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T Egeland

Publications and source records attributed to T Egeland.

At least 55 records · Page 3Linked to original sources
PubMed1998

Demonstration of identical expanded clones within both CD8+CD28+ and CD8+CD28- T cell subsets in HIV type 1-infected individuals.

In HIV-1-infected individuals, the CD8+CD28- T cell subset is considerably expanded and is frequently the largest subset of T cells found in peripheral blood. It has been assumed, but not proven, that CD8+CD28- T cells derive from CD8+CD28+ T cells in vivo. To further study the ontogeny of CD8+CD28- T cells, we have performed analyses of the complementarity determining region 3 (CDR3) of the TCRB of CD8+CD28+ and CD8+CD28- T cells from the peripheral blood of HIV-1-infected individuals. When cells from the same individual were compared, expanded peaks in CDR3 length analysis within a given BV family were frequently observed at the same location in both CD8+ subsets (p < 0.001). Sequencing of cDNA corresponding to dominant peaks revealed the presence of identical expanded CD8+ T cell clones within both the CD28+ and CD28- subsets on eight of nine attempts. Our results show that CD8+CD28+ and CD8+CD28- T cells are phenotypic variants of the same lineage, most likely evolving from CD8+CD28+ to end-stage CD8+CD28- T cells.

Adult↗
PubMed1998

In vivo expansion of hemopoietic stem cells.

Under conditions of steady-state hemopoiesis, a small fraction of immature hemopoietic cells, including stem cells, circulates in peripheral blood (PB). In rhesus monkeys, a median number of 1.2 x 10(7)/l CD34+ cells was observed as opposed to a median number of 1.5 x 10(9)/l in aspirated bone marrow (BM). The concentration of circulating CD34+ cells is therefore approximately two logs less than that in BM. Since a 4-kg rhesus monkey has an estimated number of 3 x 10(10) BM cells and approximately 300 ml of blood, the fraction of CD34+ cells that circulates can be estimated at approximately 0.4% of the total pool of CD34+ cells. During hemopoietic reconstitution following a cytotoxic insult such as results from a midlethal dose of TBI, PB CD34+ cell numbers appeared to be correlated to those of BM, suggesting that PB CD34+ cells may reflect reconstitution of BM CD34+ cells. Reconstitution of BM immature cells can be accelerated by treatment with pharmacological doses of growth factors, resulting in largely expanded immature cell populations within a few weeks after TBI. Growth factors observed to exert such an effect included, notably, thrombopoietin. Such an acceleration can be monitored by daily assessment of circulating CD34+ cells. Expansion of immature circulating cells indicates expansion of similar cells in the bone marrow rather than growth factor-induced selective mobilization of immature cells.

Animals↗
PubMed1998

Effects of anal invasive treatment and incontinence on mental health and psychosocial functioning of adolescents with Hirschsprung's disease and low anorectal anomalies.

BACKGROUND/PURPOSE: Recent studies of adolescents with Hirschsprung's disease (HD) and low anorectal anomalies (LARA) showed persistent impairment of fecal control in both groups, but very different mental and psychosocial outcome. METHODS: To explore possible reasons for these differences, 19 adolescents with HD (aged 10 to 20 years; median, 16) operated on by the Duhamel technique were compared with 17 adolescents with LARA (aged 12 to 20 years; median, 15). The 36 adolescents were assessed for treatment procedures, bowel function, and mental and psychosocial outcome by data collected from medical records, physical examination, semistructured interview, and standardized questionnaires. The parents of 30 adolescents were also interviewed and completed questionnaires. RESULTS: Duration of anal invasive treatment procedure and current bowel function were associated with mental and psychosocial outcome. The treatment variable, duration of anal dilation, was the most significant predictor of the adolescents's mental health (R2 = .41, P < .01), whereas chronic family difficulties and parental warmth together with the current bowel function variables, fecal and flatus continence function, best explained the variance in psychosocial outcome (R2 = .77, P < .0001). Thus, the differences in treatment procedures and continence function between the HD and LARA groups may partially explain differences in mental and psychosocial outcome. CONCLUSIONS: These findings suggest that anal dilatation and continence dysfunction may have negative impact on mental health and psychosocial functioning. Indications for and ways of performing the procedure of dilation, and the treatment of persistent incontinence problems, are questioned.

Adaptation, Psychological↗
PubMed1998

Prognostic significance of CT contrast enhancement within histological subgroups of intracranial glioma.

UNLABELLED: We report the prognostic significance of tumor CT contrast enhancement within histological subgroups in 831 consecutive adult glioma patients of high-grade (n = 516) and low-grade (n = 315) histology. In the present report, a negative prognostic factor is associated with shortened survival. METHODS: Survival analysis including Kaplan-Meier plots, log-rank tests, Cox analysis, and Aalen's linear model as implemented in SPSS and S-PLUS. RESULTS: Sensitivity and specificity of contrast enhancement as a test for high-grade glioma was 0.87 and 0.79, respectively. Enhancement was a strong negative prognostic factor comparable to high-grade histology in the total patient population. Enhancement was also a negative prognostic factor within the subgroups adult high-grade (Grade 3-4), anaplastic (Grade 3), and low-grade (Grade 1-2) gliomas (p < 0.001). The prognostic implications of initial enhancement declined in high-grade patients surviving beyond 36 months. Tumor contrast enhancement or calcifications (in parentheses) were present in 96% (3.6%) of glioblastomas, in 87% (7.4%) of high-grade gliomas, in 56.5% of anaplastic gliomas, and in 21% (16.2%) of low-grade gliomas. Calcification was a positive prognostic factor within the high-grade group of patients (p < 0.0001). CONCLUSION: Enhancement was a major prognostic factor comparable to high-grade histology in this glioma patient population. Enhancement was a negative prognostic factor within each of the adult subgroups high-grade, anaplastic (grade 3), and low-grade gliomas. Enhancement was strongly associated with but not pathognomonic for high-grade histology.

Adult↗
PubMed1998

Increased number of substitutions in the D-loop of mitochondrial DNA in the sudden infant death syndrome.

The purpose of the present study was to investigate substitutions in the D-loop of mitochondrial DNA (mtDNA) in sudden infant death syndrome (SIDS) and controls, since several observations indicate the involvement of mtDNA mutations in SIDS. These include elevated levels of vitreous humour hypoxanthine in SIDS victims, familial clustering without mendelian traits, and observations of increased sleepiness and a lower activity score in infants who later succumbed to SIDS. Eighty-two cases of SIDS and 133 controls were investigated and the D-loop sequences were recorded in the base-pair range 16055-16500 in the mtDNA sequence. The sequencing was carried out using the Applied Biosystems Sequenase dye terminator method and a ABD373A sequencer. The recorded D-loop sequences were compared with the Cambridge sequence and differences were recorded as substitutions. The SIDS cases had a tendency towards a higher substitution rate in the D-loop than the controls (p = 0.088). This observation makes it interesting to search for deleterious mutations in other locations in the mtDNA.

DNA Mutational Analysis↗
PubMed1998

The CD34 molecule and hematopoietic progenitor cell studies--a challenge in clinical medicine.

The CD34 molecule, which is expressed at various levels on virtually all human hematopoietic progenitor cells (HPC), is a heavy glycosylated molecule with many different epitopes. A large series of CD34-specific monoclonal antibodies specific for different epitopes has been generated. Some of these antibodies do not react with particular HPC subpopulations. Thus, the antibodies used for HPC enumeration and isolation have to be carefully chosen with respect to what is aimed at.

Antibodies, Monoclonal↗
PubMed1998

CD34 molecule epitope distribution on cells of haematopoietic origin.

The CD34 molecule belongs to the mucin membrane molecule family and is expressed on virtually all normal haematopoietic progenitor cells (HPC). Due to its heavy glycosylation, several different epitopes exist on the molecule. Based on the sensitivity of the glycosylated molecule to degradation with a glycoprotease from Pasteurella haemolytica and neuraminidase, three classes of epitopes have been identified. The class I and II epitopes are probably related to the glycosylated part of the molecule while class III epitopes are core protein related. It has been known for some time that CD34 class I epitopes are absent on CD34 molecules expressed on high endothelial venules. Here we review recent observations that expression of both class I and II epitopes, but not class III epitopes, is impaired on mature myeloid CD34-pos. HPC while no diverse class epitope expression was observed on immature HPC. In addition, cells from patients with CD34-pos. acute myeloid leukaemia of FAB classification M4-M5, i.e., leukaemic blast cells of relatively mature morphologic phenotype, also express less class I and II epitopes than class III epitopes. It therefore seems that HPC maturation and class I and II epitope deprivation are concomitant events and that CD34 class I and II epitopes are lost prior to downregulation of the CD34 molecule per se. The biological significance of this observation is discussed as well as the need to carefully select CD34-specific monoclonal antibodies for research and clinical purposes.

Antigens, CD34↗
PubMed1997

Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age.

BACKGROUND: Retrospective studies on the prevalence of posttransplant diabetes mellitus (PTDM) in patients on triple-drug immunosuppressive therapy have shown great dispersity, while the incidence of posttransplant impaired glucose tolerance (IGT) is unknown. The aim of our study was to prospectively examine the incidence of posttransplant glucose intolerance and to assess potential risk factors. METHODS: Glucose intolerance was prospectively examined in 173 consecutive kidney transplant recipients by oral glucose tolerance tests (n=167) or the diagnosis of manifest diabetes mellitus (n=6) at 10 weeks after transplant. RESULTS: We found a high incidence of PTDM (18%) and IGT (31%). Univariate analysis revealed that age, family history of diabetes, HLA-B27 phenotype, DR mismatch, rejection, actual prednisolone dose, total methylprednisolone dose, total steroid dose, cytomegalovirus (CMV) infection, and the use of furosemide were associated with PTDM. Age, prednisolone dose, CMV infection, and the use of beta-blockers were associated with IGT. Gender, body mass index, donor source, and cyclosporine level did not influence glucose tolerance. Prednisolone dose, age, family history of diabetes, CMV infection, and HLA-B27 phenotype were independent predictors of PTDM with the use of multiple stepwise logistic regression analysis. Age, prednisolone dose, and the use of a beta-blocker were associated with IGT in the multivariate model. Both univariate and multivariate linear regression analysis revealed a significant relationship between the 2-hr serum glucose and prednisolone dose. The risk of developing PTDM was 5% per 0.01 mg/kg/day of increase in prednisolone dose. CONCLUSIONS: Increased prednisolone dose and older age are strongly associated with the development of posttransplant glucose intolerance.

Adult↗
PubMed1997

The efficacy of single-dose administration of thrombopoietin with coadministration of either granulocyte/macrophage or granulocyte colony-stimulating factor in myelosuppressed rhesus monkeys.

Thrombopoietin (TPO) was evaluated for efficacy in a placebo-controlled study in rhesus monkeys with concurrent administration of either granulocyte/macrophage colony-stimulating factor (GM-CSF) or granulocyte CSF, (G-CSF). Rhesus monkeys were subjected to 5 Gy total-body irradiation (TBI), resulting in 3 weeks of profound pancytopenia, and received either TPO 5 microg/kg intravenously (I.V.) at day 1 (n = 4), GM-CSF 25 microg/kg subcutaneously (S.C.) for 14 days (n = 4), TPO and GM-CSF (n = 4), G-CSF 10 microg/kg/d S.C. for 14 days (n = 3), TPO and G-CSF (n = 4), or placebo (carrier, n = 4; historical controls, n = 8). Single-dose I.V. treatment with TPO 1 day after TBI effectively counteracted the need for thrombocyte transfusions (provided whenever thrombocyte levels were <40 x 10(9)/L) and accelerated platelet reconstitution to normal levels 2 weeks earlier than placebo controls. TPO/GM-CSF was more effective than single-dose TPO alone in stimulating thrombocyte regeneration, with a less profound nadir and a further accelerated recovery to normal thrombocyte counts, as well as a slight overshoot to supranormal levels of thrombocytes. Monkeys treated with TPO/GM-CSF uniformly did not require thrombocyte transfusions, whereas those treated with GM-CSF alone needed two to three transfusions, similar to the placebo-treated monkeys, which required, on average, three transfusions. Also, reticulocyte production was stimulated by TPO and further augmented in monkeys treated with TPO/GM-CSF. TPO alone did not stimulate neutrophil regeneration, whereas GM-CSF shortened the period of neutrophil counts less than 0.5 x 10(9)/L by approximately 1 week; TPO/GM-CSF treatment elevated the neutrophil nadir, but did not further accelerate recovery to normal values. TPO also augemented the neturophil response to G-CSF, resulting in similar patterns of reconstitution following TPO/G-CSF and TPO/GM-CSF treatment. TPO/GM-CSF resulted in significantly increased reconstitution of CD34+ bone marrow cells and progenitor cells such as GM-CFU and BFU-E. Adverse effects of combining TPO with the CSFs were not observed. It is concluded that (1) a single I.V. administration of TPO is sufficient to prevent severe thrombocytopenia following myelosuppression, (2) TPO/G-CSF and TPO/GM-CSF treatment result in distinct response patterns, with TPO/GM-CSF being superior to TPO/G-CSF in stimulating thrombocyte and erythrocyte recovery while being equivalent in stimulating neutrophil recovery; and (3) TPO significantly improves the performance of CSFs in alleviating severe neutropenia.

Animals↗
PubMed1997

Spatial training in a complex environment and isolation alter the spine distribution differently in rat CA1 pyramidal cells.

The hippocampus is critically involved in spatial learning. Spatial training in adult rats, which improved their spatial learning ability, increased the number of excitatory hippocampal CA1 spine synapses on basal dendrites as compared with either isolated or standardly housed animals (Moser et al. [1994] Proc. Natl. Acad. Sci. USA 91:12673-12675). In this article, we report that spine synapses on oblique apical dendritic branches do not increase in density or number after the same type of training. When examining the variability of the spine density on basal CA1 dendrites by using variance component analysis, the variance associated with the cells was twice as large in all three groups as that coupled to the rats. Analysis of the spine density plots shows that the enhanced spine density after spatial training is found in most cells recorded from the trained group but that a small subset of CA1 neurones are particularly well supplied with spines. The trained group had a significant right-skewed tail of the spine distribution, i.e., training caused high spine density to occur in a small subset of dendritic segments. Conversely, the isolated group had a significant left-skewed spine distribution, indicating that some of the dendritic segments were undersupplied with spines, whereas the paired group displayed no asymmetry.

Animals↗
PubMed1997

Hodgkin's disease in a national and hospital population: trends over 20 years.

The aim of the study was to investigate the incidence rate and time trends in a national registry population of Hodgkin's disease (HD) and the effects of selection in a hospital population. A national registry population of all HD patients from Norway and a hospital population of HD patients treated at the Norwegian Radium Hospital (NRH) were studied retrospectively from 1971 to 1993. The incidence of non-Hodgkin's lymphomas (NHL) in Norway increased steadily from 1961 in contrast to a stable incidence pattern for HD before 1980 and a decreasing incidence since 1980. Due to improved diagnostic tools after 1980, an increasing proportion of patients previously diagnosed as lymphocyte depleted and unclassified HD were classified as NHL. As these histologies are dominant in older patients, the incidence of older patients with HD and the total population of HD have decreased since 1980. As a result, the proportion of young adults with a favourable histology has increased. These changes may partly explain the increased patient survival observed both in the national and the hospital population. The hospital population comprised 92% of patients aged 15-39 years, 80% of patients aged 40-59 years and 53% of patients aged > 60 years in the national population. The selection of younger patients in the hospital material may explain a higher survival rate as compared with the national population.

Adolescent↗
PubMed1997

Efflux of CD34+ cells from bone marrow to peripheral blood is selective in steady-state hematopoiesis and during G-CSF administration.

Comparative studies of the CD34+ cell population in peripheral blood (PB) and bone marrow (BM) may contribute to understanding the mechanisms involved in mobilization of hematopoietic progenitor cells (HPCs) from BM to PB. PB-CD34+ and BM-CD34+ cells in steady-state hematopoiesis and during granulocyte colony-stimulating factor (G-CSF) administration were studied for the expression of activation-associated, lineage-associated and adhesion-associated molecules and for their cloning capacity [granulocyte-macrophage colony-forming cells (CFU-GM) and burst-forming unit-erythrocytes (BFU-E)]. G-CSF increased significantly the number of CD34+ cells in PB as well as in BM and resulted in a reduction of CD34+ cells coexpressing the adhesion-related molecule CD49d. Further, G-CSF reduced the relative number of lymphoid progenitors (CD34+ cells coexpressing CD10, CD19, CD20, CD2, or CD7) in both compartments. However, G-CSF had no major impact on the observed differences between PB-CD34+ and BM-CD34+ cells seen during steady-state hematopoiesis despite a relative decrease in PB and increase in BM of certain immature progenitors (CD34+DR- cells). Circulating CD34+ cells, even in steady-state, were enriched for colony-forming cells, and individual colonies appeared larger compared with their BM counterparts. PB-CD34+ cells contained relatively more myeloid progenitors (CD34+CD13+ cells) and fewer B lymphoid progenitors (CD10, CD19, and CD20 cells) than BM-CD34+ cells. CD34+DR-cells were present in a higher proportion of the CD34+ cells in PB than in BM. There were lower numbers of CD34+ cells expressing CD49d and c-kit in PB than in BM. To summarize, the differences between PB-CD34+ and BM-CD34+ cells observed during steady-state hematopoiesis were largely conserved during G-CSF administration. G-CSF, therefore, mainly has an effect on the quantity not the composition of the circulating CD34+ cell pool. Our data also suggest that the egress of HPCs from BM during steady-state hematopoiesis, as well as during G-CSF administration, is a selective process; that is, certain subsets are more prone to enter into circulation than others, and this release may be mediated via common pathway possibly involving downregulation of c-kit and VLA-4 (CD49d).

Antigens, CD34↗
PubMed1997

Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients.

PURPOSE: We report survival, prognostic factors, and treatment efficacy in low-grade glioma. PATIENTS AND METHODS: A total of 379 patients with histologic intracranial low-grade glioma received post-operative radiotherapy (n = 361) and intraarterial carmustine (BCNU) chemotherapy (n = 153). Overall survival and prognostic factors were evaluated with the SPSS statistical program (SPSS Inc, Chicago, IL). RESULTS: Median survival (all patients) was 100 months (95% confidence interval [CI], B7 to 113); in age group 0 to 19 years (n = 41), 226 months; in age group 20 to 49 years (n = 263), 106 months; in age group 50 to 59 years (n = 49), 76 months; and for older patients (n = 26), 39 months. Projected survival at 10 and 15 years was 42% and 29%, respectively. Patient age, World Health Organization (WHO) performance status, tumor computed tomography (CT) contrast enhancement, mental changes, or initial corticosteroid dependency were significant independent prognostic factors (p < .05), while histologic subgroup, focal deficits, presence of seizures, prediagnostic symptom duration, tumor category, and tumor stage were not. Patients aged 20 to 49 years with no independent negative prognostic factors (n = 132) had a median survival time of 139 months versus 41 months in patients with two or more factors (n = 33). Patients who presented with symptoms of expansion (n = 97) survived longer when resected (P < .03); otherwise no survival benefit was associated with initial tumor resection compared with biopsy. Intraarterial chemotherapy and radiation doses more than 55 Gy were not associated with prolonged survival. Among 66 reoperated patients, 45% progressed to high-grade histology within 25 months. CONCLUSION: Prognosis in low-grade glioma following postoperative radiotherapy seems largely determined by the inherent biology of the glioma and patient age at diagnosis.

Adolescent↗
PubMed1997

Lack of efficacy of thrombopoietin and granulocyte colony-stimulating factor after high dose total-body irradiation and autologous stem cell or bone marrow transplantation in rhesus monkeys.

The efficacy of recombinant human thrombopoietin (TPO) and recombinant human granulocyte colony stimulating factor (G-CSF) in stimulating platelet and neutrophil recovery was evaluated in a placebo-controlled study involving transplantation of limited numbers (1-3 x 10(4)/kg) of highly purified autologous stem cells (CD34++/RhLA-DR[dull]) into rhesus monkeys after the animals were subjected to 8 Gy of total body irradiation (TBI) (x-rays). The grafts shortened profound TBI-induced pancytopenia from 5 to 6 weeks to 3 weeks. Daily subcutaneous (sc) injection of TPO (10 microg/kg/day, days 1-21 after TBI) did not stimulate platelet regeneration after transplantation either alone or in combination with G-CSF (5 microg/kg/day sc, days 1-21 after TBI). G-CSF treatment failed to prevent neutropenia in the monkeys and did not stimulate recovery to normal neutrophil levels. Simultaneous administration of TPO and G-CSF did not influence the observed recovery patterns. To test the hypothesis that the limited number of cells transplanted or the subset chosen was responsible for the lack of effectiveness of TPO, three additional monkeys were transplanted with 10(7)/kg unfractionated autologous bone marrow cells. Two of these animals received TPO and the other served as a control. In this setting, as well, TPO treatment did not prevent thrombocytopenia. This study demonstrates that treatment with TPO does not accelerate platelet reconstitution from transplanted stem cells after high-dose TBI. These findings contrast with the rapid TPO-stimulated platelet recovery in myelosuppression induced by 5 Gy of TBI in rhesus monkeys; we conclude from this that the clinical effectiveness of the TPO response depends on the availability of TPO target cells in the first week after TBI, that is, before endogenous TPO levels reach the saturation point. In addition, protracted isolated thrombocytopenia was observed in two G-CSF-treated monkeys, one of which also received TPO. Furthermore, TPO treatment for 7 days in the 6th week after TBI during severe thrombocytopenia in one monkey produced prompt clinical improvement and an increase in platelet counts.

Animals↗
PubMed1996

Differences in the distribution of CD34 epitopes on normal haemopoietic progenitor cells and leukaemic blast cells.

The CD34 molecule expressed on haemopoietic progenitor cells contains a large number of epitopes whose expression may be related to the maturation or function of the cells. Monoclonal antibodies specific for different epitopes have been reported to detect different numbers of CD34+ leukaemic blast cells. We wanted to confirm this observation and study whether parallel findings could be observed for normal haemopoietic progenitor cells. The cells were immunophenotyped by flow cytometry with a series of monoclonal antibodies reactive with different CD34 epitopes. Class III epitopes (resistant to enzymatic cleavage with neuraminidase, chymopapain and a glycoprotease from Pasteurella haemolytica) showed a broader distribution on normal haemopoietic progenitor cells and leukaemic blast cells than class I epitopes (sensitive to cleavage with all three enzymes) and class II epitopes (sensitive to degradation with glycoprotease and chymopapain, and resistant to neuraminidase). The subpopulation of normal progenitor cells which exclusively expressed class III epitopes had flow cytometric characteristics compatible with mature myeloid progenitor cells whereas class I, II and III epitopes were equally expressed on cells enriched for immature subsets. No discordant epitope expression could be observed for the more immature leukaemias (AML-M0/1) and a higher percentage of the more mature leukaemic blast cells (AML-M3 and AML-M4/5) expressed class III epitopes compared to the percentage expressing class I and II epitopes. These data indicate that CD34 class III epitopes are more broadly distributed on normal haemopoietic progenitor cells and leukaemic blast cells than class I and II epitopes, and that class I and II epitopes may be down-regulated prior to class III epitopes during normal haemopoietic progenitor cell differentiation. These findings should be considered when selecting CD34 mabs for quantification and positive selection of haemopoietic progenitor cells for research and clinical purposes.

Acute Disease↗
PubMed1996

Lineage commitment of CD34+ human hematopoietic progenitor cells.

Hematopoietic cells occur in a continuum of many different stages of functional differentiation, from totipotential stem cells to terminally differentiated lineage-specific cells. At some point during differentiation, progenitor cells become committed to a particular lineage. Little is known about the surface molecules that distinguish lineage-committed progenitor cells from multipotential progenitor cells; this study was undertaken to address this issue. Exploiting a thymic stromal cell co-culture system, we show that CD34+ bone marrow cells expressing the T lymphocyte-associated CD2 and CD7 molecules, the B lymphocyte-associated CD10 and CD19, or the myeloid-associated CD33, contain progenitor cells that can generate T lymphocytes, granulocytes, and monocytes, indicating that the expression of any of these molecules on progenitor cells does not imply lineage commitment. CD34+CD13bright, CD34+CD14+, and CD34+CD15+ cells generated myeloid progeny, and CD34+CD20+ cells failed to differentiate along the T lymphoid and myeloid lineages. Thus expression of CD13, which precedes that of CD14 and CD15 during early hematopoiesis, appears to coincide with commitment to myeloid development. Our findings also indicate that expression of CD20 is restricted to progenitor cells committed to B lymphocyte development.

Adult↗
PubMed1996

Mutation rate in the hypervariable VNTR g3 (D7S22) is affected by allele length and a flanking DNA sequence polymorphism near the repeat array.

The hypervariable human minisatellite locus D7S22 (g3) is highly polymorphic. The allelic distribution in D7S22 features a size clustering of the alleles and a comparably low allelic diversity among small alleles. This reduced diversity could reflect a situation where some alleles are less likely to mutate than others. Several factors could explain such an effect, including allele size, variation in repeat composition, and allelic differences in nearby cis-acting elements affecting the mutation rate. We have characterized 40 de novo mutations found on Southern blots in a large amount of paternity-testing material. There is a significant excess of paternal mutations, and small size changes are most frequent. Mutation rate is affected by allele length, with highest rates in larger alleles. Alleles of the family groups with D7S22 mutations and 50 small alleles were analyzed by nucleotide sequencing. Two hundred thirty-six base pairs of the immediate flanking region upstream of the repeat array were PCR amplified and screened for point mutations by DNA sequencing of the PCR products. Two base substitution polymorphisms were identified: one C/G transversion and one A/G transition, 54 bp and 173 bp upstream of the repeat array, respectively. There is a significant association between mutation and occurrence of 54C, while association is not obvious between mutation rate and the 173A/G variants. There is a marked association between different flanking haplotypes and allele size, and within the smallest allele-size group, all alleles had the 54G/173A haplotype. Both allele size and allelic state at site 54 remain associated with mutation rate when the other factor is controlled. Possible mechanisms behind the variation in mutation rate in D7S22 are discussed.

Alleles↗