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PubMed1981

The status of small nuclear RNA in the ribonucleoprotein fibrils containing heterogeneous nuclear RNA.

hnRNP are made of two classes of unit, monoparticles and heterogeneous complexes. The monoparticles are much more easily dissociated by salt than the heterogeneous complexes. We made use of this differential salt sensitivity to determine the localization of snRNA in hnRNP. 1, About 50% of the snRNA were released by NaCl under the conditions of dissociation of monoparticles, U1 RNA which was enriched in monoparticles was preferentially released. 2, When the proteins resistant to salt dissociation were digested with proteinase K, an additional small proportion of snRNA was released, in particular a species designated 5 Sa RNA. Therefore, 5 Sa RNA seems to be preferentially associated with the proteins of heterogeneous complexes. 3, 40% of the snRNA remained associated with the hnRNA in the absence of any detectable protein. U1 and U2 RNA were the major RNAs in this fraction. The same RNA pattern was obtained for phenol-extracted RNA. The results indicate that all snRNA species are associated with the proteins of monoparticles, with those of heterogeneous complexes and with hnRNA. The existence of these pools of snRNA may reflect different functional states.

Animals↗
PubMed2004

A chicken mRNA similar to heterogeneous nuclear ribonucleoprotein H1.

Heterogeneous nuclear ribonucleoproteins are predominantly nuclear RNA-binding proteins that function in a variety of cellular activities. The objective of these experiments was to clone a cDNA for a chicken protein similar to other previously reported heterogeneous ribonucleoproteins for other species. The 5' and 3' ends of the chicken mRNA were cloned using Rapid Amplification of cDNA Ends (RACE). Subsequently, the expression of the mRNA sequence was confirmed via Northern analysis. The deduced amino acid sequence was approximately 86% identical to corresponding regions of human, mouse, or zebrafish proteins similar to heterogeneous nuclear ribonucleoprotein H1. The expression data confirmed the size of the predicted mRNA sequence. The newly identified sequence may be employed in future studies aimed at understanding the role of heterogeneous nuclear ribonucleoproteins in avian species.

Amino Acid Sequence↗
PubMedDate not supplied

Re-evaluating a test of the heterogeneity explanation for mortality plateaus.

[Drapeau, M.D., Gass, E.K., Simison, M.D., Mueller, L.D., Rose, M.R., 2000. Testing the heterogeneity theory of late-life mortality plateaus by using cohorts of Drosophila melanogaster, Experimental Gerontology, 35 71-84.] tested, in populations of Drosophila melanogaster, a prediction of the heterogeneity explanation for mortality plateaus. They concluded that heterogeneity could not explain their results. We contend here that the statistical analysis was flawed. It was declared that there was no difference between the mortality plateaus of three different strains, on the basis of averaged outcomes. In fact, the results for the different strains were quite different. Most trials showed the expected lowering of the mortality plateaus for the flies selected for robustness, but these effects were washed out by a small number of very large opposing deviations. There is ample reason to believe that the opposing deviations are artifacts of fitting an overly restrictive hazard-rate model. When we fit more appropriate models, the evidence points toward a rejection of the null hypothesis (of identical plateaus), hence toward modest support for the heterogeneity explanation.

Animals↗
PubMed2004

The G2028R glycine substitution mutation in COL7A1 leads to marked inter-familiar clinical heterogeneity in dominant dystrophic epidermolysis bullosa.

BACKGROUND: Glycine substitution mutations in COL7A1 not only cause dominant dystrophic epidermolysis bullosa (DDEB), but can also be silent mutations which lead to recessive dystrophic epidermolysis bullosa (RDEB) in combination with additional mutations in the other allele. OBJECTIVE: In this study, we have examined a large American Caucasian pedigree in which 10 family members from four generations presented with simple toenail dystrophy without skin fragility in autosomal dominant manner. METHOD: We sequenced COL7A1 of this pedigree. RESULTS: Mutational analysis indeed detected a heterozygous G-to-A transition at nucleotide position 6082 leading to G2028R in all the affected members. Surprisingly, mutation database revealed that this G2028R mutation had been previously identified in two distinct Asian families with DDEB showing apparent skin fragility and blister formation. One case was a 17-month-old Chinese female with classical phenotype of DDEB and the other was a 27-year-old Japanese female with typical epidermolysis bullosa (EB) pruriginosa. To better understand the molecular mechanisms of this marked inter-familiar clinical heterogeneity, we examined the entire sequence of all the exons and exon-intron borders as well as the promoter region of COL7A1 in all the three families. Sequence results demonstrated no significant nucleotide difference in COL7A1 among the three pedigrees. CONCLUSION: This paper has demonstrated for the first time that identical COL7A1 glycine substitutions can cause remarkably heterogeneous clinical phenotypes extending from simple toe nail dystrophy without skin fragility to typical DDEB and EB pruriginosa. In addition, the fact of inter-familiar, not intra-familiar clinical heterogeneity associated with G2028R suggest that the other molecular mechanisms not controlled by COL7A1 coding sequence might be responsible for the clinical heterogeneity.

Adult↗
PubMed2025

Deep Learning on Histologic Slides Accurately Predicts Consensus Molecular Subtypes and Spatial Heterogeneity in Colon Cancer.

Colon cancer (CC) is the third most prevalent cancer type. It is highly heterogeneous, particularly in terms of molecular profiles, which have both prognostic and predictive impacts on the treatment efficacy. However, CC treatment in adjuvant situations is currently guided solely by T and N staging. In this context, consensus molecular subtypes (CMSs) were introduced to stratify patients with CC based on molecular profiles. Recent studies have shown that CMS can be heterogeneous in CC, leading to a worse prognosis. This study focused on predicting CMS and its heterogeneity in CC using deep learning on digitized hematoxylin and eosin ± saffron-stained whole-slide images. Data and whole-slide images of 1996 patients from the PETACC-8, The Cancer Genome Atlas-COAD, and PRODIGE-13 cohorts were used. The model is trained to predict a 4-dimensional CMS vector, reflecting intratumor heterogeneity (ITH). It comprises a self-supervised model for embedding image patches into vectors and a weakly supervised model predicting CMS calls. Ground-truth CMS scores are obtained with the CMSclassifier package. Interpretability analyses are performed at the slide and patch levels. For homogeneous tumors, the model trained on PETACC-8 achieves 93.0% (±1.4%) macroaverage area under the curve in internal cross-validation and 94.4% macroaverage area under the curve in external validation over PRODIGE-13, whereas the The Cancer Genome Atlas-COAD model reaches 85.4% (±3.0%) in cross-validation and 92.4% over PRODIGE-13. The trained models also provide spatial distributions of CMS across tumor slides and associate specific histologic features with each CMS. Finally, the models are able to predict ITH. The results show that a deep learning model trained on routine histology slides is capable of providing an efficient and robust method for predicting CMS and characterizing a patient's ITH, paving the way for the routine consideration of CMS/ITH in clinical decision making in the adjuvant setting.

Humans↗
PubMedDate not supplied

Genetic heterogeneity of autosomal dominant amelogenesis imperfecta demonstrated by its exclusion from the AIH2 region on human chromosome 4Q.

Amelogenesis imperfecta (AI) is a group of hereditary enamel defects, characterized by large clinical diversity. On the basis of differences in clinical manifestation and inheritance pattern, 14 different subtypes have been recognized. A locus for autosomal dominant AI (ADAI) of local hypoplastic type was recently mapped to the region between D4S392 and D4S395 on the long arm of chromosome 4. To test whether the chromosome 4 locus is responsible for other forms of AI as well, a linkage study was carried out with 17 families representing at least five clinical forms of ADAI. Admixture tests for heterogeneity performed with the marker D4S2456 gave statistical support for genetic heterogeneity of ADAI with the odds 78:1. Linkage to the ADAI locus on chromosome 4q (AIH2) could only be demonstrated with families expressing the local hypoplastic type, and there was no support for heterogeneity within that group of families. Furthermore, linkage could be excluded for five families with other clinical forms of ADAI. The data therefore demonstrated that ADAI is genetically heterogeneous, and that at least two loci for it exist.

Amelogenesis Imperfecta↗
PubMed1998

The fractionation experiment: reducing heterogeneity to investigate age-specific mortality in Drosophila.

Age-specific mortality rates decelerate at older ages in both genetically homogenous and heterogeneous populations of Drosophila. One explanation proposed for deceleration is population heterogeneity. This hypothesis suggests that a population consists of sub-populations that differ in mortality characteristics and that the deceleration is the result of selective survival of stronger individuals. Here we describe an experiment that fractionates populations into several sub-populations without changing the physiological characteristics of the post-fractionated populations. Through a careful process of selection of Drosophila eggs, larvae, pupae and adults, we attempt to reduce as much as possible the degree of pre-adult, environmentally induced heterogeneity among individuals of a genetically identical cohort. We then ask whether such cohorts, when compared to non-fractionated populations, exhibit a lesser degree of mortality deceleration at advanced ages. From a total of 106 fractionated and control populations, consisting of 51331 individuals, 101 populations (93% of the fractionated populations and 100% of the control populations) exhibit a significant amount of mortality deceleration late in life. These observations suggest that environmental heterogeneity accrued during larval development is not a major factor contributing to mortality deceleration at older ages.

Aging↗
PubMed2002

Karyotypic heterogeneity and clonal evolution in squamous cell carcinomas of the head and neck.

Head and neck squamous cell carcinomas (HNSCC) are often characterized by complex karyotypic changes, and a substantial proportion of the reported tumors have shown intratumor heterogeneity in the form of cytogenetically related (40%) or unrelated clones (20%). In order to study intratumor heterogeneity and to distinguish the temporal order of chromosome rearrangements in these tumors, two or more samples from different areas of the same tumor were separately examined in 19 HNSCC, yielding karyotypes from a total of 42 tumor samples. Intrasample heterogeneity was observed in 16 samples. Two samples displayed both related and unrelated multiple clones, four samples showed only multiple unrelated clones, and the remaining 10 samples had only related subclones. Intersample heterogeneity was detected in all but one tumor. Five tumors showed both cytogenetically related and unrelated multiple clones, 11 were found to have only related subclones, and the remaining two tumors showed only unrelated clones. Clonal evolution could be assessed in 13 tumors. A comparison of chromosome imbalances in different subclones from these tumors suggests that partial or entire loss of 3p, 8p, 9p, and 18q and gain of genetic material from 3q and 8q are likely to be early genetic events. In contrast, loss of 1q, 6p, 7q, and chromosome 10, as well as gain of chromosome arms 5p and 7p, are most probably later genetic events. One of the examined tumors contained two highly complex clones that were cytogenetically unrelated, indicating that this tumor had a multicellular origin.

Adult↗
PubMed2003

Intragenomic heterogeneity between multiple 16S ribosomal RNA operons in sequenced bacterial genomes.

The availability of a large number of completely sequenced bacterial genomes allows the rapid and reliable determination of intragenomic sequence heterogeneity of 16S rRNA genes. In the present study we assessed the intragenomic sequence heterogeneity of 16S rRNA genes in 55 bacterial genomes, representing various phylogenetic groups. The total number of rRNA operons in genomes included ranged from 2 to 13. The maximum number of nucleotides that were different between any pair of 16S rRNA genes within a genome ranged from 0 to 19. The corresponding minimal similarity ranged from 100 to 98.74%. This indicates that the intragenomic heterogeneity between multiple 16S rRNA operons in these genomes is rather limited and is unlikely to have a profound effect on the classification of taxa. Among the multiple copies of the 16S rRNA genes present in the genomes included, 199 mutations were counted with transitions being the dominant type of mutations over the total length of the 16S rRNA gene. Most heterogeneity occurred in variable regions V1, V2, and V6.

Genetic Heterogeneity↗
PubMed2001

Indication of linkage and genetic heterogeneity of asthma according to age at onset on chromosome 7q in 107 French EGEA families.

It is generally believed that an early age at the onset of disease is associated with a stronger genetic component. Our aim here was to investigate both linkage and genetic heterogeneity of asthma, the latter corresponding to different genotype relative risks of a putative linked gene according to age at onset of asthma. This analysis was conducted in 107 French EGEA families with at least two asthmatic siblings, considering 157 markers that were part of our previous genome screen, using the TTS (the Triangle Test Statistic) which has been developed to detect both linkage and intra-sibpair genetic heterogeneity. This test has been applied to 38 asthmatic sib-pairs discordant for age at the onset of asthma. To confirm the existence of genetic heterogeneity, we also used the predivided sample test (PST) which compares the IBD (identity by descent) distribution of marker alleles between asthmatic sib-pairs concordant (67) and discordant (38) for the age at onset. The cutoff point used for the age at onset was 4 years, the median age at onset in our sample of asthmatic sibs. Linkage and genetic heterogeneity for a region located on chromosome 7q (at 109 cM from pter) were indicated by both tests, TTS (P=0.005, P>0.5 after correction for multiple testing) and PST (P=0.0001, 0.015 after correction). These results suggest a genetic factor on 7q involved in asthma with genotype relative risks differing according to age at onset of disease.

Age of Onset↗
PubMed2003

Indication of linkage and genetic heterogeneity for asthma and atopy on chromosomes 8p and 12q in 107 French EGEA families.

Using the sample of 107 families with at least two asthmatic siblings, as part of the EGEA study, we have investigated linkage to asthma (or atopy) and genetic heterogeneity according to the presence/absence of atopy (or asthma) using two approaches: (1) the triangle test statistic (TTS), which considers the identical by descent (IBD) distribution among affected sib-pairs discordant for another associated phenotype (eg asthmatic sib-pairs discordant for atopy) and (2) the predivided sample test (PST), which compares the IBD distribution of marker alleles between affected sib-pairs concordant and discordant for the associated phenotype. Two regions, 8p and 12q, already reported to be linked to both asthma and atopy, were examined here. A total of 20 asthmatic sib-pairs discordant for atopy and 24 atopic pairs discordant for asthma were analyzed by both TTS and PST methods and 83 pairs with atopic asthma by PST. Some evidence for linkage was observed for two markers in the 8p23.3-p23.2 region; D8S504 for asthma with genetic heterogeneity according to the presence/absence of atopy and D8S503 for atopy with genetic heterogeneity according to the presence/absence of asthma. In the 12q14.2-q21.33 region, there was also some evidence of linkage to two markers, D12S83 and D12S95, for atopy and asthma, respectively, with genetic heterogeneity according to the presence/absence of the associated trait. Provided the small distance between the two markers on either 8p (16 cM) or 12q (21 cM), it is unclear whether one or two genetic factors are involved in either region.

Asthma↗
PubMed2004

The chronic myeloproliferative disorders: clonality and clinical heterogeneity.

The chronic myeloproliferative disorders (MPD), polycythemia vera (PV), chronic idiopathic myelofibrosis (IMF), essential thrombocytosis (ET), and chronic myelogenous leukemia (CML), are thought to be clonal disorders arising in a multipotent hematopoietic progenitor cell. However, establishing the diagnosis of an MPD other than CML is problematic due to a lack of clinically applicable clonal markers. Furthermore, in some patients, in whom a classical MPD phenotype is present, the hematopoietic stem cells appear to be polyclonal, suggesting that the chronic MPD other than CML may actually be a genetically heterogeneous group of disorders. Furthermore, since the aberrant clone is believed to arise from a multipotent hematopoietic stem cell, the non-CML chronic MPD-ET, PV, and IMF-could be related. Additional unresolved issues regarding the MPD include: identification of the multipotent hematopoietic progenitor cell involved, the molecular basis for the clinical heterogeneity amongst the individual MPD, the clinical significance of clonality in non-CML MPD, and reconciliation of therapy with the clonal and clinical heterogeneity of these disorders. Determination of clonality has largely been carried out using X chromosome-linked polymorphisms, but such studies are limited to women and with increasing patient age are compromised by skewing of allelic expression in both neutrophils and T lymphocytes, making the results difficult to interpret. X chromosome-linked polymorphism studies have indicated that in PV the target stem cell is one that gives rise to both lymphoid and myeloid progenitors. Recently, two epigenetic markers have been identified in the MPD: impaired expression of the thrombopoietin receptor, Mpl, in platelets and megakaryocytes, and overexpression in neutrophils of the mRNA of a gene designated polycythemia rubra vera-1 (PRV-1). The role of these epigenetic abnormalities in the diagnosis of the MPD remains to be established. Currently, given the unresolved issues with respect to the clinical and clonal heterogeneity of the MPD, treatment needs to be tailored individually in patients with an MPD.

Age Factors↗
PubMed1983

Structure of nuclear ribonucleoprotein: heterogeneous nuclear RNA is complexed with a major sextet of proteins in vivo.

Mouse erythroleukemia cells were pulse-labeled with [3H]uridine and irradiated with 254-nm light to produce covalent crosslinks between RNA and proteins in close proximity to one another in vivo. Nuclear ribonucleoprotein particles containing heterogeneous nuclear RNA were isolated and digested with nucleases, and the resulting proteins were subjected to gel electrophoresis. Proteins carrying covalently crosslinked [3H]uridine nucleotides were identified by fluorography. The results demonstrate that heterogeneous nuclear RNA is complexed in vivo with a set of six major proteins having molecular weights between 32,500 and 41,500. Analysis of chromatin fractions indicates that nascent heterogeneous nuclear RNA chains assemble with these six proteins as a very early post-transcriptional event. These data, and other results [Nevins, J. R. & Darnell, J. E. (1981) Cell 15, 1477-1493], lead us to propose the usual order of post-transcriptional events to be: heterogeneous nuclear RNA-ribonucleoprotein particle assembly leads to poly(A) addition leads to splicing.

Animals↗
PubMed1997

Effect of genetic heterogeneity and assortative mating on linkage analysis: a simulation study.

Linkage studies of complex genetic traits raise questions about the effects of genetic heterogeneity and assortative mating on linkage analysis. To further understand these problems, I have simulated and analyzed family data for a complex genetic disease in which disease phenotype is determined by two unlinked disease loci. Two models were studied, a two-locus threshold model and a two-locus heterogeneity model. Information was generated for a marker locus linked to one of the disease-defining loci. Random-mating and assortative-mating samples were generated. Linkage analysis was then carried out by use of standard methods, under the assumptions of a single-locus disease trait and a random-mating population. Results were compared with those from analysis of a single-locus homogeneous trait in samples with the same levels of assortative mating as those considered for the two-locus traits. The results show that (1) introduction of assortative mating does not, in itself, markedly affect the estimate of the recombination fraction; (2) the power of the analysis, reflected in the LOD scores, is somewhat lower with assortative rather than random mating. Loss of power is greater with increasing levels of assortative mating; and (3) for a heterogeneous genetic disease, regardless of mating type, heterogeneity analysis permits more accurate estimate of the recombination fraction but may be of limited use in distinguishing which families belong to each homogeneous subset. These simulations also confirmed earlier observations that linkage to a disease "locus" can be detected even if the disease is incorrectly defined as a single-locus (homogeneous) trait, although the estimated recombination fraction will be significantly greater than the true recombination fraction between the linked disease-defining locus and the marker locus.

Computer Simulation↗
PubMed2000

Reproducibility and complications in gene searches: linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy.

Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosomal origins of those influences conflict. One early study reported that human leukocyte antigen (HLA) markers were genetically linked to juvenile myoclonic epilepsy (JME); this was confirmed in a later study. Other reports did not find linkage to HLA markers. One found evidence of linkage to markers on chromosome 15, another to markers on chromosome 6, centromeric to HLA. We identified families through a patient with JME and genotyped markers throughout chromosome 6. Linkage analysis assuming equal male-female recombination probabilities showed evidence for linkage (LOD score 2.5), but at a high recombination fraction (theta), suggesting heterogeneity. When linkage analysis was redone to allow independent male-female thetas, the LOD score was significantly higher (4.2) at a male-female theta of.5,.01. Although the overall pattern of LOD scores with respect to male-female theta could not be explained solely by heterogeneity, the presence of heterogeneity and predominantly maternal inheritance of JME might explain it. By analyzing loci between HLA-DP and HLA-DR and stratifying the families on the basis of evidence for or against linkage, we were able to show evidence of heterogeneity within JME and to propose a marker associated with the linked form. These data also suggest that JME may be predominantly maternally inherited and that the HLA-linked form is more likely to occur in families of European origin.

Alleles↗
PubMed2001

Regression models for linkage heterogeneity applied to familial prostate cancer.

Linkage heterogeneity frequently occurs for complex genetic diseases, and statistical methods must account for it to avoid severe loss in power to discover susceptibility genes. A common method to allow for only a fraction of linked pedigrees is to fit a mixture likelihood and then to test for linkage homogeneity, given linkage (admixture test), or to test for linkage while allowing for heterogeneity, using the heterogeneity LOD (HLOD) score. Furthermore, features of the families, such as mean age at diagnosis, may help to discriminate families that demonstrate linkage from those that do not. Pedigree features are often used to create homogeneous subsets, and LOD or HLOD scores are then computed within the subsets. However, this practice introduces several problems, including reduced power (which results from multiple testing and small sample sizes within subsets) and difficulty in interpretation of results. To address some of these limitations, we present a regression-based extension of the mixture likelihood for which pedigree features are used as covariates that determine the probability that a family is the linked type. Some advantages of this approach are that multiple covariates can be used (including quantitative covariates), covariates can be adjusted for each other, and interactions among covariates can be assessed. This new regression method is applied to linkage data for familial prostate cancer and provides new insights into the understanding of prostate cancer linkage heterogeneity.

Age of Onset↗
PubMed2001

Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.

Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogeneity would increase the power to identify genes, the effect on evidence for linkage of restricting a sample of autism-affected relative pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD, for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or more individuals with autism or related disorders, a maximal multipoint heterogeneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric linkage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysis to the subset of families (n=49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD score of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that the restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci.

Autistic Disorder↗
PubMed1998

Extraordinary ribosomal spacer length heterogeneity in a neotyphodium endophyte hybrid: implications for concerted evolution.

An extraordinary level of length heterogeneity was found in the ribosomal DNA (rDNA) of an asexual hybrid Neotyphodium grass endophyte, isolate Lp1. This hybrid Neotyphodium endophyte is an interspecific hybrid between two grass endophytes, Neotyphodium lolii, and a sexual form, Epichlöe typhina, and the length heterogeneity was not found in either of these progenitor species. The length heterogeneity in the hybrid is localized to the intergenic spacer (IGS) and is the result of copy-number variation of a tandemly repeated subrepeat class within the IGS, the 111-/119-bp subrepeats. Copy number variation of this subrepeat class appears to be a consequence of mitotic unequal crossing over that occurs between these subrepeats. This implies that unequal crossing over plays a role in the concerted evolution of the whole rDNA. Changes in the pattern of IGS length variants occurred in just two rounds of single-spore purification. Analysis of the IGS length heterogeneity revealed features that are unexpected in a simple model of unequal crossing over. Potential refinements of the molecular details of unequal crossing over are presented, and we also discuss evidence for a combination of homogenization mechanisms that drive the concerted evolution of the Lp1 rDNA.

Acremonium↗