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PubMed2003

How common are common fragile sites in humans: interindividual variation in the distribution of aphidicolin-induced fragile sites.

To obtain an estimate of the variation in common fragile sites (CFSs) among individuals, aphidicolin (APC)-induced chromosomal breakage data were analyzed for 20 karyotypically normal adult humans. As it is specifically designed to meet the analytical requirements for considering fragile sites as presence/absence characters in single individuals, the FSM methodology (Böhm et al., 1995) was used to statistically distinguish fragile from nonfragile sites. These analyses indicated that the APC-induced fragile sites are not ubiquitous but vary extensively among individuals; the per-individual number of fragile sites ranged from as few as seven to as many as 20. Of the 45 different sites identified as fragile, 19 (42%) occurred in more than half of the individuals, but only two sites (3p14 and 16q23) were fragile in all of the individuals; 12 (27% of the total) were fragile in single individuals only. Although these analyses provide statistical confirmation (and initial estimates of population variation) for 43 of the 88 APC-inducible fragile sites currently recognized as occurring among humans, they are consistent with the hypothesis that many of the currently recognized human CFSs have been erroneously identified. These results indicate the need for per-individual statistical identification of CFSs for larger samples of individuals and that studies of particular fragile sites should be conducted on individuals documented to be fragile at the loci under consideration.

Adult↗

PubMed1995

Diameter and compliance in the human common carotid artery--variations with age and sex.

In this study, age and sex differences in diameter and compliance of the common carotid artery (CCA) were evaluated in 119 healthy subjects with a phase-locked echo-tracking system. The diameter and pulsatile diameter changes were measured, and pressure strain elastic modulus (Ep) and stiffness (beta) were calculated and used as the inverse estimate of compliance. The carotid diameter increased more rapidly in males and was larger than in females from 25 years of age. The relative diameter change was equal in both sexes, and decreased from 12% to 14% in younger subjects to approximately 5% in elderly subjects. Compliance decreased almost linearly and in parallel in males and females up to 45 years of age. Between 45 and 60 years the decrease was more marked in females than in males, whereas it was by far more marked in males between 60 and 70 years of age.

Adolescent↗

PubMed2003

Allelic variation in gene expression is common in the human genome.

Variations in gene sequence and expression underlie much of human variability. Despite the known biological roles of differential allelic gene expression resulting from X-chromosome inactivation and genomic imprinting, a large-scale analysis of allelic gene expression in human is lacking. We examined allele-specific gene expression of 1063 transcribed single-nucleotide polymorphisms (SNPs) by using Affymetrix HuSNP oligo arrays. Among the 602 genes that were heterozygous and expressed in kidney or liver tissues from seven individuals, 326 (54%) showed preferential expression of one allele in at least one individual, and 170 of those showed greater than fourfold difference between the two alleles. The allelic variation has been confirmed by real-time quantitative PCR experiments. Some of these 170 genes are known to be imprinted, such as SNRPN, IPW, HTR2A, and PEG3. Most of the differentially expressed genes are not in known imprinting domains but instead are distributed throughout the genome. Our studies demonstrate that variation of gene expression between alleles is common, and this variation may contribute to human variability.

Alleles↗

PubMed1985

Common childhood problems: variation in management.

A patient management questionnaire was written to assess the range of advice being offered to parents on common paediatric problems. It was sent to hospital doctors, clinical medical officers, health visitors, and general practitioner trainers and trainees. In the 95 completed questionnaires just over half the items elicited conflicting advice, and some differences between different professional groups could be identified. It is suggested that such conflicts are potentially damaging to relationships between patients and health care professionals and that there are ways to avoid conflict.

Child↗

PubMed1976

[Anatomic variations of the common trunk of the left coronary artery (apropos of 80 dissections)].

An anatomic study of the main left coronary artery is reported : important anatomic variations may occur:--sometimes, the main left coronary artery is missing (1 % of the cases),--its origin may be unusual (from the pulmonary artery),--its average length is 11 mm; but, it may be longer (35 mm) and sometimes very short (less than 8 mm in 15 per cent of the cases) : this last aspect has to be taken in account by the surgeon during aortic valve surgery if a coronary perfusion has been decided.--At last, its division into two branches (anterior descending and left circumflex) is the most usual (65 or 70 per cent of the cases). A third branch of division may exist (diagonal or lateral branch) in about 20 to 30 per cent of the cases. The left coronary artery may also divide into four (or even five) branches in 5 to 10 per cent of the cases.

Coronary Vessel Anomalies↗

PubMed2003

Latitudinal countergradient variation in the common frog (Rana temporaria) development rates--evidence for local adaptation.

Adaptive genetic differentiation along a climatic gradient as a response to natural selection is not necessarily expressed at phenotypic level if environmental effects on population mean phenotypes oppose the genotypic effects. This form of cryptic evolution--called countergradient variation--has seldom been explicitly demonstrated for terrestrial vertebrates. We investigated the patterns of phenotypic and genotypic differentiation in developmental rates of common frogs (Rana temporaria) along a ca. 1600 km latitudinal gradient across Scandinavia. Developmental rates in the field were not latitudinally ordered, but displayed large variation even among different ponds within a given latitudinal area. In contrast, development rates assessed in the laboratory increased strongly and linearly with increasing latitude, suggesting a genetic capacity for faster development in the northern than the southern larvae. Experiments further revealed that environmental effects (temperature and food) could easily override the genetic effects on developmental rates, providing a possible mechanistic explanation as to why the genetic differentiation was not seen in the samples collected from the wild. Our results suggest that the higher developmental rates of the northern larvae are likely to be related to selection stemming from seasonal time constrains, rather than from selection dictated by low ambient temperatures per se. All in all, the results provide a demonstration of environmental effects concealing substantial latitudinally ordered genetic differentiation understandable in terms of adaptation to clinal variation in time constrains.

Adaptation, Physiological↗

PubMed2026

The contribution of common and rare genetic variation to emotional and behavioural symptoms in childhood and adolescence.

Genetic factors influence vulnerability to common mental health conditions, but their role in early-life mental health remains understudied. We analysed genotype array (n = 4709-6687) and exome sequence data (n = 4500-5424) from the Millennium Cohort Study (MCS) and Avon Longitudinal Study of Parents and Children (ALSPAC) to assess the contribution of common variants and rare deleterious coding variants to internalising and externalising symptoms across development. In longitudinal analysis spanning ages 5-17 years, we identified several associations between common genetic variation, indexed by polygenic indices (PGIs), and both symptom domains that generally remained stable across development. Effect sizes were modest, with the largest estimates observed for PGIs for attention deficit hyperactivity disorder (ADHD) and externalising behaviour with externalising symptoms (β = 0.13-0.18; p-adj<3.5×10⁻29). Evidence for direct genetic effects was strongest for externalising symptoms, including for associations with the ADHD and externalising behaviour PGIs. Concordant results were observed in the Born in Bradford cohort. A higher exome-wide burden of deleterious rare variants was associated with increased externalising and internalising symptoms (β = 0.04-0.06, p-adj<0.03); within-family models indicated direct genetic effects on externalising in MCS (β = 0.07; p < 0.05, p-adj>0.05) and on internalising symptoms in ALSPAC (β = 0.12, p-adj<0.02). Common and rare genetic variants contributed independently, jointly explaining 2% of the variance in internalising and 5-7% in externalising symptoms. This study shows that early-life mental health is influenced by both common and rare genetic variation, with several associations explained by direct genetic effects.

Journal Article↗

PubMed1985

Isoenzyme variation in the common shrew (Sorex araneus) in Britain, in relation to karyotype.

Samples of common shrews with an Aberdeen race, Oxford race and Hermitage race karyotype and from the Oxford-Hermitage hybrid zone were screened for genotype at six polymorphic enzyme loci. The common allele at all loci was the same in all samples suggesting that the degree of genic divergence between the karyotypic races is not great. However, shrews of the Aberdeen race appear to be somewhat distinct. There were differences in allele frequencies, range of alleles and heterozygosities at the Mpi-1, Pgm-2 and Pgm-3 loci between the Aberdeen race samples and samples of other karyotypic categories. The allele frequency variation across the Oxford-Hermitage hybrid zone is not substantially linked with karyotype frequency change, but there is notable allele frequency variation between close sites of similar habitat, particularly at the Pgm-2 and Pgm-3 loci. This suggests that gene flow between close sites may be reduced sufficiently in some instances to allow allele frequency change by genetic drift. This may have implications for the mode of origin of karyotypic races of common shrew.

Alleles↗

PubMed1989

Calcaneus secundarius. Variation of a common accessory ossicle.

The calcaneus secundarius is an accessory ossicle of the anterior calcaneal facet. Dry bone examination of 1,367 calcanei revealed this trait 47 times (3.4%). Familiarity with the calcaneus secondarius may prove to be of clinical and radiographic value in distinguishing pathologic from normal variants in the calcaneus.

Adolescent↗

PubMed2000

Bipolar disorder and variation at a common polymorphism (A1832G) within exon 8 of the Wolfram gene.

A number of linkage studies provide evidence consistent with the existence of a bipolar susceptibility gene on chromosome 4p16. The gene for Wolfram syndrome, a rare recessive neurodegenerative disorder, lies in this region and has recently been cloned. Psychiatric disturbances including psychosis, mood disorder, and suicide have been reported at increased frequency in Wolfram patients and in heterozygous carriers of a Wolfram mutation. In the current investigation we have undertaken a case-control association study using a single nucleotide polymorphism (causing an amino acid change) in exon 8 of the Wolfram gene in a UK Caucasian sample of 312 Diagnostic and Statistical Manual of Mental Disorders (fourth edition; DSM IV) bipolar I probands and 301 comparison individuals. We found no evidence that variation at this polymorphism influences susceptibility to bipolar disorder. It remains possible that variation at other sites within or near the Wolfram gene plays important roles in determining susceptibility to affective illness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:154-157, 2000.

Bipolar Disorder↗

PubMed1995

The relationship between normal variation in IQ and common childhood psychopathology: a clinical study.

The relationship between normal variation in IQ and common psychopathology was examined in a sample of 339 5- to 16-year-olds who were seen at a tertiary psychiatric clinic. The mean IQ was 9.6 points lower (95% CI 5.5 to 13.6 points lower) for conduct than for emotional disorders, with mixed disorders in between. For these common disorders, the mean IQ was 6.0 points lower (95% CI 1.6 to 10.3 points lower) for females than males. IQ variation in the normal range was inversely related to a dimensional measure of conduct problems - an association that was not attributable to social class or mediated by scholastic attainments. Other dimensional measures of psychopathology - covering emotional symptoms, developmental immaturity and relationship difficulties - were not significantly correlated with IQ. Limitations of the study are discussed in the paper.

Adolescent↗

PubMed1997

How common are common fragile sites: variation of aphidicolin-induced chromosomal fragile sites in a population of the deer mouse (Peromyscus maniculatus).

Aphidicolin (APC)-induced chromosomal gaps and breaks were analyzed for ten deer mice (Peromyscus maniculatus) from a natural population. The FSM statistical methodology was used to identify fragile sites as chromosomal loci exhibiting significantly non-random numbers of gaps/breaks in each individual and enabled an assessment of variation in fragile sites among the individuals. The individual deer mice exhibited as few as 7 to as many as 19 of the populational total of 34 sites. Two sites were fragile in all individuals and 13 sites were fragile in single individuals only. Defined by populational frequencies of greater than 50%, high-frequency fragile sites constituted 26% of the populational total. Approximately 35% of the total fragile sites were fragile in 20-40% of the population (low-frequency fragile sites) and about 38% were fragile in single individuals only. Analysis of the data pooled over all individuals identified significantly non-random breakage at 80 sites, 47 of which were not identified as fragile in any single individual. It appears, therefore, that fragile site identifications from pooled data have fostered an inflated estimate of the numbers and frequencies of common fragile sites. Comparison of the fragile site and spontaneous breakage (control) data suggest that APC-induced fragile sites represent regions of chromosomes that experience elevated levels of somatic mutation. Additionally, the occurrence of APC-induced fragile sites at or near the interstitial breakpoints of two pericentric-inversion polymorphisms in this population supports the hypothesis that fragile sites experience an increased rate of meiotic chromosomal mutation and are predisposed to undergo phylogenetic rearrangement.

Animals↗

PubMed1984

Quantitative variation of the common acute lymphoblastic leukemia antigen (gp100) on leukemic marrow blasts.

Marrow blasts from children with B cell precursor acute lymphoblastic leukemia (ALL) were studied for differences in quantitative expression of the common ALL antigen (CALLA). Of 42 untreated patients, 35 had detectable amounts of CALLA by flow cytometric (FCM) analysis of J-5 monoclonal antibody binding. Using an FCM technique that provides correlated measurements of a given cell surface antigen, cell size, and DNA content, we detected increased CALLA expression as lymphoblasts moved from G0/G1 phase through S phase of the cell cycle. The density of the antigen (per unit of blast surface area) remained relatively constant over the same interval, indicating that the change was not due to S phase-specific enhancement of CALLA expression. Eight cases had hyperdiploid cellular DNA content and in seven of these, only cells with clonal abnormalities of DNA content expressed the CALLA marker. Mean amounts of CALLA for each patient ranged widely within the study group, from very high to marginally detectable. This variation had no discernible relation to cell size, stem-line DNA content, percentage of cells in S phase, or the presence or absence of cytoplasmic immunoglobulin. Results of a univariate proportional hazards analysis showed that both quantitative level of CALLA for S phase cells (P = 0.048) and white blood cell count (P = 0.012) had made significant contributions to treatment outcome. Patients with relative amounts of CALLA less than the median value for the entire CALLA+ group had a higher rate of failure, which was virtually identical to that for the seven HLA-DR+ patients whose blasts lacked detectable CALLA. The observed interpatient variation in quantitative expression of CALLA is consistent with recognized steps in B cell precursor differentiation and may be useful in distinguishing patients with a less favorable prognosis.

Antibodies, Monoclonal↗

PubMed2000

Effect of variation in the common "a" determinant on the antigenicity of hepatitis B surface antigen.

Antibody to the common "a" determinant of hepatitis B surface antigen (HBsAg) protects against infection with hepatitis B virus. A number of variant surface antigens with amino acid substitutions within the "a" determinant have been described in patients around the world. Both wild type and variant HBsAgs were expressed in the yeast Pichia pastoris and the antigens were semi-purified and quantitated. The effect on antigenicity of these changes was investigated in a quantitative fashion using four monoclonal antibodies known to bind to different epitopes within the common "a" determinant. The results suggest that amino acid substitution of T131I, K141E and G145R and insertion of 3 amino acids between residues 123 and 124 markedly affect the antigenic structure of HBsAg. These substitutions and insertions in the viral envelope may lead to evasion of the virus neutralizing antibody response and also to reduce efficiency of detection by immunoassays used for diagnosis and blood-bank screening.

Amino Acid Sequence↗

PubMed2002

Evolution of nitrate reductase: molecular and structural variations on a common function.

The biological transformation of nitrogen oxyanions is widespread in nature and gives rise to a robust biogeochemical cycle. The first step in nitrate reduction is carried out by the enzyme nitrate reductase (NR). Although NR always catalyzes the same chemical reaction (conversion of nitrate into nitrite), its location in the cell, structure, and function are organism-dependent. We use protein sequence data to determine phylogenetic relationships and to examine similarities in structure and function. Three distinct clades of NR are apparent: the eukaryotic assimilatory NR (Euk-NR) clade, the membrane-associated prokaryotic NR (Nar) clade, and a clade that includes both the periplasmic NR (Nap) and prokaryotic assimilatory NR (Nas). The high degree of sequence similarity and a phylogenetic distribution that follows taxonomic classification suggest a monophyletic origin for the Euk-NR early on in the evolution of eukaryotic cells. In contrast, sequence conservation, phylogenetic analysis, and physiology suggest that both Nar and Nap were acquired by horizontal gene transfer. Nap and Nas share a lesser degree of similarity, with Nap a subclade of Nas. Nap from strict anaerobic bacteria such as Desulfovibrio desulfuricans is ancestral to facultative species and may provide an evolutionary link between Nap and Nas. We observed conserved binding sites for molybdenum and pterin cofactors in all four proteins. In pathways involving Euk-NR, Nas, and Nar, for which ammonia is the end product, nitrite is reduced to ammonia by a siroheme nitrite reductase. Nap, however, is coupled to a pentaheme nitrite reductase. In denitrification, whether Nar or Nap is involved, nitrite is reduced to nitric oxide by either a cytochrome cd1 or a copper-containing nitrite reductase. This complexity underscores the importance of nitrate reduction as a key biological process.

Amino Acid Sequence↗

PubMed2002

Canonical and non-canonical Wnt signaling pathways in Caenorhabditis elegans: variations on a common signaling theme.

Wnt glycoproteins are signaling molecules that control a wide range of developmental processes in organisms ranging from the simple metazoan Hydra to vertebrates. Wnt signaling also plays a key role in the development of the nematode C. elegans, and is involved in cell fate specification and determination of cell polarity and cell migration. Surprisingly, the first genetic studies of Wnt signaling in C. elegans revealed major differences with the established (canonical) Wnt signaling pathways of Drosophila and vertebrates. Thus, the Wnt-dependent induction of endoderm in the early embryo and the specification of several asymmetric cell divisions during larval development are mediated by as yet novel Wnt signaling pathways that repress, rather than activate the TCF/LEF-1 transcription factor POP-1. Recently, however, it has been shown that, in addition to these divergent Wnt pathways, C. elegans also has a canonical Wnt pathway that converts POP-1 into an activator and controls the expression of several homeobox genes. Interestingly, these different Wnt pathways use distinct beta-catenins to control POP-1 function: the endoderm induction pathway requires the beta-catenin WRM-1 and parallel input from a mitogen-activated kinase (MAPK) pathway to downregulate POP-1, whereas the canonical Wnt pathway employs the beta-catenin BAR-1 to activate Wnt target gene expression.

Animals↗

PubMed1987

Length of stay for common surgical procedures: variation among districts.

Lengths of stay for appendicectomy, inguinal hernia repair and cholecystectomy for the 16 districts in the Northern Regional Health Authority (NRHA) and 15 districts in the South East Thames Regional Health Authority (SETRHA) are examined using data recorded in the Hospital Activity Analysis. Considerable variations exist among districts, with the three longest stay districts for each procedure in NRHA having an age-adjusted length of stay of 113 per cent of the regional average for appendicectomy, 125 per cent for hernia and 115 per cent for cholecystectomy. This resulted in greater than 2000 additional bed days per year being occupied in the three longest stay districts in the NRHA compared with the regional average. The age adjusted length of stay for the three shortest stay districts for each procedure is 83 per cent of the regional average for appendicectomy, 75 per cent for hernia and 85 per cent for cholecystectomy. Similar differences are seen in the SETRHA, and derive from differences in the length of both preoperative and postoperative stay. Explanations for the observed variations are considered in terms of population, organizational and clinical variables.

Adolescent↗

PubMed1999

The GTP-binding domain of McrB: more than just a variation on a common theme?

The methylation-dependent restriction endonuclease McrBC from Escherichia coli K12 cleaves DNA containing two R(m)C dinucleotides separated by about 40 to 2000 base-pairs. McrBC is unique in that cleavage is totally dependent on GTP hydrolysis. McrB is the GTP binding and hydrolyzing subunit, whereas MrC stimulates its GTP hydrolysis. The C-terminal part of McrB contains the sequences characteristic for GTP-binding proteins, consisting of the GxxxxGK(S/T) motif (position 201-208), followed by the DxxG motif (position 300-303). The third motif (NKxD) is present only in a non-canonical form (NTAD 333-336). Here we report a mutational analysis of the putative GTP-binding domain of McrB. Amino acid substitutions were initially performed in the three proposed GTP-binding motifs. Whereas substitutions in motif 1 (P203V) and 2 (D300N) show the expected, albeit modest effects, mutation in the motif 3 is at variance with the expectations. Unlike the corresponding EF-Tu and ras -p21 variants, the D336N mutation in McrB does not change the nucleotide specificity from GTP to XTP, but results in a lack of GTPase stimulation by McrC. The finding that McrB is not a typical G protein motivated us to perform a search for similar sequences in DNA databases. Eight microbial sequences were found, mainly from unfinished sequencing projects, with highly conserved sequence blocks within a presumptive GTP-binding domain. From the five sequences showing the highest homology, 17 invariant charged or polar residues outside the classical three GTP-binding motifs were identified and subsequently exchanged to alanine. Several mutations specifically affect GTP affinity and/or GTPase activity. Our data allow us to conclude that McrB is not a typical member of the superfamily of GTP-binding proteins, but defines a new subfamily within the superfamily of GTP-binding proteins, together with similar prokaryotic proteins of as yet unidentified function.

Amino Acid Sequence↗