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PubMed2006

Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder.

CONTEXT: There is strong evidence from family and twin studies that genetic determinants play an important role in the etiology of obsessive-compulsive disorder (OCD). In the only genome scan of OCD to date that we are aware of, suggestive linkage was reported to the chromosomal region 9p24, a finding that was subsequently replicated. This region contains the gene encoding the neuronal glutamate transporter, SLC1A1. SLC1A1 represents an excellent candidate gene for OCD based on evidence from neuroimaging and animal studies that altered glutamatergic neurotransmission is implicated in the pathogenesis of this disorder. OBJECTIVE: To determine whether sequence variants in SLC1A1 are associated with transmission of the OCD trait. DESIGN: A family-based candidate gene association study. SETTING: A specialized anxiety disorders outpatient clinic. PARTICIPANTS: One hundred fifty-seven white probands with DSM-IV OCD recruited from consecutive referrals and their first-degree relatives (476 individuals in total). INTERVENTION: Nine single nucleotide polymorphisms spanning SLC1A1 were genotyped. Single-locus and haplotype analyses were performed using the Family-Based Association Test and the Transmission Disequilibrium Test. Traits examined included DSM-IV OCD diagnosis and highest lifetime symptom severity as measured using the Yale-Brown Obsessive-Compulsive Scale. Correction for multiple comparisons was performed using permutation tests. RESULTS: After correction for multiple comparisons, 2 variants, rs301434 (chi 2 = 12.04; P = .006) and rs301435 (chi 2 = 9.24; P = .03), located within a single haplotype block were found to be associated with transmission of OCD. Furthermore, a specific 2-marker haplotype within this block was significantly associated with OCD (chi 2 = 12.60; P = .005). This haplotype association was statistically significant in transmissions to male but not female offspring. CONCLUSIONS: Although requiring replication in larger samples, these findings provide preliminary evidence that sequence variation in SLC1A1 is associated with susceptibility to OCD, particularly in males. Furthermore, these results provide support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.

Adolescent↗

PubMed2002

The extent and analysis of cytokine and cytokine receptor gene polymorphism.

Cytokines play an important role in the regulation of normal immune function. In recent years cytokines and their receptors have been shown to be highly polymorphic. Polymorphisms in these genes have been associated with a number of immune diseases as well as organ transplant complications. The current disease association data is confusing and often contradictory. Whilst single locus analyses are the predominant form of cytokine polymorphism analysis, the use of polymorphic haplotypes is becoming increasingly common. This may help to give a clearer picture of the association of cytokine polymorphism with immune disfunction.

Autoimmune Diseases↗

PubMed2005

Evolutionarily stable strategies and short-term selection in Mendelian populations re-visited.

This note concerns a one locus, two allele, random mating diploid population, subject to frequency-dependent viability selection. It is already known that in such a population, any evolutionarily stable strategies (ESS), if only accessible by the genotype-to-phenotype mapping, is the phenotypic image of a stable genetic equilibrium (Eshel, I. 1982. Evolutionarily stable strategies and viability selection in Mendelian populations. Theor. Popul. Biol. 22(2), 204-217; Cressman et al. 1996. Evolutionary stability in strategic models of single-locus frequency-dependent viability selection. J. Math. Biol. 34, 707-733). The opposite is not true. We find necessary and sufficient parametric conditions for global convergence to the ESS, but we also demonstrate conditions under which, although a unique, genetically accessible ESS exists, there is another, "non-phenotypic" genetically stable equilibrium.

Animals↗

PubMed1989

A major histocompatibility locus in fish: serological identification and segregation of transplantation antigens in the common carp (Cyprinus carpio L.).

In this study, experiments are described that were designed to investigate whether fish have an immune regulatory systems similar to the major histocompatibility complex (MHC) in higher vertebrate species. From combinations of gynogenetic carp showing either slow or fast rejection of skin transplants, the latter were chosen for alloantiserum production by hyperimmunization with peripheral blood leucocytes. The resulting alloantisera were analyzed for hemagglutinating reactivity with gynogenetic siblings and proved to be operationally monospecific in absorption experiments. The serologically determined carp erythrocyte specificities were shown to correspond to two codominantly expressed allelic products of a single locus and were designated K1 and K2, respectively. Flow cytometer analysis revealed that the same products are also present on leucocytes from peripheral blood, thymus, spleen, and pronephros. K1- and K2-homozygous second-generation gynogenetic siblings were used to study the histocompatibility nature of the K locus products. Skin transplants between K-allogeneic gynogenetic siblings were rejected significantly faster than within K-syngeneic combinations. Taken together, these data suggest that the K locus incorporates MHC class I-like characteristics.

Animals↗

PubMed1995

Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes.

To investigate the genetic component of multifactorial diseases such as type 1 (insulin-dependent) diabetes mellitus (IDDM), models involving the joint action of several disease loci are important. These models can give increased power to detect an effect and a greater understanding of etiological mechanisms. Here, we present an extension of the maximum lod score method of N. Risch, which allows the simultaneous detection and modeling of two unlinked disease loci. Genetic constraints on the identical-by-descent sharing probabilities, analogous to the "triangle" restrictions in the single-locus method, are derived, and the size and power of the test statistics are investigated. The method is applied to affected-sib-pair data, and the joint effects of IDDM1 (HLA) and IDDM2 (the INS VNTR) and of IDDM1 and IDDM4 (FGF3-linked) are assessed with relation to the development of IDDM. In the presence of genetic heterogeneity, there is seen to be a significant advantage in analyzing more than one locus simultaneously. Analysis of these families indicates that the effects at IDDM1 and IDDM2 are well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 follow a heterogeneity model.

Diabetes Mellitus, Type 1↗

PubMed1989

X-ray-induced specific-locus mutations in the ad-3 region of two-component heterokaryons of Neurospora crassa. II. More extensive genetic tests reveal an unexpectedly high frequency of multiple-locus mutations.

More extensive genetic tests have been performed on a series of 832 X-ray-induced specific-locus mutations in the ad-3 region of a 2-component heterokaryon (H-12) of Neurospora crassa, reported earlier (Webber and de Serres 1965). Using new tester strains and techniques for performing large-scale genetic tests (heterokaryon, dikaryon and trikaryon) to characterize ad-3 mutants induced in 2-component heterokaryons, new data have been obtained on this sample of X-ray-induced ad-3 mutants. These new data show that unexpectedly high frequencies of both single-locus (gene/point) mutations and multilocus deletions in the ad-3 region have additional, but separate, sites of recessive lethal (RLCL) damage in the immediately adjacent genetic regions. The frequencies of these X-ray-induced multiple-locus mutants in the ad-3 region are orders of magnitude higher than expected on the basis of target theory and classical models of chromosome structure during interphase. Current models of interphase chromosome structure in higher eukaryotes as revealed by chromosome "painting" offer a possible explanation of the Neurospora data.

Adenine↗

PubMed2000

Identification of cDNAs encoding two novel nuclear proteins, IMUP-1 and IMUP-2, upregulated in SV40-immortalized human fibroblasts.

Using a model system of young, senescent and SV40-immortalized WI-38 fibroblasts, we identified two mRNAs upregulated in immortalized cells (imup-1, immortalization-upregulated protein 1, and imup-2). Compared to normal tissues, both genes were more frequently expressed in cancer cells. The open reading frame of imup-1 spans 321bp, coding for a 10.9 kDa protein of 106 amino acids, while an insertion of 59bp in the otherwise identical mRNA of imup-2 leads to a frameshift, resulting in an 8.5 kDa protein of 85 amino acids. Database searches identified these genes on chromosome 19, which could account for the cloned imup-1 and imup-2 transcripts by alternative splicing. Southern blot analysis of digested genomic DNA confirmed that both transcripts are derived from a single locus. The expressed proteins IMUP-1 and IMUP-2 share 46 identical N-terminal amino acids, whereas the C-termini are unrelated. Green fluorescent protein-fusions of both IMUP-1 and IMUP-2 accumulated in the nucleus of HeLa cells. The C-terminus of IMUP-1 contains a bipartite nuclear localization signal, the deletion of which impaired nuclear translocation. In-vitro translated proteins bound to poly(rG), but did not interact with single-stranded DNA or double-stranded DNA. The nuclear localization of IMUP-1 and IMUP-2 as well as the upregulation of both underlying mRNAs in immortalized cells suggest a function in immortalization.

Alternative Splicing↗

PubMed2003

Methods for analysis and visualization of SNP genotype data for complex diseases.

SNP markers are becoming central for studying genetic determinants of complex diseases. Large SNP data collected in such studies call for the development of specialized analysis tools. We present methods for selecting sets of SNPs that can be associated to sample properties in case/control studies. We also describe how scoring and selection can be statistically tested. This is done at the single locus as well as at the set level.

Bayes Theorem↗

PubMedDate not supplied

Gene-environment interactions and the affected-sib-pair designs.

In genetic mapping of complex traits, the affected-sib-pair method (ASP) and the transmission disequilibrium test (TDT) are two methods of choice. The major appeal of both ASP and TDT is that they do not require the knowledge of mode of inheritance underlying the trait in question. The relative ease and economy for data collection also is the reason for their popularity. The basic idea of the ASP is to identify genes or chromosomal regions through identifying genetic similarity based on phenotypical similarity. TDT, on the other hand, detects susceptibility genes through detecting unusual transmission patterns in families. Since phenotypic similarity can also be caused by environmental similarity, we investigate how the presence of gene-environment interaction (GEI) affects the power of both methods. For a simple one-locus-one-risk-factor model, our results indicate that, in the presence of GEI, methods developed based on marginal penetrance functions (i.e. ignoring the risk factor) can give spurious results. The triangular restriction on allele-sharing probability may no longer be valid. If the environment effect is strong, using exposure-discordant affected sib pairs may have advantage over other designs. Above all, a genetic model involving both genetic and environmental factors behaves differently from a single-locus genetic model.

Analysis of Variance↗

PubMed2004

Mapping a Mendelian form of intracranial aneurysm to 1p34.3-p36.13.

The identification of pathways that underlie common disease has been greatly impacted by the study of rare families that segregate single genes with large effect. Intracranial aneurysm is a common neurological problem; the rupture of these aneurysms constitutes a frequently catastrophic neurologic event. The pathogenesis of these aneurysms is largely unknown, although genetic and environmental factors are believed to play a role. Previous genomewide studies in affected relative pairs have suggested linkage to several loci, but underlying genes have not been identified. We have identified a large kindred that segregates nonsyndromic intracranial aneurysm as a dominant trait with high penetrance. Genomewide analysis of linkage was performed using a two-stage approach: an analysis of ~10,000 single-nucleotide polymorphisms in the 6 living affected subjects, followed by the genotyping of simple tandem repeats across resulting candidate intervals in all 23 kindred members. Analysis revealed significant linkage to a single locus, with a LOD score of 4.2 at 1p34.3-p36.13 under a dominant model with high penetrance. These findings identify a Mendelian form of intracranial aneurysm and map the location of the underlying disease locus.

Adult↗

PubMed2006

Topographic molecular profile of pheochromocytomas: role of somatic down-regulation of mismatch repair.

CONTEXT AND OBJECTIVE: Despite extensive molecular investigation of adrenal pheochromocytomas, no information is available on their molecular and mismatch repair (MMR) profiles by topographic compartments. DESIGN AND SETTING: Microdissected samples from the peripheral and internal zones of 143 pheochromocytomas from a referral hospital (95 sporadic and 48 associated with multiple endocrine neoplasia type 2A) were selected for loss of heterozygosity and single nucleotide polymorphism analyses. Five polymorphic DNA regions from TP53, RB1, WT1, and NF1 were systematically studied by PCR-denaturing gradient gel electrophoresis. PATIENTS, OUTCOME MEASURES, AND INTERVENTIONS: Pheochromocytomas were classified as malignant (16 sporadic tumors with distant metastases), locally invasive (30 sporadic tumors showing retroperitoneal infiltration only), and benign (all remaining tumors). Statistical differences were evaluated using Fisher's exact test. MMR was assessed by MLH1/MSH2 sequencing and immunostaining in pheochromocytomas with two or more abnormal microsatellites. No interventions were performed in this study. RESULTS: Loss of heterozygosity/single nucleotide polymorphism involved TP53 in 40 of 134 informative cases (29.9%), RB1 in 22 of 106 informative cases (20.8%), WT1 in 32 of 120 informative cases (26.7%), and NF1 in 32 of 80 informative cases (40.0%). More genetic abnormalities involving the peripheral compartment were revealed in 34 pheochromocytomas (23.8%): 12 of 16 malignant, 10 of 30 locally invasive, and 12 of 97 benign. Multiple and coexistent genetic abnormalities characterized malignant pheochromocytomas (P < 0.001), whereas locally invasive pheochromocytomas showed a significantly higher incidence of NF1 alterations (P < 0.001). No mutations were identified in MLH1/MSH2, but MMR proteins significantly decreased in peripheral compartments. CONCLUSIONS: Multiple microsatellite alterations and topographic intratumor heterogeneity characterize malignant pheochromocytomas, suggesting a multistep tumorigenesis through somatic topographic down-regulation of MMR proteins. Locally invasive pheochromocytomas reveal topographic heterogeneity and single-locus microsatellite alterations, especially involving NF1.

Adrenal Gland Neoplasms↗

PubMedDate not supplied

Probable localisation of the Coffin-Lowry locus in Xp22.2-p22.1 by multipoint linkage analysis.

The Coffin-Lowry syndrome (McKusick No. 30360) is a rare genetically transmitted disorder characterized by severe mental retardation, "coarse" facial appearance, thick soft skin, tapering fingers, and progressive skeletal abnormalities. X-linked inheritance is implied since the males are severely affected with variably mild manifestations in carrier women. We have performed a linkage analysis with many X-linked RFLP markers in 4 families. Positive two-point lod scores were obtained with DXS28 (z(theta) = 2.00 at theta = 0.05) and DXS41 (z(theta) = 1.26 at theta = 0.10). We performed a 5-point linkage analysis using the LINKMAP program assuming that DXS16 and DXS43 are a single locus and using the following fixed map (distances in centimorgans): DXS85 - 18cM - (DXS16, DXS43) - 13cM - DXS41 - 5cM -DXS28. This gave a multipoint lod score of 3.41 for a localisation in Xp22.2-p22.1, between DXS43 and DXS41.

Bone Diseases, Developmental↗

PubMed1996

Sequence and context effects on origin function in mammalian cells.

Jacob and Brenner proposed a model for control of DNA replication in which a trans-acting initiator protein binds to a cis-acting replicator to effect initiation of nascent DNA chains at a fixed locus. Although replicators have been identified in prokaryotic and simple eukaryotic genomes, it has been much more difficult to demonstrate their presence in mammalian chromosomes. Owing to the lack of genetic approaches for identifying mammalian replicators, investigators have directed attention to localizing nascent strand start sites, which should lie close to replicators. Toward this end, a variety of clever techniques have been invented for analyzing replication intermediates, but only rarely have more than one of these techniques been applied to a single locus. However, virtually all have been used to analyze the dihydrofolate reductase locus in CHO cells. The picture that has developed in this locus is that initiation can occur at any of a large number of sites scattered throughout a broad zone, but somewhat more frequently near two sites that may correspond to true genetic replicators. Furthermore, it appears that local transcriptional activity, as well as appropriate torsional stress (as imparted by local attachment to the nuclear matrix), may have profound effects on origin activity.

Animals↗

PubMed1980

Evolutionary conservation of linkage groups: additional evidence from murid and cricetid rodents.

In Mus musculus, family Muridae, the glucosephosphate isomerase (Gpi-l), pink-eyed dilution (p), albinism (c), and beta-type globin (Hbb) loci are known to be linked in the order Gpi-l-p-c-Hbb. In Rattus norvegicus, another murid rodent, the p, c, and Hbb loci are known to be linked in the same order and with similar recombination frequencies. In Peromyscus maniculatus, family Cricetidae, it was previously known that p and c are linked and by analogy to Mus musculus that linkage group should be bounded by Gpi-l near p and by a beta-globin locus near c. Linkage has now been established between Gpi-l and the Hbe globin locus in Peromyscus. However, the observed recombination frequency in Peromyscus (16.3%) is significantly lower than in Mus, suggesting that perhaps a chromosomal inversion has occurred during the evolutionary divergence of the two rodent families. Linkage relationships were also tested between the Hbc1, Hbd1, and Hbe1 globin variants. Hbc1 (presumably an alpha-type globin) segregated independently from Hbd1 and Hbe1 (presumably beta-type globins). No recombination was observed between Hbd1 and Hbe1. Those two globin genes may be alleles at a single locus, although circumstantial evidence suggests that they represent tightly linked duplicate loci.

Animals↗

PubMed1994

The molecular genetics and evolution of primate colour vision.

Until recently, the genetic basis of colour vision could only be inferred from measuring the colour vision of family groups. However, in the past few years the sites of the genes for visual pigments have been located and sequenced. The genes that specify the opsins for the rod and short-wavelength cone pigments are located on the third and seventh chromosomes, respectively. In Old World primates the genes for the middle- and long-wavelength pigments are located on the q arm of the X chromosome in a head-to-tail array. The close sequence similarity of the two genes on the X chromosome leads to a high frequency of unequal inter- and intragenic recombination leading to gene deletion or the creation of hybrid genes. In New World primates there is only a single locus on the X chromosome for a middle- to long-wavelength cone pigment. However, three alleles can occur at this locus and each codes for a slightly different cone pigment. As a result there are three types of male dichromat and three types of female dichromat and trichromat in each species. Colour vision in New World primates might be an intermediate stage between the uniform dichromacy of non-primate mammals and the uniform trichromacy of Old World primates. Alternatively, colour vision in New World primates might be an adaptation to allow a wide variety of colour-vision types within a single family group.

Alleles↗

PubMed1976

Multilocus behavior in random environments. I. Random Levene models.

In this paper the consequences of natural selection acting on several loci simultaneously in a spatially fluctuating environment are described. The fitnesses of the genotypes are assumed to be additive both within and between loci. The environment is assumed to be made up of a very large (effectively infinite) number of patches in which fitnesses are assigned at random. The resulting deterministic model is called a Random Levene Model and its properties are approximate by a system of differential equations. The main equilibrium properites are that (1) the linkage disequilibrium is zero and (2) the correlations in fitness between alleles at different loci are the principle determinants of the dynamic inter-locus interactions. Although there is no epistasis as conventionally defined, the equilibrium state at the two loci are highly interdependent, the governing principle being that two alleles at different loci whose fitness are negatively correlated across environments have a higher overall fitness due to the reduction in their variance in fitness through the negative correlation. When a large number of loci are considered, they naturally fall into correlation groupings which lead to an enhanced likelihood for polymorphism over that predicted by single-locus theory.

Biological Evolution↗

PubMed2001

A new locus for a dominant form of multinodular goiter on 3q26.1-q26.3.

A mass screening program for congenital hypothyroidism has markedly improved prognosis of children with congenital hypothyroidism and also revealed several cases with unknown pathogenesis. We here report two independent Japanese multigeneration families with multinodular goiter (MNG) with euthyroidism and with high TSH. The propositi, 3- and 8-year-old girls in two families, were found during a mass screening. An autosomal dominant pattern of inheritance was suggested in both families. The clinical examinations suggested impaired hormonogenesis but discarded known defects in iodine transport, organification, deficiency of hydrogen peroxide, and thyroid peroxidase. Linkage analysis of the two families including 10 members each using 343 microsatellite markers mapped a single locus independently at D3S1618 (theta = 0) on 3q26.1-q26.3 with a two-point LOD score 3.62 (1.81 for each family) and multipoint LOD score of 3.61 (1.80 for each family). Haplotype inspection delimited an 18-cM interval between D3S1565 and D3S3686.

Adult↗

PubMed1993

A trans-acting locus regulates transcriptional repression of the female-specific steroid 15 alpha-hydroxylase gene in male mice.

Steroid 15 alpha-hydroxylase (P450(15 alpha)) is a female-specific enzyme in the livers of many inbred mice including DBA/2J. Run-on assays using liver nuclei from GH-deficient Little mice indicated that the P450(15 alpha) gene is transcriptionally repressed by GH in male mice. BALB/cJ is a variant strain in which the gene is expressed in the males as well as in the females. Genetic crosses between DBA/2J and BALB/cJ indicated that expression of the P450(15 alpha) gene in BALB/cJ males is inherited as a recessive trait and is regulated by a single locus. The parental origin of the P450(15 alpha) genes, determined using restriction site polymorphism in the exons of the P450(15 alpha) genes, divided the F2 males expressing the P450(15 alpha) gene into three phenotypes at a ratio of 1:1:2, the individuals expressing the gene from only BALB/cJ or DBA/2J and the individuals expressing the genes from both parents respectively. The results indicate that the repression of the P450(15 alpha) gene in male mice is regulated by a trans-acting regulatory locus between the DBA/2J and BALB/cJ pairs. Because hypophysectomy derepressed the P450(15 alpha) gene in F1 males and GH repressed the gene in hypophysectomized F1 males, the hormone appears to regulate gene repression through a trans-acting locus, named GH-dependent repression, GDR.

Animals↗