. Not only has this opened up more sophisticated ways to make genomic alterations, but it has provided the opportunity to create animal models for sporadic human genetic diseases.

Animals↗
PubMed2002

Rice genome organization: the centromere and genome interactions.

Over the last decade, many varied resources have become available for genome studies in rice. These resources include over 4000 DNA markers, several bacterial artificial chromosome (BAC) libraries, P-1 derived artificial chromosome (PAC) libraries and yeast artificial chromosome (YAC) libraries (genomic DNA clones, filters and end-sequences), retrotransposon tagged lines, and many chemical and irradiated mutant lines. Based on these, high-density genetic maps, cereal comparative maps, YAC and BAC physical maps, and quantitative trait loci (QTL) maps have been constructed, and 93 % of the genome has also been sequenced. These data have revealed key features of the genetic and physical structure of the rice genome and of the evolution of cereal chromosomes. This Botanical Briefing examines aspects of how the rice genome is organized structurally, functionally and evolutionarily. Emphasis is placed on the rice centromere, which is composed of long arrays of centromere-specific repetitive sequences. Differences and similarities amongst various cereal centromeres are detailed. These indicate essential features of centromere function. Another view of various kinds of interactive relationships within and between genomes, which could play crucial roles in genome organization and evolution, is also introduced. Constructed genetic and physical maps indicate duplication of chromosomal segments and spatial association between specific chromosome regions. A genome-wide survey of interactive genetic loci has identified various reproductive barriers that may drive speciation of the rice genome. The significance of these findings in genome organization and evolution is discussed.

Centromere↗
PubMed2026

Multimodal Analysis Reveals Aberrant Expression of SUMO2 and Its Significant Association With Key Mechanisms of Metabolic Pathways in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. However, the role of small ubiquitin-like modifier 2 (SUMO2), a core member of the small ubiquitin-like modifier (SUMO) family, regarding its expression patterns and metabolism-related functions in HCC remains inadequately understood. METHODS: A multidimensional analytical framework was applied, integrating immunohistochemistry (153 HCC vs. 21 non-HCC samples), proteomics (159 paired samples), bulk transcriptomics (3240 HCC vs. 2267 non-HCC samples), single-cell RNA sequencing (RNA-seq) (10 HCC vs. 8 non-HCC samples), spatial transcriptomics, and external CRISPR/Cas9 functional genomics data. Systematic analyses included standardized mean difference (SMD), pathway enrichment, pseudotime trajectory inference, in silico knockout, cell-cell communication, metabolic flux scoring, immune infiltration, clinical correlation, drug sensitivity prediction, and molecular docking. RESULTS: At the protein level, immunohistochemistry (nuclear positivity) and external proteomic data collectively demonstrated consistent SUMO2 overexpression in HCC. Consistent upregulation was also observed at the mRNA level across large-scale cohorts. Single-cell RNA-seq and spatial transcriptomics localized SUMO2 enrichment to malignant hepatocytes and tumor-dominant regions. CRISPR-mediated SUMO2 knockout suppressed proliferation in multiple HCC cell lines. Mechanistically, high SUMO2 expression was significantly associated with metabolic reprogramming involving glycolysis/gluconeogenesis, pyruvate metabolism, and the tricarboxylic acid cycle. SUMO2-high malignant hepatocyte subpopulations exhibited enhanced activity of the macrophage migration inhibitory factor signaling axis and enhanced iron-sensor interactions. Further, the immune infiltration analysis revealed a negative correlation between SUMO2 expression and M1 macrophages and a positive correlation between follicular helper T cells and regulatory T cells. Clinically, elevated SUMO2 levels were found to be associated with adverse prognostic features. Furthermore, high SUMO2 expression was associated with increased sensitivity to dasatinib, and molecular docking simulations predicted potential binding between SUMO2 and dasatinib, with a Vina score of -8.5 kcal/mol. CONCLUSIONS: SUMO2 is aberrantly expressed at the protein, mRNA, single-cell, and spatial transcriptomic levels in HCC and is significantly associated with metabolic reprogramming and altered migration inhibitory factor (MIF)-mediated intercellular communication, suggesting its potential as a novel biomarker for diagnosis and treatment.

Humans↗
PubMed2004

Multiple promoters direct expression of three AKAP12 isoforms with distinct subcellular and tissue distribution profiles.

A Kinase Anchoring Protein 12 (AKAP12; also known as src-suppressed C kinase substrate (SSeCKS) and Gravin) is a multivalent anchoring protein with tumor suppressor activity. Although expression of AKAP12 has been examined in a number of contexts, its expression control remains to be elucidated. Herein, we characterize the genomic organization of the AKAP12 locus, its regulatory regions, and the spatial distribution of the proteins encoded by the AKAP12 gene. Using comparative genomics and various wet-lab assays, we show that the AKAP12 locus is organized as three separate transcription units that are governed by non-redundant promoters coordinating distinct tissue expression profiles. The proteins encoded by the three AKAP12 isoforms (designated alpha, beta, and gamma) share >95% amino acid sequence identity but differ at their N termini. Analysis of the targeting of each isoform reveals distinct spatial distribution profiles. An N-terminal myristoylation motif present in AKAP12alpha is shown to be necessary and sufficient for targeted expression of this AKAP12 isoform to the endoplasmic reticulum, a novel subcellular compartment for AKAP12. Our results demonstrate heretofore unrecognized complexity within the AKAP12 locus and suggest a mechanism for genetic control of signaling specificity through distinct regulation of alternately targeted anchoring protein isoforms.

3T3 Cells↗
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↗
PubMed2003

A high-order trans-membrane structural linkage is responsible for mitochondrial genome positioning and segregation by flagellar basal bodies in trypanosomes.

In trypanosomes, the large mitochondrial genome within the kinetoplast is physically connected to the flagellar basal bodies and is segregated by them during cell growth. The structural linkage enabling these phenomena is unknown. We have developed novel extraction/fixation protocols to characterize the links involved in kinetoplast-flagellum attachment and segregation. We show that three specific components comprise a structure that we have termed the tripartite attachment complex (TAC). The TAC involves a set of filaments linking the basal bodies to a zone of differentiated outer and inner mitochondrial membranes and a further set of intramitochondrial filaments linking the inner face of the differentiated membrane zone to the kinetoplast. The TAC and flagellum-kinetoplast DNA connections are sustained throughout the cell cycle and are replicated and remodeled during the periodic kinetoplast DNA S phase. This understanding of the high-order trans-membrane linkage provides an explanation for the spatial position of the trypanosome mitochondrial genome and its mechanism of segregation. Moreover, the architecture of the TAC suggests that it may also function in providing a structural and vectorial role during replication of this catenated mass of mitochondrial DNA. We suggest that this complex may represent an extreme form of a more generally occurring mitochondrion/cytoskeleton interaction.

Animals↗
PubMed2006

Structure of virioplankton in the Charente Estuary (France): transmission electron microscopy versus pulsed field gel electrophoresis.

Changes in the composition of viral communities were investigated along a salinity gradient and at different times by means of transmission electron microscopy (TEM) and pulsed field gel electrophoresis (PFGE). Samples were collected in fresh (Charente River), estuarine (Charente Estuary), and coastal (Pertuis d'Antioche, French Atlantic coast) waters. Both methods revealed similar patterns in viral community structure with a dominance of small viral particles (capsid and genome size). Viruses with a head size below 65 nm made up 71 +/- 5% of total virus-like particles, and virus-like genomes (VLG) below 100 kb accounted for 89 +/- 9% of total VLG. Despite this apparent stability of virioplankton composition over spatial scale (salinity gradient), the occurrence of large viruses (capsid and genome size) in estuarine and seawater samples indicated the presence of viral populations specific to a geographical location. Temporal changes in the structure (capsid and genome size) of viral communities were more pronounced than those reported at the spatial scale. From January to May 2003, seasonal changes in viral abundance and bacterial production occurred concomitantly with an increase in viral genomic diversity (richness), suggesting that virioplankton composition was strongly linked to changes in microbial activity and/or in the structure of the host communities. Although PFGE and TEM yielded complementary results in the description of virioplankton structures, it seems that the use of PFGE alone should be enough for the monitoring of community changes.

Capsid↗
PubMed2002

Subchromosomal positioning of the epidermal differentiation complex (EDC) in keratinocyte and lymphoblast interphase nuclei.

The epidermal differentiation complex (EDC) at 1q21 is host to many structurally and functionally related genes coding for proteins involved in the differentiation process of keratinocytes. The grouping together of these genes which share spatial and temporal expression and interrelated functions is a remarkable genomic feature which has led to suggestions that the region may have a coordinated transcription control mechanism. With the growing awareness that the organization of the genome within the interphase nucleus is relevant to transcriptional activity, we have investigated the spatial organization of the EDC in the nuclei of keratinocytes, where the EDC genes are highly expressed, and lymphoblasts, where they are silent. Using 2D and 3D FISH we find that in keratinocyte nuclei the EDC is frequently positioned external to the chromosome 1 territory compared to lymphoblasts where the EDC more often adopts a peripheral or internal location. It has been previously shown that the MHC region can extend from the chromosome 6 territory in relation to transcriptional activity. This study of the EDC thus provides a further example of a gene-dense complex capable of assuming extraterritorial positioning in relation to cell type/transcription status.

B-Lymphocytes↗
PubMed2002

Spatial autocorrelation and linkage of Mendelian RAPD markers in a population of Picea abies Karst.

The spatial clustering of single- and di-locus genotypes in a natural, continuous population of Norway spruce was investigated using 69 Mendelian Random Amplified Polymorphic DNA (RAPD) markers that covered about 15 of the species genome, and whose linkage relationships were known. Spatial autocorrelation techniques and randomization tests, applied to both single- and di-locus genotypes, revealed a weak, though significant, spatial structure at the scale 0-200 m (5 of single-locus and 7 of di-locus genotypes). To assess the relative importance of isolation by distance and linkage between markers on their spatial genetic structuring, we grouped joins between sampled trees into equivalence categories expected to show similar, specific patterns of spatial distribution under isolation by distance. Results from both single- and di-locus analyses were consistent with the existence of patches of like homozygotes (about 8 and 11 of loci at the single- and di-locus level, respectively) surrounded by a mix of like heterozygotes. Similar structuring has been predicted by simulation models under isolation by distance and selective neutrality. Overall, linkage between markers accounted for an increase of spatial clumping of di-locus genotypes involving tightly linked loci with recombination fractions up to 0.1, a consequence of limited, stochastic spread of single-locus genotypes in space. Our results support the hypothesis that isolation by distance and linkage have a small, though significant, effect even within continuous forest tree populations. In general, the spatial distribution of multilocus genotypes within populations should be interpreted with caution when linkage relationships among the markers used are unknown.

DNA↗
PubMed2026

Direct visualization of MCM helicase activation and replisome coupling in situ.

Deciphering the spatial organization of molecular machines that copy the genome remains a fundamental challenge in biology. Essential for eukaryotic DNA replication, Mini-Chromosome Maintenance (MCM2-7) helicases are loaded during G1 as double hexamers (DHs) to license replication origins. Upon activation in S phase, each DH is thought to split into two single hexamers (SHs) that form the active CMG helicases and travel bidirectionally. However, the field has long been divided: biochemical and structural studies define CMG helicases as autonomous, independent motors, while genomic and cellular imaging assays suggest sister replisomes remain physically coupled within replication factories. Here, we use MINFLUX nanoscopy to localize individual MCM complexes down to nanometer precision in situ, directly resolving DHs in human cells and capturing their separation into SHs upon origin firing. We find that the resulting sister replisomes do not diffuse apart: they remain coupled at a characteristic distance of ~40 nm throughout S phase. Depletion experiments identify two distinct contributions to this coupling: local, protein-mediated tethering by the AND1 scaffold, and higher-order spatial confinement dependent on cohesin, which is dispensable for MCM loading in G1 but required to maintain coupling in S phase. By linking the nanometer-scale architecture of the replisome to the genome-wide topology of replication fountains, these findings provide direct spatial evidence that sister forks are coupled during DNA synthesis and define the molecular forces that organize replisomes within their native nuclear context.

DNA replication↗