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Founder populations hold tremendous promise for mapping genes for complex traits, as they offer less genetic and environmental heterogeneity and greater potential for genealogical research. Not all founder populations are equally valuable, however. The Afrikaner population meets several criteria that make it an ideal population for mapping complex traits, including founding by a small number of initial founders that likely allowed for a relatively restricted set of mutations and a large current population size that allows identification of a sufficient number of cases. Here, we examine the potential to conduct genealogical research in this population and present initial results indicating that accurate genealogical tracing for up to 17 generations is feasible. We also examine the clinical similarities of schizophrenia cases diagnosed in South Africa and those diagnosed in other, heterogeneous populations, specifically the US. We find that, with regard to basic sample descriptors and cardinal symptoms of disease, the two populations are equivalent. It is, therefore, likely that results from our genetic study of schizophrenia will be applicable to other populations. Based on the results presented here, the history and current size of the population, as well as our previous analysis addressing the extent of background linkage disequilibrium (LD) in the Afrikaners, we conclude that the Afrikaner population is likely an appropriate founder population to map genes for schizophrenia using both linkage and LD approaches.
X-linked mental retardation (XLMR) is genetically heterogeneous and clinically variable. We describe a new XLMR syndrome of severe mental retardation and multiple congenital anomalies. Two sisters have (with 3 different partners) 3 severely handicapped sons. In 2 cases, oligohydramnios and intrauterine growth retardation were noted. Common anomalies included a square-shaped face, high and broad forehead, frontal bossing, downward slant of palpebral fissures, hypertelorism, epicanthic folds, long philtrum, thin upper lip, and apparently low-set ears. One boy has bilateral microphthalmos and sclerocornea, and his cousin has atrophy of the optic nerve. All 3 patients are blind and have profound statomotor and mental retardation, seizures, and a grossly abnormal electroencephalographic pattern. Additional findings are short stature, delayed bone maturation, hydronephrosis, vesicorenal reflux, cryptorchidism, clinodactyly of the 5th fingers, and transverse palmar creases. The karyotype is normal (46,XY). Segregation analysis showed perfect coinheritance between the clinical phenotype and alleles at several loci in Xp22.3, whereas recombinants were identified with marker loci from Xp22.2-qter. Analysis of multiple informative meioses suggests that the disease locus maps in Xp22.3 distal to DXS16.
The spinal muscular atrophies (SMAs) are among the most common autosomal recessive disorders. The mapping of the gene responsible for SMA to chromosome 5 has allowed the assessment of genetic heterogeneity in kindreds with a putative diagnosis of SMA. We report linkage analysis of 71 Canadian SMA families (types 1, 2, and 3) using polymorphisms that both flank and are linked to SMA. Data demonstrating nonlinkage to 5q markers were initially obtained in five kindreds; reexamination of the clinical status of these families showed that one fulfilled all the SMA diagnostic criteria, two showed patterns for which a diagnosis of SMA was possible but not conclusive, and two showed patterns for which the diagnosis of SMA appeared unlikely. This results in a degree of genetic heterogeneity between 1.5% and 4.5%. The three kindreds for which SMA appeared either possible or likely were simplex (ie, contained only one affected individual), and therefore the possibility that they represented new mutations could not be discounted. Thus, the significant majority of classic SMA cases are caused by a mutation in the 5q13.1 locus. Low genetic heterogeneity has implications for both genetic counseling and the applicability of conventional and genetic therapies following cloning of the SMA gene.
Systematically mapped samples cut from lungs previously labeled with intravascular and aerosol microspheres can be used to create high-resolution maps of regional perfusion and regional ventilation. With multiple radioactive or fluorescent microsphere labels available, this methodology can compare regional flow responses to different interventions without partial volume effects or registration errors that complicate interpretation of in vivo imaging measurements. Microsphere blood flow maps examined at different levels of spatial resolution have revealed that regional flow heterogeneity increases progressively down to an acinar level of scale. This pattern of scale-dependent heterogeneity is characteristic of a fractal distribution network, and it suggests that the anatomic configuration of the pulmonary vascular tree is the primary determinant of high-resolution regional flow heterogeneity. At approximately 2-cm(3) resolution, the large-scale gravitational gradients of blood flow per unit weight of alveolar tissue account for <5% of the overall flow heterogeneity. Furthermore, regional blood flow per gram of alveolar tissue remains relatively constant with different body positions, gravitational stresses, and exercise. Regional alveolar ventilation is accurately represented by the deposition of inhaled 1.0-microm fluorescent microsphere aerosols, at least down to the approximately 2-cm(3) level of scale. Analysis of these ventilation maps has revealed the same scale-dependent property of regional alveolar ventilation heterogeneity, with a strong correlation between ventilation and blood flow maintained at all levels of scale. The ventilation-perfusion (VA/Q) distributions obtained from microsphere flow maps of normal animals agree with simultaneously acquired multiple inert-gas elimination technique VA/Q distributions, but they underestimate gas-exchange impairment in diffuse lung injury.
BACKGROUND AND OBJECTIVE: Intratumoral heterogeneity for prognostic factors (ploidy, proliferation, hormone receptor positivity) has been demonstrated in primary breast carcinoma by both flow cytometric and image analysis methods. Previously, heterogeneity in tumors had been demonstrated for only singular parameters. Our objective, using maps of tumors in which discrete regions can be analyzed simultaneously for DNA index (DI) and proliferative activity, was to demonstrate heterogeneity with respect to two parameters and to determine whether any interparametric relationships existed. METHODS: We analyzed 25 cases of archived, paraffin-embedded breast carcinoma (ductal) for Feulgen stain DNA analysis and MIB-1 immunohistochemistry using the CAS 200 Image Cytometer. For each tumor, four discrete regions were analyzed including tumor-host tissue interface sectors. RESULTS: Of 25 cases, 19 (76%) were homogeneously diploid or near-diploid aneuploid, and 6 (24%) were heterogeneous. Within the heterogeneous group, all cases had at least one diploid and one or more aneuploid populations from separate discrete regions. Five of six DI heterogeneous tumors displayed diploid values for the overall measurements of the respective tumors, based on analysis of 200 or more nuclei. Eight of 25 cases (32%) showed significant measurable variation for MIB-1 proliferative activity in various sectors of tumor. All the MIB-1 heterogeneous tumors, with one exception, were homogeneously diploid. CONCLUSIONS: These findings demonstrate that (1) heterogeneity is present with respect to DI and proliferative activity in breast carcinoma and is relatively common, (2) tumors homogeneous for one parameter may be heterogeneous for another, and (3) heterogeneity for proliferative activity is more common in homogeneously diploid tumors than in heterogeneous/aneuploid tumors.
Late simian virus 40 (SV40) mRNA contains eight different cap structures which we have previously identified and mapped on the viral genome. As reported here, 5'-cap heterogeneity is a common feature to both the early and the late SV40 mRNA's. methyl-3H-labeled viral mRNA was purified from cells infected at 41 degrees C with SV40 mutant tsA209. Three different cap cores were identified: m7GpppGm, m7GpppCm, and m7GpppAm. An average of three to four m6A residues per mRNA molecule was found. RNase T2-resistant 32P-labeled early caps from tsA209-infected cells isolated and characterized. Six distinct cap I structures were identified: m7GpppCmpU (30%), m7GpppGmpC (24%), m7GpppAmpG (18%), m7GpppGmpU (13%), m7GpppGmpG (12%), and m7GpppAmpU (3%). A similar 5'-end heterogeneity was observed in early SV40 mRNA from BSC-1 cells infected with wild-type SV40 strain 777 in the presence of cytosine arabinoside and in the SV40 UV-transformed permissive line C-6. Five of these capped dinucleotides are complementary to DNA sequences at 0.66 map unit in a region previously identified by the primer extension method (Reddy et al., J. Virol. 30:279-296, 1979; Thompson et al., J. Virol. 31:437-438, 1979) as the 5' end of the early message. DNA sequences upstream from this region contain the TATTTAT (Hogness-Goldberg box), which is missing from upstream of the 5'-cap sites of late SV40 mRNA. Thus, 5'-end heterogeneity is not necessarily related to the presence or the absence of this putative transcriptional "initiation signal." When the possibility that SV40 5' caps represent transcriptional initiation sites is considered, the data also suggest that, on SV40 DNA, eucaryotic RNA polymerase II initiates transcription at multiple nucleotide sequences, including pyrimidines.
The D21S13 locus has shown linkage to a gene for familial Alzheimer disease (FAD) on chromosome 21 (St. George-Hyslop et al. 1987). The limited informativeness of probes for this locus have hindered precise mapping of the FAD locus and analysis of nonallelic heterogeneity in FAD (Schellenberg et al. 1988; St. George-Hyslop et al. 1987). We describe a new EcoRI polymorphism at the D21S13 locus that may be useful for the further study of FAD families.
The relationships between genes in neighboring clusters in a self-organizing map (SOM) and properties attributed to them are sometimes difficult to discern, especially when heterogeneous datasets are used. We report a novel approach to identify correlations between heterogeneous datasets. One dataset, derived from microarray analysis of polysomal distribution, contained changes in the translational efficiency of Caenorhabditis elegans mRNAs resulting from loss of specific eIF4E isoform. The other dataset contained expression patterns of mRNAs across all developmental stages. Two algorithms were applied to these datasets: a classical scatter plot and an SOM. The outputs were linked using a two-dimensional color scale. This revealed that an mRNA's eIF4E-dependent translational efficiency is strongly dependent on its expression during development. This correlation was not detectable with a traditional one-dimensional color scale.
Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders that affect the peripheral nervous system. Three loci are known for the autosomal dominant forms of axonal CMT (CMT2), but none have yet been identified for autosomal recessive axonal CMT (ARCMT2). We have studied a large consanguineous Moroccan ARCMT2 family with nine affected sibs. The onset of CMT was in the 2d decade in all affected individuals who presented with a severe motor and sensory neuropathy, with proximal muscle involvement occurring in some patients. After exclusion of known loci for CMT2 and for demyelinating ARCMT2, a genomewide search was performed. Evidence for linkage was found with markers on chromosome 1q. The maximum pairwise LOD score was above the threshold value of 3.00, for markers D1S514, D1S2715, D1S2777, and D1S2721, and it reached 6.10 at the loci D1S2777, D1S2721, and D1S2624, according to multipoint LOD-score analysis. These markers defined a region of homozygosity that placed the gene in a 4.4-cM interval. Moreover, a recombination event detected in an unaffected 48-year-old individual excludes the D1S506 marker, thereby reducing the interval to 1.7 cM. In addition, the P0 gene, an attractive candidate because of both its location on chromosome 1q and its role in myelin structure, was excluded by physical mapping and direct sequencing.
Treacher Collins syndrome is an autosomal dominant disorder of abnormal craniofacial development. Linkage analysis was performed in Treacher Collins families with restriction fragment length or microsatellite polymorphisms associated with eight loci previously mapped to 5q31----qter. Positive lod scores were obtained for four loci, D5S119, D5S207, D5S209, and D5S210, which map to 5q31.3----q33.3. The Treacher Collins syndrome locus was linked closest to locus D5S210, which is associated with microsatellite polymorphisms, with a maximum lod score of 8.65 at theta = 0.02. The Treacher Collins syndrome locus was excluded from locus ADRB2R, which maps to 5q31----q32, and loci D5S22, D5S61, and D5S43, which map to 5q34----qter. There was no evidence for genetic heterogeneity among eight families with variable expression of the condition.
UNLABELLED: To analyze ploidy alterations during progression of colorectal tumors, we mapped the ploidy constitutions by cytofluorometry using (measurements of metaphase cells in) tissue sections as well as cell suspensions isolated from the tissue sections. Clonality of the tumor with heterogeneous ploidy constitution was checked by mutation pattern of K-ras codon 12. To assess the significance of polyploidy detected in the diploid tumor component, the present materials were confined to 23 tumors that contained diploid tumor cells. RESULTS: 1) Eight diploid tumors without polyploidy that invaded the submucosa or deeper were greater than 2 cm in diameter. 2) Aneuploidy was detected in tissue sections from 9 out of 15 tumors that had diploid component with polyploidy, and was occasionally predominant in the extramucosal invasive parts. 3) Near-diploid aneuploidy was detected in the cells isolated from diploid (+ polyploid) regions of 2 tumors with aneuploidy. 4) Three of the 6 tumors with heterogeneous ploidy constituents had ras mutation with the mutation patterns common to diploid and aneuploid parts. These findings suggest that aneuploid cells evolve preferentially from the diploid tumor cell population with polyploidy, which often include near-diploid aneuploidy.
Chemical imaging analysis holds great potential in probing the chemical heterogeneity of samples with high spatial resolution and molecular specificity. This paper demonstrates the implementation of Raman mapping for microscopic characterization of tablets containing chloramphenicol palmitate polymorphs with the aid of a new multivariate image segmentation approach based on spatial directed agglomeration clustering. This approach performs the agglomeration clustering by stepwise merging the pixels possessing both spatial closeness and spectral similarity into clusters that define the image segmentation. The incorporation of spatial closeness into the clustering process enables the approach to improve the robustness and avoid poorly defined image segmentation arising from clusters with highly separated pixels. Additionally, the stepwise merging of clusters offers an F-statistic-based procedure to automatically ascertain the number of image segments. Raman mapping analysis of tablets containing two polymorphs of chloramphenicol palmitate followed by multivariate image segmentation reveals that the proposed technique offers the identification of each polymorph and a quantitative visualization of the spatial distribution of the polymorphs identified. This technique holds promise in rapid, noninvasive, and quantitative polymorph analysis for pharmaceutical production processes.
Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disorder which usually becomes clinically manifest in early childhood, although the spectrum of ARPKD is much more variable than generally known. Presentation of ARPKD at later ages and survival into adulthood have been observed in many cases. The responsible gene has been mapped to chromosome 6p. Thus there is no evidence of genetic heterogeneity. The most important indication for DNA diagnosis is the prenatal diagnosis in families with at least one affected child. The critical region has been narrowed with the use of recombinant families of about 4 cM. Several possible candidate genes have been excluded.
The surface of mammalian sperm is known to exhibit regional heterogeneity. Using monoclonal antibodies, we have analyzed the nature of this regional variation at the molecular level. A map of the surface of guinea pig sperm has been constructed that defines a number of regions in which surface antigens are localized and analyzes the diversity of antigens found in each region. In an initial screening of 117 hybridoma antibodies to a sperm membrane preparation, a remarkable result was obtained: all the antibodies bound to a localized region of the cell. From the initial hybrid lines, we established a collection of 56 stable hybridomas producing antibodies to surface antigens. These antibodies detect antigens localized in five surface regions: anterior head (AH), posterior head (PH), whole head (WH), posterior tail (PT), and whole tail (WT). At least 12 distinct surface antigens are recognized that bind antibodies in one of the localized regions (five AH antigens, three PH, two WH, one PT, and one WT). Some of the recognized antigens have been identified as proteins, comprised of either one or several 125I-labeled polypeptides. The identified AH antigens have labeled polypeptides of molecular weights (Mr) 52,000 (52K); 70K, 62K, 46K, 25K, and 18K; 62K, 52K, and 38K; 16K; and 38K. Identified PH antigens have polypeptides of Mr 60K; 66K, 48K, and 41K; and 58K and 48K. Identified WH antigens have polypeptides of Mr 89K and 45K; and 42K. We conclude that the sperm cell can maintain contiguous membrane domains which have quite different compositions. Its surface is a mosaic consisting of multiple regions and each region can contain several localized antigens.
The first series of studies on the rDNA satellite of the sea urchin, Lytechinus variegatus, based on saturation hybridization of rRNA-rDNA and renaturation kinetics, showed that repeat length of rRNA gene was of about 8 kb in which there was no provision for NTS. The EM denaturation mapping, however, revealed (1) that the gene was 75% larger (longer) than 8 kb, within which there was a NTS whose length varied in repeating units, (3) and there was a region of high GC almost in the middle of the transcribed part. The suggestion of length and sequential heterogeneity in the gene copies coming from the first denaturation mapping prompted further studies with techniques so that the conclusions of the previous results could be stated with finality. The results that emanated from further studies established that the rDNA repeat length of L. variegatus was of about 12 kb and that the NTS ranged from 3.8 to 6.4 kb. Earlier demonstration of a moderately high-GC segment within the transcribed part was also confirmed by sequence analysis. However, the stipulations on the NTS regarding sequential and length heterogeneity, still awaits elucidation by sequence analysis.
BACKGROUND: The routine diagnosis of genodermatoses is significantly complicated by the fact that in this group of disorders, clinical manifestations may result from mutations in unrelated genes (genetic heterogeneity) and mutations in the same gene often lead to dissimilar clinical signs (phenotypic heterogeneity). METHODS: In this study, we applied the principles of homozygosity mapping as a screening method before formal mutational analysis in an attempt to facilitate the molecular diagnosis of genodermatoses in consanguineous families. The method was evaluated in a retrospective fashion in 4 families previously assessed with junctional epidermolysis bullosa and in a prospective manner in 11 families with congenital recessive ichthyosis. RESULTS: The method was found to be efficient in directing the molecular analysis to one of the 4 genes commonly involved in the pathogenesis of junctional epidermolysis bullosa or in identifying cases of congenital recessive ichthyosis caused by mutations in TGM1. We found that this diagnostic strategy results in a 5-fold decrease in the cost of mutation analysis. LIMITATIONS: The proposed diagnostic strategy is applicable to consanguineous families only and, therefore, cannot be used in outbred populations. CONCLUSION: Our results indicate that homozygosity mapping may serve as a useful adjunct in the molecular diagnosis of junctional epidermolysis bullosa or congenital recessive ichthyosis in inbred populations. This study emphasizes the usefulness in human genetics of diagnostic strategies tailored to the demographic features of target populations.
A statistical analysis of physical map data for eight restriction enzymes covering nearly the entire genome of E. coli is presented. The methods of analysis are based on a top-down modeling approach which requires no knowledge of the statistical properties of the base sequence. For most enzymes, the distribution of mapped sites is found to be fairly homogeneous. Some heterogeneity in the distribution of sites is observed for the enzymes Pstl and HindIII. In addition, BamHI sites are found to be more evenly dispersed than we would expect for random placement and we speculate on a possible mechanism. A consistent departure from a uniform distribution, observed for each of the eight enzymes, is found to be due to a lack of closely spaced sites. We conclude from our analysis that this departure can be accounted for by deficiencies in the physical map data rather than non-random placement of actual restriction sites. Estimates of the numbers of sites missing from the map are given, based both on the map data itself and on the site frequencies in a sample of sequenced E. coli DNA. We conclude that 5 to 15% of the mapped sites represent multiple sites in the DNA sequence.