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PubMed1989

Identifying pedigrees segregating at a major locus for a quantitative trait: an efficient strategy for linkage analysis.

Having found evidence for segregation at a major locus for a quantitative trait, a logical next step is to identify those pedigrees in which major-locus segregation is occurring. If the quantitative trait is a risk factor for an associated disease, identifying such segregating pedigrees can be important in classifying families by etiology, in risk assessment, and in suggesting treatment modalities. Identifying segregating pedigrees can also be helpful in selecting pedigrees to include in a subsequent linkage study to map the major locus. Here, we describe a strategy to identify pedigrees segregating at a major locus for a quantitative trait. We apply this pedigree selection strategy to simulated data generated under a major-locus or mixed model with a rare dominant allele and sampled according to one of several fixed-structure or sequential sampling designs. We demonstrate that for the situations considered, the pedigree selection strategy is sensitive and specific and that a linkage study based only on the pedigrees classified as segregating extracts essentially all the linkage information in the entire sample of pedigrees. Our results suggest that for large-scale linkage studies involving many genetic markers, the savings from this strategy can be substantial and that, compared with fixed-structure sampling, sequential sampling of pedigrees can greatly improve the efficiency for linkage analysis of a quantitative trait.

Genetic Linkage↗

PubMed1985

Eye-specific segregation requires neural activity in three-eyed Rana pipiens.

The addition of a third eye primordium to the forebrain region of a Rana pipiens embryo invariably results in the development of a series of periodic, mutually exclusive eye-specific bands in tectal lobes dually innervated by the host and supernumerary fibers. A number of investigators have proposed that such source-specific segregation arises as a compromise between two mechanisms that are normally involved in retinotectal map formation: one which is dependent on cell surface affinities to align the map and produce a rough retinotopy and a second that "fine tunes" the map by stabilizing adjacent terminals from neighboring retinal ganglion cell bodies at the expense of terminals from non-neighboring cells. In this study we have tested the idea that this second "fine-tuning" mechanism is dependent on neural activity by blocking impulse activity in the optic nerves of three-eyed tadpoles. To assess the requirement for activity on the formation of bands, both normal optic nerves of 17 three-eyed tadpoles were crushed intraorbitally. Two weeks after this operation, the supernumerary retinal projection had debanded and spread to cover the entire tectum in a continuous fashion. By 4 weeks, however, the host optic fibers regenerated back to the tecta and began to form segregated stripes with the fibers from the third eye. Six to 7 weeks after the optic nerve crush the periodic pattern of eye-specific segregation characteristic of dually innervated tecta was again pronounced. When activity in all three optic nerves was eliminated with tetrodotoxin (TTX; embedded in a slow release plastic) during the last 3 weeks of this process, the fibers from the two competing eyes failed to segregate and, instead, formed two completely overlapping, continuous projections across the tectal surface. To test for the requirement of activity in the maintenance of segregation, we also subjected three-eyed tadpoles without optic nerve crush to TTX blockade for 2, 3, and 4 weeks. Animals sacrificed at 2 weeks show overlap of the projections in the rostral tectum but distinct interdigitating stripes in other regions of these lobes. After 3 weeks of blockade, segregation of the projections was less distinct in the central tectum as well. After 4 weeks of TTX blockade the terminals from both eyes spread to form continuous overlapping projections throughout the tectum. Examination of well isolated, individual retinal ganglion cell terminal arbors during this period reveals that they occupy a significantly greater area of tectum following the TTX treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1979

Residential segregation of Spanish Americans in United States urbanized areas.

Residential segregation among Spanish Americans, whites and blacks is measured in the 29 largest U.S. urbanized areas. Results show that Spanish Americans are much less segregated from whites than are blacks and are less concentrated within central cities. Spanish-white segregation also tends to be much lower in suburbs than in central cities, while back-white segregation is maintained at a high level in both areas. Segregation of Spanish Americans from whites is found to decline with generations spent in the United States. Finally, the relative proportion of Spanish who live in a central city and the relative number of Spanish who are foreign stock, are both highly related, across urbanized areas, to variations in the level of Spanish-white segregation.

Black or African American↗

PubMed1982

A model for inferring the voluntary and involuntary causes of residential segregation.

It is clear that both voluntary and involuntary forces normally contribute to the residential segregation existing between groups. For the most part, the contribution of each dimension has not been determined. Rather, researchers operate as if either one or the other force is operating. In the United States, for example, black-white segregation is assumed to be imposed by whites on blacks, as if the latter were themselves totally indifferent to the racial composition in their areas of residence. On the other hand, it is assumed that segregation between white ethnic groups is at present purely a voluntary matter. In an earlier period, it was assumed that their segregation was both voluntary (reflecting desires to be among copatriots) and involuntary (reflecting the imposition of restrictions on residential movement by other groups as well as economic forces). But it has not been possible for investigators to determine the relative importance of each factor. Using asymmetrical segregation indexes, a rudimentary procedure is proposed for determining the relative importance of voluntary and involuntary forces operating to generate a given level of segregation. Data based on Black, Anglo, and Spanish residential patterns are then considered in terms of the proposed model.

Ethnicity↗

PubMed1994

Spatial and structural segregation of the transcribed and nontranscribed alleles of c-myc in Namalva-S cells.

By using various approaches we received evidence that, in Namalva-S cells carrying a t(8;14) translocation and highly expressing c-myc, the two alleles of the gene are spatially and structurally segregated. Spatial segregation of the alleles was observed in all nuclei analyzed by in situ hybridization technique. Their structural segregation, i.e., association with different intranuclear structures, was confirmed in a number of experiments. When high-salt extracted nuclei were digested with EcoRI, which is known to produce fragments containing the entire c-myc locus, the sequences of the gene were found separated between the pellet, containing sequences firmly associated with the heavier matrix structures, and the supernatant, containing sequences from the free length of the DNA loops. Southern hybridization performed with a probe representative for the constant region of the human IgH locus revealed that this fractionation in fact segregates the reorganized from the normal allele of c-myc. Run-on experiments carried out with two fractions, topologically equivalent to the above P and S but isolated as intact chromatin structures, indicated that the allele associated with nuclear matrix is actively transcribed, while that located in the free length of the chromatin loops is practically nontranscribed. Studies on the chromatin organization of transcribed and nontranscribed alleles revealed the existence in them of two alternative chromatin structures. Control experiments with beta-globin gene, performed with cells constitutively nontranscribing or actively transcribing this gene, confirmed our conclusions about the spatial segregation of the two alleles and clarified that their structural segregation occurs when the gene is activated for transcription.

Alleles↗

PubMed1994

Two stages in visual texture segregation: a lesion study in the cat.

We have used five cats to investigate the effects of two distinct visual cortex lesions on the segregation of two different texture stimuli. The ablation of areas 17 and 18 (tier I) severely impaired the segregation between textures made of line elements differing in orientation, but spared the segregation between annulus and dot textures. In contrast, the ablation of those areas receiving direct afferents from areas 17 and 18 (tier II) destroyed the segregation for both texture stimuli. Strong deficits remained up to 1 year after the lesion, although limited recovery was observed after tier II lesions. We suggest that tier I areas are involved in the local filtering of the texture elements, and that tier II areas compute texture differences on the basis of the filtered image provided by tier I areas. The crucial contribution to texture segregation of visual areas belonging to a second level in the cortical hierarchy challenges the notion that texture segregation is entirely an early process in vision.

Animals↗

PubMed1998

The analysis of sex segregation: when is index measurement not index measurement?

In their paper in this issue, Grusky and Charles (1998) make a number of dubious claims about the measurement and interpretation of sex segregation. First, they incorrectly claim that only log-odds measures yield margin-free measures of segregation. Second, the estimation and testing of a limited class of log-linear models does not provide an independent test of the appropriateness of a log-odds ratio index to measure segregation. Their estimation in forms them of the statistically justifiable degree of occupational disaggregation, not whether a log-odds ratio is superior to, say, a linear index in the measurement of segregation. Finally, their index A is beset with problems of interpretation, not withstanding their arguments, and their additional measures, AW and AB, suffer similar problems. Grusky and Charles are, however, correct in arguing that measurement procedures should be margin-free. Further, I concur with the view that the adoption of a single annual summary measure of segregation cannot be justified, because it is premised on the assumption that individual occupations, or groups of occupations, exhibit similar trends in sex segregation.

Female↗

PubMed1998

Meiotic pairing and segregation of translocation quadrivalents in yeast.

Meiotic pairing and segregation were studied in three different heterozygous reciprocal translocation strains of the baker's yeast, Saccharomyces cerevisiae. Pachytene translocation quadrivalents were identified by a combination of immunofluorescence and fluorescence in situ hybridization and the karyotypes of meiotic products were determined by pulsed-field gel electrophoresis. The translocations differed with respect to the relative sizes of the chromosomes involved and the positions of translocation breakpoints, and produced translocation quadrivalents of widely different shapes. This allowed us to study the influence of the morphology of quadrivalents on their segregation behaviour. In all cases alternate predominated over adjacent segregation. 3:1 disjunction of chromosomes was more frequent when translocation breakpoints were close to the centromeres. If a translocation breakpoint was distant from the centromere, the occurrence of an intervening chiasma influenced the pattern of segregation. In general, quadrivalent formation and segregation resembled the behaviour of translocation heterozygotes in most higher eukaryotes. We therefore conclude that, although chromosome condensation does not occur in yeast metaphase, centromere orientation and chromosome disjunction are governed in a way similar to that of higher eukaryotes.

Centromere↗

PubMed1998

Segregational fidelity of chromosomes in human thyroid tumour cells.

Using fluorescence in situ hybridisation (FISH) we have analysed the segregational fidelity of all the human chromosomes during mitotic cell division. The losses and gains of chromosomes were analysed in human polyploid cell lines derived from a well-differentiated papillary thyroid cancer. These thyroid cells can be cultured for more than 300 population doublings. For the purpose of our study the polyploid nature of the cells may act as a protective buffer against the cell-lethal effects of the loss of individual chromosomes. To evaluate the role of the p53 gene product in maintaining the fidelity of chromosome segregation we compared the frequencies of chromosome loss and gain in cultures with wild-type p53 activity (K1E7neo3) and cultures transfected with plasmids expressing a mutant p53 product (K1E7scx6). Cultures were analysed for the presence of both structurally normal and rearranged chromosomes at both early and late passages. Cell cultures with defective p53 activity showed progressive chromosome loss from a median chromosome number of 87-97 to 75-86. Cell growth in cultures with wild-type p53 activity showed the loss of chromosomes 6, 7, and 8 and the gain of 17 and 20. Cultures expressing mutant p53 activity showed the loss of chromosomes 2, 5, 14 and 17 and the gain of 4 and 22. The combination of defective p53 and growth resulted in further destabilisation with the additional losses of chromosomes 3, 11, 15, 16 and 21. Chromosomes 1, 9, 10, 12, 13, 18, 19, X and Y segregated stably under all the culture conditions as did the structurally rearranged marker chromosomes. The study has demonstrated variation in the fidelity of mitotic chromosome segregation and the influence of p53 gene activity upon the segregation of individual human chromosomes.

Chromosome Segregation↗

PubMed2003

Fluorescence in situ hybridisation (FISH) analysis of chromosome segregation and interchromosomal effect in spermatozoa of a reciprocal translocation t(9,10)(q11;p11.1) carrier.

A couple was referred for exploration of repetitive abortions. The man was found to be a carrier of a balanced reciprocal translocation t(9;10)(q11;p11.1). The meiotic segregation of chromosomes 9 and 10 was analysed in 5,157 spermatozoa from this translocation carrier and in 15,255 spermatozoa from three control donors using three-colour fluorescence in situ hybridisation (FISH). The theoretical viability of the different segregation patterns was performed using the computer system HC Forum developed by the Department of Cytogenetics at the Grenoble University Medical School, La Tronche, France. A normal or balanced constitution was found in 56.25% of the analysed spermatozoa. The tertiary 3:1 segregation mode was the most frequently observed (14.37%). The frequencies of adjacent-1, adjacent-2 and 3:1 interchange modes were 12.85, 9.38 and 7.14% respectively. The cumulative frequency of non-viable imbalance was estimated at 20.91% according to the theorical viability of the different segregation patterns. Spermatozoa aneuploidy frequency was also evaluated for chromosomes X, Y and 18, and there was no evidence of interchromosomal effect in spermatozoa from the translocation carrier. FISH analysis of spermatozoa in combination with the viability theorical estimation of the different segregation patterns could be considered a useful tool for genetic counselling in carriers of reciprocal translocation.

Adult↗

PubMed2004

The occurrence of chromosome segregational defects is an intrinsic and heritable property of oral squamous cell carcinoma cell lines.

Chromosomal segregational defects are commonly observed in cancer cells and are an important source of genetic instability. It is currently unknown whether these mitotic defects are the result of a subpopulation of defective cells or reflect characteristics of the population of cells as a whole. In this study, we compared chromosomal segregational defects in two oral squamous cell carcinoma cell lines and five single-cell clones from each of those cell lines. We used immunofluorescence microscopy to quantitate the occurrence of multipolar metaphase spindles, lagging chromosomes at metaphase and anaphase, and anaphase bridges. We conclude that chromosome segregational defects in these cancer cell lines represent an intrinsic and inherited tendency toward segregational defects in the general cell population, rather than the existence of a subpopulation of cells with segregational defects.

Carcinoma, Squamous Cell↗

PubMed2005

MreB actin-mediated segregation of a specific region of a bacterial chromosome.

Faithful chromosome segregation is an essential component of cell division in all organisms. The eukaryotic mitotic machinery uses the cytoskeleton to move specific chromosomal regions. To investigate the potential role of the actin-like MreB protein in bacterial chromosome segregation, we first demonstrate that MreB is the direct target of the small molecule A22. We then demonstrate that A22 completely blocks the movement of newly replicated loci near the origin of replication but has no qualitative or quantitative effect on the segregation of other loci if added after origin segregation. MreB selectively interacts, directly or indirectly, with origin-proximal regions of the chromosome, arguing that the origin-proximal region segregates via an MreB-dependent mechanism not used by the rest of the chromosome.

Actins↗

PubMed2005

The meiotic defects of mutants in the Drosophila mps1 gene reveal a critical role of Mps1 in the segregation of achiasmate homologs.

The conserved kinase Mps1 is necessary for the proper functioning of the mitotic and meiotic spindle checkpoints (MSCs), which monitor the integrity of the spindle apparatus and prevent cells from progressing into anaphase until chromosomes are properly aligned on the metaphase plate. In Drosophila melanogaster, a null allele of the gene encoding Mps1 was recently shown to be required for the proper functioning of the MSC, but it did not appear to exhibit a defect in female meiosis. We demonstrate here that the meiotic mutant ald1 is a hypomorphic allele of the mps1 gene. Both ald1 and a P-insertion allele of mps1 exhibit defects in female meiotic chromosome segregation. The observed segregational defects are substantially more severe for pairs of achiasmate homologs, which are normally segregated by the achiasmate (or distributive) segregation system, than they are for chiasmate bivalents. Furthermore, cytological analysis of ald1 mutant oocytes reveals both a failure in the coorientation of achiasmate homologs at metaphase I and a defect in the maintenance of the chiasmate homolog associations that are normally observed at metaphase I. We conclude that Mps1 plays an important role in Drosophila female meiosis by regulating processes that are especially critical for ensuring the proper segregation of nonexchange chromosomes.

Animals↗

PubMed2003

The Cdc14 phosphatase and the FEAR network control meiotic spindle disassembly and chromosome segregation.

During meiosis, DNA replication is followed by two consecutive rounds of chromosome segregation. Cells lacking the protein phosphatase CDC14 or its regulators, SPO12 and SLK19, undergo only a single meiotic division, with some chromosomes segregating reductionally and others equationally. We find that this abnormal chromosome behavior is due to an uncoupling of meiotic events. Anaphase I spindle disassembly is delayed in cdc14-1, slk19Delta, or spo12Delta mutants, but the chromosome segregation cycle continues, so that both meiotic chromosome segregation phases take place on the persisting meiosis I spindle. Our results show that Cdc14, Slk19, and Spo12 are not only required for meiosis I spindle disassembly but also play a pivotal role in establishing two consecutive chromosome segregation phases, a key feature of the meiotic cell cycle.

Anaphase↗

PubMed2005

The roles of MAD1, MAD2 and MAD3 in meiotic progression and the segregation of nonexchange chromosomes.

Errors in meiotic chromosome segregation are the leading cause of spontaneous abortions and birth defects. In humans, chromosomes that fail to experience crossovers (or exchanges) are error-prone, more likely than exchange chromosomes to mis-segregate in meiosis. We used a yeast model to investigate the mechanisms that partition nonexchange chromosomes. These studies showed that the spindle checkpoint genes MAD1, MAD2 and MAD3 have different roles. We identified a new meiotic role for MAD3; though dispensable for the segregation of exchange chromosomes, it is essential for the segregation of nonexchange chromosomes. This function of Mad3p could also be carried out by human BubR1. MAD1 and MAD2 act in a surveillance mechanism that mediates a metaphase delay in response to nonexchange chromosomes, whereas MAD3 acts as a crucial meiotic timer, mediating a prophase delay in every meiosis. These findings suggest plausible models for the basis of errant meiotic segregation in humans.

Cell Cycle Proteins↗

PubMed2002

The role of co-transcriptional translation and protein translocation (transertion) in bacterial chromosome segregation.

Many recent reviews in the field of bacterial chromosome segregation propose that newly replicated DNA is actively separated by the functioning of specific proteins. This view is primarily based on an interpretation of the position of fluorescently labelled DNA regions and proteins in analogy to the active segregation mechanism in eukaryotic cells, i.e. to mitosis. So far, physical aspects of DNA organization such as the diffusional movement of DNA supercoil segments and their interaction with soluble proteins, leading to a phase separation between cytoplasm and nucleoid, have received relatively little attention. Here, a quite different view is described taking into account DNA-protein interactions, the large variation in the cellular position of fluorescent foci and the compaction and fusion of segregated nucleoids upon inhibition of RNA or protein synthesis. It is proposed that the random diffusion of DNA supercoil segments is transiently constrained by the process of co- transcriptional translation and translocation (transertion) of membrane proteins. After initiation of DNA replication, a bias in the positioning of transertion areas creates a bidirectionality in chromosome segregation that becomes self-enhanced when neighbouring genes on the same daughter chromosome are expressed. This transertion-mediated segregation model is applicable to multifork replication during rapid growth and to multiple chromosomes and plasmids that occur in many bacteria.

Bacteria↗

PubMed2002

Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation.

Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the G(2)/M phase. Hec1 localizes to kinetochores, and its inactivation either by genetic deletion or antibody neutralization leads to severe and lethal chromosomal segregation errors, indicating that Hec1 plays a critical role in chromosome segregation. The mechanisms by which Hec1 is regulated, however, are not known. Here we show that human Hec1 is a serine phosphoprotein and that it binds specifically to the mitotic regulatory kinase Nek2 during G(2)/M. Nek2 phosphorylates Hec1 on serine residue 165, both in vitro and in vivo. Yeast cells are viable without scNek2/Kin3, a close structural homolog of Nek2 that binds to both human and yeast Hec1. When the same yeasts carry an scNek2/Kin3 (D55G) or Nek2 (E38G) mutation to mimic a similar temperature-sensitive nima mutation in Aspergillus, their growth is arrested at the nonpermissive temperature, because the scNek2/Kin3 (D55G) mutant binds to Hec1 but fails to phosphorylate it. Whereas wild-type human Hec1 rescues lethality resulting from deletion of Hec1 in Saccharomyces cerevesiae, a human Hec1 mutant or yeast Hec1 mutant changing Ser(165) to Ala or yeast Hec1 mutant changing Ser(201) to Ala does not. Mutations changing the same Ser residues to Glu, to mimic the negative charge created by phosphorylation, partially rescue lethality but result in a high incidence of errors in chromosomal segregation. These results suggest that cell cycle-regulated serine phosphorylation of Hec1 by Nek2 is essential for faithful chromosome segregation.

Alanine↗

PubMed2002

Genetic segregation analysis of alcohol and other substance-use disorders in families with recurrent, early-onset major depression.

OBJECTIVE: The goal of this study was to conduct a complex segregation analysis of alcohol and other substance-use disorders in families identified by probands with recurrent, early-onset major depression (RE-MDD). METHOD: Eighty-one families were identified through probands over the age of 18, who met criteria for recurrent (> or = 2 episodes), early-onset (< or = 25 years), nonpsychotic, unipolar major depression (RE-MDD) and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Segregation analyses were performed using the REGD routine in S.A.G.E. release 4.0. RESULTS: The best-fitting models for the transmission of "alcohol use disorders" or "alcohol/other substance use disorders" were sex-dependent Mendelian recessive models with significant residual spousal effects. Moreover, the parameter estimates for the models were very similar for these phenotypes. In contrast, the segregation analysis of "substance use disorder" supported a transmissible, but non-Mendelian, major effect. CONCLUSIONS: Our results suggest that a major locus contributes to the expression of alcohol use disorders or alcohol/other substance-use disorders within families identified by probands with RE-MDD. Due to the limitations of the segregation analysis model, our results cannot address whether the same major locus is segregating across families in our sample or whether multiple major loci are involved (genetic heterogeneity). Previous studies supported single gene transmission of recurrent major depression and major mood disorders in these families [Marazita et al. Am. J. Hum. Genet. 1997, 61, 1370-1378; Maher et al. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 2002. 114 (2), 214-221]. Mounting evidence suggests that at.least some of this "comorbidity" may result from the effects of shared susceptibility genes or an overlap in the sets of genes that contribute to the vulnerability of developing these mental disorders [Zubenko, G.S. Mol. Psychiatry 2000, 5, 131-136].

Adult↗