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Results for “Heterogeneity Mapping”

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PubMed1999

Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity.

Joubert syndrome is a rare developmental defect of the cerebellar vermis, with autosomal recessive inheritance. The phenotype is highly variable and may include episodic hyperpnea, abnormal eye movements, hypotonia, ataxia, developmental delay, and mental retardation. Even within sibships the phenotype may vary, making it difficult to establish the exact clinical diagnostic boundaries of Joubert syndrome. To genetically localize the gene region, we have performed a whole-genome scan in two consanguineous families of Arabian/Iranian origins, with multiple affected probands. In one family, we detected linkage to the telomeric region of chromosome 9q, close to the marker D9S158, with a multipoint LOD score of Z=+3.7. The second family did not show linkage to this region, giving a first indication of genetic heterogeneity underlying Joubert syndrome. These findings were supported by subsequent analysis of two smaller families-one compatible with linkage to 9q; the other, unlinked. We conclude that Joubert syndrome is clinically and genetically heterogeneous and that one locus maps to chromosome 9q.

Abnormalities, Multiple↗

PubMed1981

Occurrence of heterogenous forms of the subunits of creatine kinase in various muscle and nonmuscle tissues and their behaviour during myogenesis.

Purified, homodimeric creatine kinases from chicken were subjected to two-dimensional gel analysis under dissociating conditions. Each of the subunits M-creatine kinase and B-creatine kinase was resolved into a basic and an acidic subspecies with very similar mobilities in the sodium dodecylsulfate dimension. The M-creatine kinase subspecies were found in myogenic cells, fast muscle, slow muscle and the B-creatine kinase subspecies were present in heart, gizzard and brain. The creatine kinase subunits were identified in these tissues by a variety of methods like immunoreplicas of two-dimensional gels, immunoprecipitations, or coelectrophoresis with purified creatine kinase and all gave the same results. In the course of myogenic development in vitro the subspecies were synthesized coordinately and no indication was found for a differential regulation of any of the subspecies of the creatine kinase subunits. No radioactive phosphorus was incorporated into either one of the subspecies, hence phosphorylation could be ruled out as the source of heterogeneity. Furthermore, peptide mapping analysis of partial proteolytic digests did not reveal differences among the subspecies of the same subunit. Not only chicken but also rat creatine kinase displayed this type of heterogeneity. All subspecies were observed after translation of chicken RNA in a cell-free protein-synthesizing system. The heterogeneity probably might best be explained by the existence of multiple, but closely related genes for the creatine kinase subunits.

Animals↗

PubMed1991

Detection of linkage for heterogeneous disorders by using multipoint linkage analysis.

We have compared the efficiency of the lod score test which assumes heterogeneity (lod2) to the standard lod score test which assumes homogeneity (lod1) when three-point linkage analysis is used in successive map intervals. If it is assumed that a gene located midway between two linked marker loci is responsible for a proportion of disease cases, then the lod1 test loses power relative to the lod2 test, as the proportion of linked families decreases, as the flanking markers are more closely linked, and as more map intervals are tested. Moreover, when multipoint analysis is used, linkage for a disease gene is more likely to be incorrectly excluded from a complete and dense linkage map if true genetic heterogeneity is ignored. We thus conclude that, in general, the lod2 linkage test is more efficient for detecting a true linkage when a complete genetic marker map is screened for a heterogeneous disorder.

Child↗

PubMed2003

Genome-wide linkage analysis of blood pressure under locus heterogeneity.

We describe a method for mapping quantitative trait loci that allows for locus heterogeneity. A genome-wide linkage analysis of blood pressure was performed using sib-pair data from the Framingham Heart Study. Evidence of linkage was found on four markers (GATA89G08, GATA23D06, GATA14E09, and 049xd2) at a significance level of 0.01. Two of them (GATA14E09 and 049xd2) seem to overlap with linkage signals reported previously, while the other two are not linked to any known signals.

Adult Children↗

PubMed2026

Optics-free spatial genomics for mapping mammalian brain aging by IRISeq.

Spatial transcriptomics has emerged as a transformative approach for in situ mapping of cellular heterogeneity and interactions, yet existing methods often compromise throughput, cost and tissue coverage. Here we introduce Imaging Reconstruction using Indexed Sequencing (IRISeq): an optics-free, cost-effective platform that leverages spatial interaction mapping by indexed sequencing to profile tissues at adjustable sizes and resolutions (5-50 µm). We applied IRISeq to map gene expression across more than 70 coronal sections from both adult and aged mouse brains, including wild-type and two lymphocyte-deficient models (Rag1 and Prkdc mutants) and generated more than 460,000 spatial transcriptome profiles. Our integrated analysis with 783,264 single-cell transcriptomes revealed region-specific aging signatures that are lymphocyte dependent, notably a downregulation of interferon signaling and inflammation in ventricular regions upon lymphocyte depletion, alongside mutant-specific upregulation of senescence pathways. Furthermore, lymphocyte deficiency was linked to preserved abundance of ependymal cells that line the brain's ventricles and to distinct microglial state dynamics, highlighting a key role for lymphocytes in driving inflammatory processes during brain aging. Overall, IRISeq provides a high-throughput and cost-effective solution for spatially resolved transcriptomic profiling, opening new avenues for elucidating region-specific cellular mechanisms underlying aging and identifying potential therapeutic targets to preserve brain homeostasis.

Animals↗

PubMed1987

Multiple tissue-specific sites of transcriptional initiation of the mouse anion antiport gene in erythroid and renal cells.

Primer extension and nuclease protection analysis were used to map the 5' end of mRNA transcripts of the single gene encoding the mouse erythroid anion-exchange protein, band 3. RNA from induced Friend murine erythroleukemia cells contains transcripts whose 5' ends are heterogeneous but that map to five clustered sites between 146 and 189 nucleotides upstream of the initiator AUG codon. The steady-state level of band 3 mRNA increases markedly following dimethyl sulfoxide-induced differentiation, but the pattern of transcription initiation does not vary. mRNA from anemic and normal mouse spleen exhibits the same pattern, with the addition of another transcript whose 5' end maps to position -260. In contrast, mRNA from mouse kidney has a single predominant transcript, mapping to -260. These data establish that the band 3 gene is expressed in kidney as well as in erythroid cells and suggest the presence of tissue-specific alternate promoter elements within the first exon of the band 3 gene. The nucleotide sequence of 1.7 kilobases of genomic DNA 5' to the first intron of the single-copy mouse band 3 gene, although moderately (G + C)-rich, has no "TATA" or "CAAT" boxes or other homologies with globin or other eukaryotic polymerase II promoter regions.

Animals↗

PubMed1994

Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity.

Familial juvenile nephronophthisis (NPH) is an autosomal recessive progressive tubulo-interstitial kidney disorder, responsible for 6-10% of end-stage renal failure in children, and is frequently associated with Leber amaurosis (termed Senior-Løken syndrome). The biochemical basis of NPH is unknown. We recently reported linkage of the purely renal form of NPH to three markers on chromosome 2. Our results also suggested the existence of genetic heterogeneity between NPH and SLS. To map this NPH gene more precisely, we have now tested the segregation of six new microsatellite markers and five additional families. Haplotype analyses show unequivocally that four NPH families are not linked to the chromosome 2 markers, although there are no clinical or pathological features discernible in these families that could separate them from the families linked to the chromosome 2 NPH locus (NPH1). This reveals genetic heterogeneity in the purely renal form of NPH. In situ hybridization of YAC clones isolated with two closely linked markers assigned the NPH1 region to 2q13. Furthermore, based on haplotype analysis and specific recombination events, the NPH1 gene has been placed between D2S293/D2S340 and D2S121, a genetic interval of about 5-7 cM.

Chromosomes, Human, Pair 2↗

PubMed1988

An excised SV40 intron accumulates and is stable in Xenopus laevis oocytes.

Xenopus laevis oocytes injected with simian virus 40 (SV40) DNA synthesize abundant quantities of viral late region RNA. In a previous analysis of the 5' ends of oocyte SV40 late RNAs, it was observed that, in contrast to the majority of the late RNA species, an abundant class of viral late RNAs, whose 5' ends mapped at or near nucleotide 294, was not polyadenylated. The structure of this RNA class has now been characterized further. We have shown that this species consists of a class of small uncapped RNA molecules with heterogeneous 3' ends mapping between nucleotides 417 and 433. This corresponds well with the position of a 139-nucleotide intron within the leader region of late 16S RNA (nucleotides 294-433). The identification of this RNA class as an excised intron was strongly supported by the fact that it displayed anomalous mobilities on different percentage polyacrylamide gels, a property of lariat introns. Furthermore, incubation of oocyte RNA with a HeLa cell extract with lariat debranching activity converted the small RNA to a class that now migrated as less than or equal to 140 nucleotides in length in 8% gels, consistent with the size of the linear intraleader intron. Additional analysis of this RNA showed that it is primarily nuclear in localization and is probably the most stable viral RNA species in the oocyte. These data suggest that oocytes accumulate large quantities of the 16S intraleader intron because of their failure to debranch this RNA efficiently.

Animals↗

PubMed1996

Histological grade heterogeneity in multifocal prostate cancer. Biological and clinical implications.

In order to understand the clinical and biological implications of prostate cancer multifocality and heterogeneity, we investigated their occurrence in relation to variables such as tumour volume, local invasion, and biopsy findings. In a series of 61 completely sectioned whole-mount radical prostatectomy specimens with clinical stage T2 prostate cancer, we mapped histological grade heterogeneity and tumour multifocality. We also evaluated 55 prostate biopsy cases to assess the accuracy of pre-operative grading. Among all of the prostates, only 28 per cent had a single tumour and in 16 per cent one histological grade of cancer was evident. Extracapsular invasion was not restricted to the largest tumour in each case, but also occurred in tumours of relatively small volume and low histological grade. Variability of histological grade was directly proportional to tumour volume. Both grade heterogeneity and tumour multifocality of the prostatectomy specimen showed no significant relationship to the grade accuracy of biopsies. Biopsy grading error proved greatest among small, well-differentiated, tumours. Whole-mount sectioning of prostatectomy specimens in patients with clinically localized adenocarcinoma demonstrates that grade heterogeneity is most closely related to tumour volume; that the largest (index) tumour lesion may not be representative of the pathological stage; and that grading error in prostate needle biopsies can be only partly explained by grade heterogeneity or tumour multifocality.

Adenocarcinoma↗

PubMedDate not supplied

[Suggestions for implementation of DRG in the fields of Orthopaedics and Trauma Surgery for 2004].

OBJECTIVE: The Implementation of a DRG-Variant in Germany - voluntarily since January 1 st, 2003 and obligatory from January 1 st, 2004 - has been leading to uncertainty, particularly in the hospitals, due to fears that currently practised German diagnostic and therapeutic measures will not be financed properly by a DRG-Variant. The G-DRG-Version 1.0 that was drawn up in connection with an executive order law is to a large degree identical to the Australian AR-DRG-Version 4.1. Adjustments to German requirements were made only marginally. Therefore it is necessary for every medical field to investigate by stock-taking to what extent currently practised German diagnostic and therapeutic measures are considered in the G-DRG-Version 1.0 and whether and where modifications and adaptations need to be made. In order to make qualified statements scientific evaluations of possible problems have to be made based German data. Therefore an evaluation was made of the mapping of the medical fields of orthopaedics and trauma surgery. The German Society of Trauma Surgery (DGU), the German Society of Orthopaedy and Orthopaedic Surgery (DGOOC) in cooperation with the DRG-Research-Group of the University Hospital Muenster, the German Hospital Federation (DKG) and the German Medical Association carried out a DRG evaluation project in order to investigate the medical and economical homogeneity of the case groups. METHOD: 12,645 orthopaedic and trauma surgery cases from 23 hospitals - 11 university hospitals and 12 non-university hospitals - were collected within an period of three months and were scientifically evaluated with regard to their performance homogeneity and length of stay homogeneity. RESULTS: The data formed the basis for the proof of suspected deficiencies of mapping of orthopaedic and trauma surgery cases within the G-DRG-Variant. Based on the data and additionally on conclusions of medical experts when the number of cases were small, 14 suggestions for adaptation were proposed and submitted by the deadline of March 31 st, 2003 to the InEK. CONCLUSION: The results of the DRG-Evaluation Project demonstrate the problems of mapping the very heterogenous and complex medical performances of orthopaedy and trauma surgery to a flat rate financing system that is not adapted properly to German conditions. The G-DRG-Variant Version 1.0 does not offer the sufficient possibilities of differentiation that are needed to map the various orthopaedical and trauma surgical measures in Germany.

Cost-Benefit Analysis↗

PubMed2003

Mapping cerebral glutamate 13C turnover and oxygen consumption by in vivo NMR.

Regional rates of 13C incorporation from glucose to glutamate were detected in anesthetized rat brain in vivo at 7T with high temporal and spatial resolution using NMR method ICED PEPSI (in vivo carbon edited detection with proton echo planar spectroscopic imaging). Time courses of regional glutamate 13C turnover were fitted by a metabolic model to obtain regional tri-carboxylic acid (TCA) cycle flux and cerebral metabolic rate of oxygen consumption (CMRO2) in each voxel (8 microL) of rat cortex. CMRO2 maps obtained for rats under either alpha-chloralose or morphine anesthesia revealed average cortical values of 1.5 +/- 0.2 (n = 3) and 3.2 +/- 0.3 (n = 4) mumol/g/min, respectively. These values of CMRO2 are in good agreement with previous cortical measurements with coarser spatial resolution. The heterogeneity within each map, which depicted predominantly gray and white matter differences, was significantly greater under morphine (higher cortical activity) than under-alpha-chloralose (lower cortical activity) anesthesia. The regional variations in the basal awake state, which are expected to be even greater, should be considered to avoid partial-volume artifacts in functional activation studies of awake subjects.

Animals↗

PubMed2002

Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family.

FG syndrome (FGS, MIM 305450) is a rare X-linked recessive disorder comprising mental retardation and multiple malformations. Various families have been described to date, increasing our knowledge of the phenotype variability and making the clinical diagnosis complex, especially in sporadic patients. The first locus for FG syndrome (FGS1) was linked to chromosome region Xq12-q21.31, but other families have been excluded from this locus. The genetic heterogeneity of FG syndrome has been confirmed by analysis of an X chromosome inversion [inv(X)(q11q28)] in an affected boy and in his mentally retarded maternal uncle, suggesting that an additional locus for FG syndrome (FGS2, MIM 300321) is located at either Xq11 or Xq28. Recently, a third locus (FGS3) has been mapped to Xp22.3. We have identified and clinically characterized an Italian FG family, including 31 members with three affected males in two generations and two obligate carriers. We have excluded linkage to known FGS loci, whereas an extensive study of the whole X chromosome has yielded a maximum LOD score (Z(max)) of 2.66 (recombination fraction=0) for markers between DXS8113 and sWXD805. This new locus for FG syndrome corresponds to a region of approximately 4.6 Mb on the X chromosome.

Abnormalities, Multiple↗

PubMed1994

Analysis of stage-specific transcripts of the Plasmodium falciparum serine repeat antigen (SERA) gene and transcription from the SERA locus.

We evaluated the stage-specific transcription and processing of serine repeat antigen (SERA) messenger RNA to further examine mechanisms regulating gene expression in Plasmodium falciparum. SERA mRNA was expressed exclusively in trophozoite and schizont stages. Transcription from the SERA gene was first detected between 24 and 29 h following erythrocyte invasion. The transcript mapping data revealed heterogeneity of the SERA mRNA 5' and 3' ends. RNA sequencing revealed that SERA transcripts were not generated by a trans-splicing mechanism. A new SERA gene, SERA3, was identified 1.8 kb upstream of SERA. The direction of transcription of the SERA locus genes, SERA3, SERA, and SERA2, was mapped relative to the location of other chromosome 2 genetic markers. The SERA locus and the closely linked MSA2 locus were found to be transcriptionally regulated in a coordinate fashion. Collectively, the results of these experiments show that parallel and coordinately controlled transcription units reside on chromosome 2. These results implicate a novel mechanism of transcriptional control in Plasmodium.

Amino Acid Sequence↗

PubMed2001

Clinical features and genetic analysis of a new form of spinocerebellar ataxia.

BACKGROUND: The autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of disorders. The mutations for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA-12 are identified and caused by an expansion of a CAG or a CTG repeat sequence of these genes. Six additional loci for SCA4, SCA5, SCA-10, SCA-11, SCA-13, and SCA-14 are mapped. The growing heterogeneity of the autosomal dominant forms of these diseases shows that the genetic etiologies of at least 20% of ADCA have yet to be elucidated. METHODS: The authors ascertained and clinically characterized a four-generation pedigree segregating an autosomal dominant phenotype for SCA. Direct mutation analysis, repeat expansion detection analysis, and linkage analysis for all known SCA loci were performed. RESULTS: Direct mutational analysis excluded SCA1, 2, 3, 6, 7, 8, and 12; genetic linkage analysis excluded SCA4, 5,10, 11, 13, and 14, giving significant negative lod scores. Examination of the family showed that all affected members had gait ataxia and akinesia with variable features of dysarthria, hyporeflexia, and mild intellectual impairment. Eye movements were normal. Head MRI showed atrophy of the cerebellum without involvement of the brainstem. In 10 parent-child pairs, median onset occurred 10.5 years earlier in offspring than in their parents, suggesting anticipation. CONCLUSION: This family is distinct from other families with SCA and is characterized by cerebellar ataxia and extrapyramidal signs.

Adult↗

PubMed2003

A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23.

The autosomal dominant cerebellar ataxias (ADCA) are a clinically, pathologically and genetically heterogeneous group of disorders. Ten responsible genes have been identified for spinocerebellar ataxia types SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12 and SCA17, and dentatorubral pallidoluysian atrophy (DRPLA). The mutation is caused by an expansion of a CAG, CTG or ATTCT repeat sequence of these genes. Six additional loci, SCA4, SCA5, SCA11, SCA13, SCA14 and SCA16 have also been mapped. The growing heterogeneity of the autosomal dominant forms of these diseases shows that the genetic aetiologies of at least 20% of ADCA have yet to be elucidated. We ascertained and clinically characterized a four-generation Chinese pedigree segregating an autosomal dominant phenotype for cerebellar ataxia. Direct mutation analysis, linkage analysis for all known SCA loci and a genome-wide linkage study were performed. Direct mutation analysis excluded SCA1, 2, 3, 6, 7, 8, 10, 12, 17 and DRPLA, and genetic linkage analysis excluded SCA4, 5, 11, 13, 14 and 16. The genome-wide linkage study suggested linkage to a locus on chromosome 1p21-q23, with the highest two-point LOD score at D1S1167 (Zmax = 3.46 at theta = 0.00). Multipoint analysis and haplotype reconstruction traced this novel SCA locus (SCA22) to a 43.7-cM interval flanked by D1S206 and D1S2878 (Zmax = 3.78 under four liability classes, and 2.67 using affected-only method). The age at onset ranged from 10 to 46 years. All affected members had gait ataxia with variable features of dysarthria and hyporeflexia. Head MRI showed homogeneous atrophy of the cerebellum without involvement of the brainstem. In six parent-child pairs, median onset occurred 10 years earlier in offspring than in their parents, suggesting anticipation. This family is distinct from other families with SCA and is characterized by a slowly progressive, pure cerebellar ataxia.

Adult↗

PubMed2006

Evaluation of cartilage repair in the distal femur after autologous chondrocyte transplantation using T2 relaxation time and dGEMRIC.

OBJECTIVES: To investigate the potential of combining T2 relaxation time and delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) measurements after autologous chondrocyte transplantation (ACT). MATERIALS AND METHODS: T2 and dGEMRIC maps were measured in the sagittal and coronal directions in 12 patients 10-15 months after ACT surgery. Grafts were assessed for bulk full thickness, superficial and deep tissue T2 and dGEMRIC values, and were compared to control cartilage. RESULTS: All ACT grafts showed filling of the repair area to the level of or above the articular surface. Matrix of the grafts lacked the classical laminar structure and appeared more heterogenous on T2 maps than control cartilage. As compared to control cartilage, ACT grafts showed significantly longer T2 values for bulk tissue as well as for the superficial 50% and deep 50% of tissue except for superficial cartilage in the coronal direction. dGEMRIC assessment in the sagittal and coronal directions did not show a significant difference between bulk, superficial or deep tissue as compared to the control cartilage. Superficial and deep ACT tissue did not differ statistically in terms of their T2 or dGEMRIC values. CONCLUSIONS: These preliminary results suggest that, according to T2 measurements, ACT repair tissue at 10-15 months differs from normal cartilage and probably lacks the preferential collagen arrangement of normal cartilage, while according to dGEMRIC a varying degree of proteoglycan replenishment takes place. Combining these two quantitative magnetic resonance imaging techniques enables a more comprehensive characterization of cartilage repair than before.

Adult↗

PubMed2004

Conformational heterogeneity of an equilibrium folding intermediate quantified and mapped by scanning mutagenesis.

It is challenging to experimentally define an energy landscape for protein folding that comprises multiple partially unfolded states. Experimental results are often ambiguous as to whether a non-native state is conformationally homogeneous. Here, we tested an approach combining systematic mutagenesis and a Brønsted-like analysis to reveal and quantify conformational heterogeneity of folding intermediate states. Using this method, we resolved an otherwise apparently homogeneous equilibrium folding intermediate of Borrelia burgdorferi OspA into two conformationally distinct species and determined their relative populations. Furthermore, we mapped the structural differences between these intermediate species, which are consistent with the non-native species that we previously proposed based on native-state hydrogen exchange studies. When treated as a single state, the intermediate ensemble exhibited fractional Phi-values for mutations and Hammond-type behaviors that are often observed for folding transition states. We found that a change in relative population of the two species within the intermediate ensemble explains these properties well, suggesting that fractional Phi-values and Hammond-type behaviors exhibited by folding intermediates and transition states may arise more often from conformational heterogeneity than from a single partial structure. Our results are consistent with the presence of multiple minima in a rugged energy landscape predicted from theoretical studies. The method described here provides a promising means to probe a complex folding energy landscape.

Antigens, Surface↗

PubMed1987

Protein glycosylation in yeast: transcript heterogeneity of the ALG7 gene.

The first enzyme in the lipid-linked oligosaccharide biosynthetic pathway, UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (UDP-N-acetyl-D-glucosamine:dolichyl-phosphate-N-acetyl- D-glucosaminephosphotransferase, EC 2.7.8.15), is encoded by the ALG7 gene. We show that this gene is essential for cell growth, since a null mutation constructed with standard gene disruption techniques results in cell lethality. The ALG7 gene is transcribed into two major messages, approximately 1.38 and 1.56 kilobase pairs (kbp) in size, and this heterogeneity has been mapped to the 3' untranslated region. Two sets of tripartite sequences implicated in transcription termination begin 15 bp and 256 bp past the translation stop codon, TGA. The ratios of the two major transcripts change with gene dosage, with the longer mRNA becoming more abundant in cells containing higher levels of the ALG7 gene. Changes in transcript ratios are also observed in mutants defective in lipid-linked sugar-donor biosynthesis. In addition, there is 5' heterogeneity in the ALG7 mRNAs. The transcripts start at four initiation sites located within a 20-bp region. Two potentially functional TATA elements have been identified at positions -157 and -139, which may be involved in initiation from multiple sites. These features point to numerous factors that may be involved in the regulation of the expression of the ALG7 gene.

Base Sequence↗