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PubMed2002

Simultaneous improvement for four quality traits of Zhenshan 97, an elite parent of hybrid rice, by molecular marker-assisted selection.

"Zhenshan 97" is the female parent of a number of widely used hybrids for rice production in China. However, this line is of poor quality because of a high amylose content (AC), a hard gel consistency (GC) and a low gelatinization temperature (GT), together with a chalky endosperm. It had been determined that the three traits for cooking and eating quality, AC, GC and GT, are controlled by the Waxy locus and/or the tightly linked genomic region. In this study we improved the eating and cooking quality of Zhenshan 97 by introgressing the Waxy gene region from Minghui 63 (wx-MH), a restorer line, that has medium AC, soft GC and high GT. The wx-MH fragment was transferred to Zhenshan 97B by three backcrosses and one selfing, then from Zhenshan 97B to Zhenshan 97A by a cross and a backcross. Molecular marker-assisted selection was applied in the series to select for individuals carrying wx-MH, to identify recombination between the Waxy and flanking markers, and also to recover the genetic background of the recurrent parent. According to the marker genotypes, the improved versions of Zhenshan 97B and Zhenshan 97A, or Zhenshan 97B(wx-MH) and Zhenshan 97A(wx-MH), were the same as the originals except for the Waxy region of less than 6.1 cM in length. The selected lines and their hybrids with Minghui 63, or Shanyou 63(wx-MH), showed a reduced AC and an increased GC and GT, coupled with a reduced grain opacity. Field examinations of agronomic performance revealed that Zhenshan 97B(wx-MH) and Shanyou 63(wx-MH) were essentially the same as the originals except for a significant decrease in grain weight. The simultaneous improvement of AC, GA, GT and opacity, indicated that the Waxy region had major effects on the four quality traits. The improved versions of Zhenshan 97 A and B should be immediately useful in hybrid rice production.

Amylose↗
PubMed2002

The genetics of autoimmune polyendocrine syndrome type II.

A series of autoimmune disorders, often Addison's disease, type 1 diabetes mellitus, and thyroid autoimmunity, frequently occurs together in patients with the autoimmune polyendocrine syndrome type II (APS-II). The highest risk HLA genotype for Addison's disease, either as a single disease or in APS-II patients, consists of the genotype DR3/4, DQ2/DQ8 with DRB1*0404. As many as 30% of patients with Addison's disease have this genotype versus less than 0.5% of controls. An additional and important associated locus within the HLA region is the class I related gene, MIC-A. Patients who develop Addison's disease often have a delayed diagnosis and may die from Addisonian crisis; therefore, improved genetic testing combined with testing for 21-hydroxylase autoantibodies might allow the identification of relatively high-risk populations (greater than 1 in 200 defined genetic risk compared with 1 in 10,000 population risk).

Abatacept↗
PubMed2002

Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila.

In inbred mouse strains, permissiveness to intracellular replication of Legionella pneumophila is controlled by a single locus (Lgn1), which maps to a region within distal Chromosome 13 that contains multiple copies of the gene baculoviral IAP repeat-containing 1 (Birc1, also called Naip; refs. 1-3). Genomic BAC clones from the critical interval were transferred into transgenic mice to functionally complement the Lgn1-associated susceptibility of A/J mice to L. pneumophila. Here we report that two independent BAC clones that rescue susceptibility have an overlapping region of 56 kb in which the entire Lgn1 transcript must lie. The only known full-length transcript coded in this region is Birc1e (also called Naip5).

Animals↗
PubMed1974

Complementation studies of lethal alleles in the mouse causing deficiencies of glucose-6-phosphatase, tyrosine aminotransferase, and serine dehydratase.

The pleiotropic effects of six radiation-induced lethal alleles at the albino locus in the mouse include deficiencies of various enzymes and of serum proteins. Closely correlated with the biochemical deficiencies are severe ultrastructural abnormalities of endoplasmic reticulum membranes and the Golgi apparatus in liver and kidney cells. Complementation studies led to the distinction of four different complementation groups among the six lethal alleles. The results are compatible with the interpretation that the six lethal alleles represent overlapping deletions of various sizes at and around the albino locus in the mouse, in a region concerned with the control of biochemical and structural differentiation.

Alleles↗
PubMed1999

The Ig heavy chain intronic enhancer core region is necessary and sufficient to promote efficient class switch recombination.

The intronic IgH enhancer E(mu), which consists of the core enhancer (cE(mu) flanked by 5' and 3' matrix attachment regions (MAR), has been implicated in the control of IgH locus recombination and transcription. Both cE(mu) and the MAR are required to enhance transcription of an IgH transgene. To elucidate the regulatory functions of cE(mu) versus its associated MAR in IgH class switch recombination (CSR), we have assayed ES cell lines which have targeted deletions of these elements, both individually and in combination, by the Rag-2-deficient blastocyst complementation method. Mutant B cells from chimeric mice were activated in culture and the influence of the mutations on CSR was assessed by analysis of B cell hybridomas. We find that the cE(mu) is necessary and sufficient for providing the functions of E(mu) required for efficient CSR at the IgH locus. However, the 5' and 3' MAR sequences, as well as the known I(mu) transcription start sites and the bulk of I(mu) coding sequences, were dispensable for the process.

Animals↗
PubMed1990

DNaseI hypersensitive sites 1, 2 and 3 of the human beta-globin dominant control region direct position-independent expression.

The human beta-globin dominant control region (DCR) which flanks the multigene beta-globin locus directs high level, site of integration independent, copy number dependent expression on a linked human beta-globin gene in transgenic mice and stably transfected mouse erythroleukemia (MEL) cells. We have assayed each of the individual DNaseI hypersensitive regions present in the full 15kb DCR for position independence and copy number dependence of a linked beta-globin gene in transgenic mice. The results show that at least three of the individual DNaseI hypersensitive site regions (sites 1, 2 and 3), though expressing at lower levels than the full DCR, are capable of position independent, copy number dependent expression. Site 2 alone directs the highest level of expression of the single site constructs, producing nearly 70% of the level of the full DCR. Sites 1 and 3 each provide 30% of the full activity. Deletion of either site 2 or 3 from the complete set significantly reduces the level of expression, but does not effect position independence or copy number dependence. This demonstrates that sites 2 and 3 are required for full expression and suggests that all the sites are required for the full expression of even a single gene from this multigene locus.

Animals↗
PubMed1997

HSP70 genes and historecognition in Botryllus schlosseri: implications for MHC evolution.

The colonial protochordate Botryllus schlosseri possesses a historecognition system which has long invited comparison to the vertebrate MHC. Upon contact, colonies either fuse or reject one another in a manner resembling graft acceptance or rejection in vertebrates. This response is controlled by a single highly polymorphic genetic region, the FuHC locus. Colonial protochordates such as B. schlosseri are among the closest relatives of the vertebrate lineage, and therefore may possess a recognizable MHC homologue. Since linkage between heat shock protein 70 (HSP70) genes and MHC appears to be conserved within the vertebrate lineage, we have analyzed HSP70 genes from B. schlosseri as a first step toward isolating the historecognition locus. Two HSP70 genes (HSP70.1 and HSP70.2) have been cloned and sequenced, and exhibit 93.6% sequence identity within the predicted coding regions. The B. schlosseri genes share a number of characteristics with vertebrate MHC-linked HSP70 genes: Northern blotting and sequence analysis suggest that the protochordate genes are cytoplasmically-expressed heat-inducible members of the HSP70 gene family (FAGAN and WEISSMAN 1996). However, unlike vertebrate MHC-linked HSP70 genes, HSP70.1 and HSP70.2 are not closely linked (FAGAN and WEISSMAN 1997). Furthermore, neither is closely linked to the locus determining historecognition (FAGAN and WEISSMAN 1997). These results do not support the hypothesis that the B. schlosseri FuHC locus is an MHC homolog. A discussion of the implications of these results for evolution of the vertebrate MHC is included.

Animals↗
PubMed2003

The dihydrofolate reductase origin of replication does not contain any nonredundant genetic elements required for origin activity.

The Chinese hamster dihydrofolate reductase (DHFR) origin of replication consists of a broad zone of potential initiation sites scattered throughout a 55-kb intergenic spacer, with at least three sites being preferred (ori-beta, ori-beta', and ori-gamma). We previously showed that deletion of the most active site or region (ori-beta) has no demonstrable effect on initiation in the remainder of the intergenic spacer nor on the time of replication of the DHFR locus as a whole. In the present study, we have now deleted ori-beta', both ori-beta and ori-beta', an 11-kb region just downstream from the DHFR gene, or the central approximately 40-kb core of the spacer. The latter two deletions together encompass >95% of the initiation sites that are normally used in this locus. Two-dimensional gel analysis shows that initiation still occurs in the early S phase in the remainder of the intergenic spacer in each of these deletion variants. Even removal of the 40-kb core fails to elicit a significant effect on the time of replication of the DHFR locus in the S period; indeed, in the truncated spacer that remains, the efficiency of initiation actually appears to increase relative to the corresponding region in the wild-type locus. Thus, if replicators control the positions of nascent strand start sites in this complex origin, either (i) there must be a very large number of redundant elements in the spacer, each of which regulates initiation only in its immediate environment, or (ii) they must lie outside the central core in which the vast majority of nascent strand starts occur.

Animals↗
PubMed2003

Microsatellite marker association at chromosome region 2p13 in Finnish patients with preeclampsia and obstetric cholestasis suggests a common risk locus.

The pathophysiology of preeclampsia is incompletely understood, but the familial nature of the disease has long been recognized. Recent genome-scan studies have indicated linkage at the p23 region of chromosome 2. We have previously reported microsatellite marker association at chromosome region 2p13 in patients with obstetric cholestasis. We conducted population-based association screening with microsatellite markers to find potential preeclampsia-associated loci on chromosome region 2p13-p12 and to test whether preeclampsia and obstetric cholestasis share a single risk locus. The study was carried out among 115 unrelated control women, 133 preeclamptic women and 57 cholestatic women. Screening with microsatellite markers at the 2p13-p12 region revealed that the marker D2S286 was significantly associated with obstetric cholestasis in the overall association analysis (P=0.03), while it revealed only borderline association with preeclampsia (P=0.08). However, single allele association analysis indicated that both preeclampsia and obstetric cholestasis showed a statistically significant association with a common allele (P < 0.05), which was overrepresented in both the obstetric cholestasis (0.42) and preeclamptic (0.37) groups when compared with the control group (0.28). In conclusion, These findings suggest a possible genetic link between chromosome region 2p13-p12, preeclampsia and obstetric cholestasis. More specifically, these data suggest that there may be a common risk locus associated with both obstetric complications located in the vicinity of the 2p13-p12 association region.

Alleles↗
PubMed1994

Regional cerebral blood flow during submergence asphyxia in Pekin duck.

The cerebrovascular response to submergence asphyxia was studied in the Pekin duck (Anas platyrhynchos var.) by use of the cerebral blood flow (CBF) tracer [14C]isopropyliodoamphetamine and quantitative autoradiography. Blood flow of the whole brain was 158 +/- 14 (SE) ml.min-1 x 100 g-1 (n = 7) in control animals. There was a doubling of flow to 320 +/- 61 ml.min-1 x 100 g-1 (n = 6) during submergence asphyxia. The hypothesis that CBF is redistributed within the brain during asphyxia was not supported. There were no regional reductions in CBF during submergence asphyxia. Mean arterial blood pressure was similar (approximately 140 mmHg), but heart rate, arterial blood gas tensions, and arterial pH were significantly different in control and submerged ducks at the time CBF was measured. The differences in CBF among submerged animals correlated strongly with arterial PCO2 and mean arterial blood pressure. The smallest proportional difference in regional CBF between control and submerged ducks occurred in the ectostriatum (+141%) and the largest in the locus ceruleus (+241%). The largest absolute difference in regional CBF was in the nucleus ruber (+322 ml.min-1 x 100 g-1). These are the first measurements of blood flow in discrete nuclei and regions of the avian brain.

Amphetamines↗
PubMed1997

Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.

In a 12.5 cM genome-wide scan for psoriasis susceptibility loci, recombination-based tests revealed linkage to the HLA region (Zmax = 3.52), as well as suggestive linkage to two novel regions: chromosome 16q (60-83.1 cM from pter, Zmax = 2.50), and chromosome 20p (7.5-25 cM from pter, Zmax = 2.62). All three regions yielded P values < or = 0.01 by non-parametric analysis. Recombination-based and allele sharing methods also confirmed a previous report of a dominant susceptibility locus on distal chromosome 17q (108.2 cM from pter, Zmax = 2.09, GENEHUNTER P = 0.0056). We could not confirm a previously reported locus on distal chromosome 4q; however, a broad region of unclear significance was identified proximal to this proposed locus (153.6-178.4 cM from pter, Zmax = 1.01). Taken together with our recent results demonstrating linkage to HLA-B and -C, this genome-wide scan identifies a psoriasis susceptibility locus at HLA, confirms linkage to 17q, and recommends two novel genomic regions for further scrutiny. One of these regions (16q) overlaps with a recently-identified susceptibility locus for Crohn's disease. Psoriasis is much more common in patients with Crohn's disease than in controls, suggesting that an immunomodulatory locus capable of influencing both diseases may reside in this region.

Adult↗
PubMed1995

Regional taste sensitivity to NaCl: relationship to subject age, tongue locus and area of stimulation.

Using a signal detection procedure and a microprocessor-controlled gustometer, sensitivity to three concentrations of NaCl (0.01, 0.1 and 1.0 M) was measured on the tongue tip, and on a region 3.0 cm posterior to the tongue tip in 12 young (20-29 years of age) and 12 elderly (70-79 years of age) subjects. Stimulus duration was 2 s; the sizes of the tongue areas stimulated were 12.5, 25 and 50 mm2. On average, the young subjects were more sensitive to NaCl on the tongue tip than on the more posterior stimulation site and exhibited, at both tongue loci, an increase in detection performance as stimulus concentration increased. The elderly subjects, on the other hand, performed at chance level at both tongue loci for all three stimulus sizes and concentrations tested. No sex differences were observed. In the young subjects, the mean R-index increased monotonically as a function of stimulus size for the two highest NaCl concentrations at both tongue loci. A hyperbolic function provided the best fit to these data at the tongue tip, and an exponential function at the more posterior tongue region, implying a different pattern of spatial summation at these two sites. Overall, this study demonstrates that marked age-related changes in regional taste sensitivity to NaCl are present in elderly persons.

Adult↗
PubMed1981

A genetic study of bovine lymphocyte antigens (BoLA) and their frequency in several breeds.

Using sera which defined the BoLA specificities at the two International BoLA workshops (Edinburgh, 1978 and Wageningen, 1980) and the European Regional workshop (Paris, 1979), 142 informative matings from 15 bulls have been studied. On the basis of this data, 11 of the 15 internationally agreed specificities and one of the regionally defined specificities behave as if controlled by alleles at a single autosomal locus. Data has not as yet been obtained for the other four internationally agreed specificities which are also believed to be at this locus. - The frequencies of 13 of the internationally agreed specificities and one of the regionally defined specificities have been studied for both sexes in one breed and for a single sex in another five breeds. The other two internationally agreed specificities are very recent and the populations have not been tested for them. The frequencies between sexes within a breed and within sexes between breeds differ significantly.

Alleles↗
PubMed1999

Genetic abnormalities in Prader-Willi syndrome and lessons from mouse models.

Prader-Willi syndrome is a multigenic disorder with developmental and neurobehavioural abnormalities. There are multiple genetic causes, although all ultimately involve the loss of paternally derived gene expression of chromosome region 15q11-q13. Multiple imprinted genes expressed only from the paternal allele have been identified in the specific region of human chromosome 15q associated with Prader-Willi syndrome and in the syntenic mouse chromosome 7C region, including a novel polycistronic gene (SNURF-SNRPN) that encodes two independent proteins. The latter genetic locus may play a key role in Prader-Willi syndrome and the evolution of imprinting in this domain, because it is uniquely involved with mutations in the imprinting process and balanced translocations in this syndrome. Indeed, based on the co-localization of SNURF and SNRPN within the imprinting control region critical to Prader-Willi syndrome, evolutionary arguments would suggest that this genetic locus is a prime candidate for mutations producing the failure-to-thrive phenotype of neonates with this syndrome and of corresponding mouse models. Hence, the SNURF-SNRPN gene may encode a paternally derived postnatal growth factor.

Angelman Syndrome↗
PubMed1999

A conserved sequence block in the murine and human TCR J alpha region: assessment of regulatory function in vivo.

Temporal control of rearrangement at the TCR alpha/delta locus is crucial for development of the gamma delta and alpha beta T cell lineages. Because the TCR delta locus is embedded within the alpha locus, rearrangement of any V alpha-J alpha excises the delta locus, precluding expression of a functional gamma delta TCR. Approximately 100 kb spanning the C delta-C alpha region has been sequenced from both human and mouse, and comparison has revealed an unexpectedly high degree of conservation between the two. Of interest in terms of regulation, several highly conserved sequence blocks (> 90% over > 50 bp) were identified that did not correspond to known regulatory elements such as the TCR alpha and delta enhancers or to coding regions. One of these blocks lying between J alpha 4 and J alpha 3, which appears to be conserved in other vertebrates, has been shown to augment TCR alpha enhancer function in vitro and differentially bind factors from nuclear extracts. To further assess a plausible regulatory role for this element, we have created mice in which this conserved sequence block is either deleted or replaced with a neomycin resistance gene driven by the phosphoglycerate kinase promoter (pgk-neor). Deletion of this conserved sequence block in vivo did have a local effect on J alpha usage, echoing the in vitro data. However, its replacement with pgk-neor had a much more dramatic, long range effect, perhaps underscoring the importance of maintaining overall structure at this locus.

Animals↗
PubMed2003

Analyses of temporal regulatory elements of the prosaposin gene in transgenic mice.

The expression of prosaposin is temporally and spatially regulated at transcriptional and post-translational levels. Transgenic mice with various 5'-flanking deletions of the prosaposin promoter fused to luciferase (LUC) reporters were used to define its temporal regulatory region. LUC expression in the transgenic mice carrying constructs with 234 bp (234LUC), 310 bp (310LUC) or 2400 bp (2400LUC) of the 5'-flanking region was analysed in the central nervous system and eye throughout development. For 310LUC and 2400LUC, low-level LUC activity was maintained until embryonal day 18 in brain, eye and spinal cord. The peak level of LUC activity was at birth, with return to a plateau (1/3 of peak) throughout adulthood. Deletion of the region that included the retinoic acid-receptor-related orphan receptor (ROR alpha)-binding site and sequence-specific transcription factor (Sp1) cluster sites (44-310 bp) suppressed the peak of activity. By comparison, the peak level for 234LUC was shifted 2 weeks into neonatal life in the brain, but not in the eye, and no peak of activity was observed in the spinal cord. The endogenous prosaposin mRNA in eye, spinal cord and cerebellum had low-level expression before birth and continued to increase into adulthood. In cerebrum, the endogenous mRNA showed similar expression profile to constructs 310LUC, 2400LUC and 234LUC, with the peak expression at 1 week and a decreased level in adult. In the brain of the newborn, 2400LUC was highly expressed in the trigeminal ganglion and brain stem regions when compared with the generalized expression pattern for endogenous prosaposin mRNA. These results suggest that the modifiers (ROR alpha- and Sp1-binding sites) residing within 310 bp of the 5'-flanking region mediate developmental regulation in the central nervous system and eye. Additional regulatory elements outside the 5' region of the 2400 bp promoter fragment appear to be essential for the physiological control of the prosaposin locus.

5' Flanking Region↗
PubMed1996

Dominant expression of a 1.3 Mb human Ig kappa locus replacing mouse light chain production.

Expression studies of multigene families, such as the immunoglobulin (Ig) loci, are difficult because of their large size and the necessity to introduce germline configured regions into an animal. Antibody diversity from Ig gene miniloci is limited by the number of variable (V) region genes and the need for distal regulatory elements to control expression. Here, we show germline transfer into mice of a 1300 kb human Ig kappa light chain locus on a yeast artificial chromosome that resulted in early DNA rearrangement and highly efficient human light chain expression. The human locus was assembled from a 300 kb authentic region using contig extension by addition of cosmid multimers to supplement the variable gene cluster. This resulted in the addition of about 100 V region genes in germline configuration from different families. In transgenic animals with Ig kappa disruption, this large human kappa locus replaced the endogenous locus, and subsequent down-regulation of Ig lambda light chain contribution led to a dominant expression of the rearranged human genes. Contrary to expectation, rather than providing a solely selective advantage for ensuring repertoire formation controlled by the sheer number of introduced genes, the lambda/kappa ratio in serum appears to be the result of competition for early surface Ig expression maintained in the developing B cell.-Zou, X., Xian, J., Davies, N. P., Popov, A. V., Brüggemann, M. Dominant expression of a 1.3 Mb human Ig kappa locus replacing mouse light chain production.

Animals↗
PubMed2003

Alternative splicing and imprinting control of the Meg3/Gtl2-Dlk1 locus in mouse embryos.

The distal part of the mouse Chr 12 contains a cluster of reciprocally imprinted genes. Recently we found a grandparental origin-dependent, transmission-ratio distortion (TRD) in this region. The TRD resulted from postimplantation loss of embryos that inherited the distal Chr 12 alleles from the maternal grandfather. These data suggested that imprinting of one or more genes in this region was not uniformly well established or maintained in all the embryos. To elucidate the mechanism underlying such a variation, we examined the expression of two genes from the distal Chr 12 imprinted region, the maternally expressed gene 3/gene-trap locus 2 ( Meg3/ Gtl2), and the delta-like homolog 1 ( Dlk1) gene. We demonstrated that the Meg3/ Gtl2 gene had two major mRNA forms. One form, Meg3-proximal ( Meg3p), contained exons 1-3. The second form, Meg3-distal ( Meg3d) did not contain exons 1-3 and was present in oocytes and in 1- and 2-cell embryos. We observed cross-dependent and splice form-specific relaxation of imprinting of the Dlk1 and Meg3d, but not Meg3p. Expression patterns of Dlk1 and Meg3/ Gtl2 in embryos from crosses between different mouse strains suggest that 1). imprinting of the Dlk1 and Meg3/ Gtl2 genes is not strictly coordi- nated; 2). parental origin-dependent expression of these genes is under control of a strain-specific, cis-acting modifier located in a 1.5-Mb region that includes the Meg3/ Gtl2-Dlk1 locus. Biallelic expression of Dlk1 and Meg3d did not affect embryo viability and, therefore, cannot be responsible for the lethal phenotypes in UPD12 embryos or for the transmission-ratio distortion.

Alternative Splicing↗