Genetic selection and differential stress responses. The Roman lines/strains of rats.
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Adrenocorticotropic Hormone↗
Biomedical subjects
J Flint
Publications and source records attributed to J Flint.
Behavioral phenotypes: conceptual and methodological issues.
Specific behavioral patterns associated with chromosomal and genetic disorders are being recognized more frequently. The hope is that the demonstration of a behavioral phenotype with a particular syndrome may lead to the isolation of the behavior's genetic determinants. Three issues are considered here: the problem of defining a behavioral phenotype, the difficulty of demonstrating the existence of a behavioral phenotype, and the likelihood of characterizing etiologically important genes. Although there are many impediments to success, the value of recognizing behavioral phenotypes within a diagnostic syndrome is emphasized, and examples are given of how this may lead to isolating behavioral genes.
Aggression↗
Examination of the X chromosome by STS-PCR screening for the presence of submicroscopic deletions.
Cytogenetically undetectable deletions are suspected to be an important cause of mental retardation and developmental delay, as suggested by the observation that about 7% of children with undiagnosed mental retardation have rearrangements affecting the chromosome ends. Screening the whole genome for regions of aneuploidy smaller than 5 Mb is not feasible, but the availability of a high resolution map of the X chromosome means that it is possible to look for deletions in males by PCR. We have screened 96 affected males and their 96 unaffected fathers with 110 markers distributed across the X chromosome. No deletions were found in either group. Our results show that the prevalence of deletions greater than 1 Mb in children with mental retardation is less than 3.9% (95% confidence interval). We conclude that X chromosome deletions in the size range 1-5 Mb are a rare cause of mental retardation in males.
Chromosome Deletion↗
Del(18p) shown to be a cryptic translocation using a multiprobe FISH assay for subtelomeric chromosome rearrangements.
We have previously described a fluorescence in situ hybridisation (FISH) assay for the simultaneous analysis of all human subtelomeric regions using a single microscope slide. Here we report the use of this multiprobe FISH assay in the study of a patient whose karyotype was reported by G banding analysis as 46,XX,del(18)(p11.2). Although the proband had some features suggestive of a chromosomal abnormality, relatively few of the specific features of del(18p) were present. She was a 37 year old female with mild distal spinal muscular atrophy (SMA), arthritis of the hands, an abnormal chest shape (pectus excavatum), and an unusual skin condition (keratosis pilaris). Reverse chromosome painting with degenerate oligonucleotide primer-polymerase chain reaction (DOP-PCR) amplified del(18p) chromosomes as a probe confirmed the abnormality as del(18p), with no evidence of any other chromosome involvement. Subsequently, the multiprobe FISH assay confirmed deletion of 18p subtelomeric sequence. However, the assay also showed that sequences corresponding to the 2p subtelomeric probe were present on the tip of the shortened 18p. The patient is therefore monosomic for 18p11.2-pter and trisomic for 2p25-pter, and the revised karyotype is 46,XX,der(18)t(2;18)(p25; p11.2). We believe that a proportion of all cases reported as telomeric deletions may be cryptic translocations involving other chromosome subtelomeric regions. Further studies such as this are necessary to define accurately the clinical characteristics associated with pure monosomy in chromosomal deletion syndromes.
Adult↗
The relationship between chromosome structure and function at a human telomeric region.
We have sequenced a contiguous 284,495-bp segment of DNA extending from the terminal (TTAGGG)n repeats of the short arm of chromosome 16, providing a full description of the transition from telomeric through subtelomeric DNA to sequences that are unique to the chromosome. To complement and extend analysis of the primary sequence, we have characterized mRNA transcripts, patterns of DNA methylation and DNase I sensitivity. Together with previous data these studies describe in detail the structural and functional organization of a human telomeric region.
Base Sequence↗
Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats.
Coronary heart disease, hypertension, non-insulin-dependent diabetes and obesity are major causes of ill health in industrial societies. Disturbances of carbohydrate and lipid metabolism are a common feature of these disorders. The bases for these disturbances and their roles in disease pathogenesis are poorly understood. The spontaneously hypertensive rat (SHR), a widely used animal model of essential hypertension, has a global defect in insulin action on glucose metabolism and shows reduced catecholamine action on lipolysis in fat cells. In our study we used cellular defects in carbohydrate and lipid metabolism to dissect the genetics of defective insulin and catecholamine action in the SHR strain. In a genome screen for loci linked to insulin and catecholamine action, we identified two quantitative trait loci (QTLs) for defective insulin action, on chromosome 4 and 12. We found that the major (and perhaps only) genetic determinant of defective control of lipolysis in SHR maps to the same region of chromosome 4. These linkage results were ascertained in at least two independent crosses. As the SHR strain manifests many of the defining features of human metabolic Syndrome X, in which hypertension associates with insulin resistance, dyslipidaemia and abdominal obesity, the identification of genes for defective insulin and catecholamine action in SHR may facilitate gene identification in this syndrome and in related human conditions, such as type-2 diabetes and familial combined hyperlipidaemia.
Animals↗
Sequence comparison of human and yeast telomeres identifies structurally distinct subtelomeric domains.
We have sequenced and compared DNA from the ends of three human chromosomes: 4p, 16p and 22q. In all cases the pro-terminal regions are subdivided by degenerate (TTAGGG)n repeats into distal and proximal sub-domains with entirely different patterns of homology to other chromosome ends. The distal regions contain numerous, short (<2 kb) segments of interrupted homology to many other human telomeric regions. The proximal regions show much longer (approximately 10-40 kb) uninterrupted homology to a few chromosome ends. A comparison of all yeast subtelomeric regions indicates that they too are subdivided by degenerate TTAGGG repeats into distal and proximal sub-domains with similarly different patterns of identity to other non-homologous chromosome ends. Sequence comparisons indicate that the distal and proximal sub-domains do not interact with each other and that they interact quite differently with the corresponding regions on other, non-homologous, chromosomes. These findings suggest that the degenerate TTAGGG repeats identify a previously unrecognized, evolutionarily conserved boundary between remarkably different subtelomeric domains.
Base Sequence↗
Characterization of short tandem repeats from thirty-one human telomeres.
Completion of genetic and physical maps requires markers from the ends (telomeres) of every human chromosome. We have searched for short tandem repeats (microsatellites) in cosmid and P1 clones and generated 661 sequence-tagged sites (STS) from the terminal 300 kb of 31 human chromosome ends. PCR assays were successfully designed for 58 microsatellites and mapped both genetically and on radiation hybrids (RHs) to confirm their telomeric location. Sequence analysis revealed marked variation in sequence composition, consistent with the hypothesis that even very highly GC-rich chromosome bands (the T bands) are not homogenous. The STSs that we have generated will be a necessary resource for the construction of physical maps of these complex regions of the genome.
Base Sequence↗
Molecular-cytogenetic detection of a deletion of 1p36.3.
We report a deletion of 1p36.3 in a child with microcephaly, mental retardation, broad forehead, deep set eyes, depressed nasal bridge, flat midface, relative prognathism, and abnormal ears. The phenotype is consistent with that described for partial monosomy for 1p36.3. Reverse chromosome painting and microsatellite and Southern blot analyses were used to map the extent of the deletion. Fluorescence in situ hybridisation (FISH) analysis using probes from every telomere indicates that the rearrangement is likely to be a chromosomal truncation or rearrangement involving subtelomeric repetitive DNA. The deletion was identified by screening a sample of children and adults with idiopathic mental retardation. In conjunction with previous work on this sample, we estimate that 7.4% of the group have subtelomeric rearrangements.
Adolescent↗
Viral transactivating proteins.
Many viruses utilize the cellular transcription apparatus to express their genomes, and they encode transcriptional regulatory proteins that modulate the process. Here we review the current understanding of three viral regulatory proteins. The adenovirus E1A protein acts within the nucleus to regulate transcription through its ability to bind to other proteins. The herpes simplex type 1 virus VP16 protein acts within the nucleus to control transcription by binding to DNA in conjunction with cellular proteins. The human T-cell leukemia virus Tax protein influences transcription through interactions with cellular proteins in the nucleus as well as the cytoplasm.
Adenovirus E1A Proteins↗
Surgically treated pneumothorax. Radiologic and pathologic findings.
OBJECTIVE: To compare the identifiable pulmonary abnormalities on preoperative chest radiographs and CT scans with the histologic findings in patients requiring surgical intervention for recurrent or persistent pneumothoraces. MATERIALS AND METHODS: Chest radiographs were reviewed retrospectively in 116 consecutive patients (aged 16 to 81 years) who had undergone thoracotomy for recurrent or persistent pneumothorax. CT scans were performed in 21 patients. Chest radiographs and CT scans were reviewed by two observers without knowledge of the histologic findings. All specimens were reviewed by a surgical pathologist. RESULTS: Seventy-nine (68%) patients had parenchymal abnormalities and five (4%) had pleural thickening evident on the radiograph. The most common radiographic abnormalities included apical bullae (n = 51), apical scarring (n = 17), and diffuse emphysema (n = 9). Twenty of 21 (95%) CT scans demonstrated either a parenchymal or a pleural abnormality. CT demonstrated emphysema in four patients with normal radiographs, as well as additional findings in six patients with abnormal radiographs. Histologically, 74 patients had focal irregular emphysema, 26 had distal acinar emphysema, six had mixed emphysema, four had isolated bullae or blebs, two had mesothelioma, and one each had the following: metastatic angiosarcoma, subpleural fibrosis, congenital cystic adenomatoid malformation, and tuberculous pleuritis with inactive interstitial fibrosis and honeycombing. CONCLUSION: Most patients with surgically treated pneumothorax have emphysema or an isolated bulla. Although these findings may not be apparent on the radiograph and seen on CT, this probably does not affect patient management. In most cases of pneumothorax related to other causes, findings consistent with the diagnosis can be seen on the radiograph.
Adolescent↗
Molecular characterization of a 130-kb terminal microdeletion at 22q in a child with mild mental retardation.
We have analyzed a recently described 22q13.3 microdeletion in a child with some overlapping features of the cytologically visible 22q13.3 deletion syndrome. Patient NT, who shows mild mental retardation and delay of expressive speech, was previously found to have a paternal microdeletion in the subtelomeric region of 22q. In order to characterize this abnormality further, we have constructed a cosmid/P1 contig covering the terminal 150 kb of 22q, which encompasses the 130-kb microdeletion. The microdeletion breakpoint is within the VNTR locus D22S163. The cloning of the breakpoint sequence revealed that the broken chromosome end was healed by the addition of telomeric repeats, indicating that the microdeletion is terminal. This is the first cloned terminal deletion breakpoint on a human chromosome other than 16p. The cosmid/P1 contig was mapped by pulsed-field gel electrophoresis analysis to within 120 kb of the arylsulfatase A gene, which places the contig in relation to genetic and physical maps of the chromosome. The acrosin gene maps within the microdeletion, approximately 70 kb from the telomere. With the distal end of chromosome 22q cloned, it is now possible to isolate genes that may be involved in the overlapping phenotype of this microdeletion and 22q13.3 deletion syndrome.
Cell Line, Transformed↗
Do animal models have a place in the genetic analysis of quantitative human behavioural traits?
It seems that the genetic basis of common psychiatric diseases such as schizophrenia and manic-depressive psychosis is amenable to the genetic mapping strategies that have been successful in other complex disorders such as diabetes. The next challenge is the genetic dissection of quantitative behavioural traits such as mood, personality and intelligence. Quantitative traits pose new problems for gene cloning experiments. We argue that one way forward is by using animal models. One of the features of quantitative traits is that the DNA sequence variants which are responsible for them are unlikely to be immediately recognizable. In contrast to many qualitative traits where a discrete phenotypic difference is often the consequence of an inactivating mutation, the allelic variation responsible for quantitative traits probably has a more subtle basis. This distinction means that strategies to clone the genetic basis of quantitative behavioural traits will have to rely on functional assays of alleles thought to be important in determining the phenotype. We suggest that an efficient strategy for detecting sequences that give rise to quantitative behavioural traits can be devised in the mouse. The importance and utility of the mouse for quantitative trait analysis make it worthwhile to investigate mouse models of human behaviour; these advantages outweigh the difficulties that arise in attempts to validate the animal models. As an example we review the evidence that validates rodent emotionality as an animal model for susceptibility to human anxiety. We show that there is good evidence that rodent emotionality is a central nervous system state with a genetic basis, and that there are neuropharmacological and neuroanatomical parallels with human anxiety. Furthermore, our own work has shown that the genetic basis of the trait is relatively simple, and that the task of characterizing it at a molecular level is feasible. We expect that future experiments will show us how genetic variation gives rise to quantitative behavioural traits.
Animals↗
Chromosomal stabilisation by a subtelomeric rearrangement involving two closely related Alu elements.
We have characterised a subtelomeric rearrangement involving the short arm of chromosome 16 that gives rise to alpha-thalassaemia by deleting the major, remote regulatory element controlling alpha-globin expression. The chromosomal breakpoint lies in an Alu family repeat located only approximately 105 kb from the 16p subtelomeric region. The broken chromosome has been stabilised with a newly positioned telomere acquired by recombination between this 16p Alu element and a closely related subtelomeric Alu element of the Sx subfamily. It seems most likely that this abnormal chromosome has been rescued by the mechanism of telomere capture which may reflect a more general process by which subtelomeric sequences are normally dispersed between chromosomal ends.
Adolescent↗
The genetics of mental retardation.
We review the advances that have been achieved using molecular genetic techniques to characterise the genetic basis of mental retardation in recognised syndromes and in discovering new genetic conditions that give rise to mental retardation. However, even with the cloning of a number of mutant genes, the pathogenesis of the condition is not understood. The genetics of mental retardation are turning out to be remarkably complex and are likely to remain a challenge for clinicians and scientists for years to come.
Chromosome Aberrations↗
The genetic basis for mental retardation.
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Chromosome Aberrations↗
Annotation: behavioural phenotypes: a window onto the biology of behaviour.
Characteristic behavioural patterns (including cognitive processes and social interactions) have been reported in a number of syndromes arising from genetic or chromosomal abnormalities, suggesting that molecular analysis of the underlying defect could reveal the biological basis of the behavioural phenotype. Because of the rarity of many of the syndromes, and the complexity of their genetic basis, there are great difficulties in establishing the validity of the association between syndrome and behavioural phenotype. Nevertheless, evidence from animal studies with relevance to human behavioural phenotypes shows that the pathway from genotype to phenotype may be accessible by careful delineation of behavioural phenotypes.
Animals↗