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Biomedical subjects

J V Neel

Publications and source records attributed to J V Neel.

At least 19 recordsLinked to original sources
PubMed1992

"Rogue" lymphocytes among Ukrainians not exposed to radioactive fall-out from the Chernobyl accident: the possible role of this phenomenon in oncogenesis, teratogenesis, and mutagenesis.

Cultured lymphocytes exhibiting extreme cytogenetic damage (rogue cells) were observed in preparations from 8 of 24 individuals sampled in Krasilovka, a Ukrainian village receiving little or no increased radiation after the Chernobyl disaster, but were not observed in an additional 24 persons from two Russian towns in the more contaminated area. This observation cements the worldwide occurrence of these cells. The present data plus a review of the literature establish that rogue cells appear in brief bursts simultaneously in certain individuals of discrete populations. We suggest that the pattern is consistent with the action of a viral trigger that acts directly or indirectly--the latter possibly through the activation of latent chromosomal retroposons. If this phenomenon occurs in other tissues, it may have important implications for oncogenesis, teratogenesis, mutagenesis, and evolution.

Accidents↗
PubMed1992

Similarity of spontaneous germinal and in vitro somatic cell mutation rates in humans: implications for carcinogenesis and for the role of exogenous factors in "spontaneous" germinal mutagenesis.

The rate of spontaneous mutation resulting in electrophoretic variants per cell generation in a human lymphoblastoid cell line, on the basis of experiments described in this paper, is found to be 7.2 x 10(-8) per locus. A review of similar data on electrophoretic variants resulting from spontaneous mutation in the human germ line leads to an estimate of 3.3 x 10(-8) per locus per cell generation. It is argued that the similarity of these two estimates, despite an average cell generation time of 18.5 hr for the cultured somatic cells but about 26 days in the germ line, suggests that spontaneous mutation involving nucleotide substitutions is much more dependent on cell generation than on time. This finding permits the inference that environmental (exogenous) variables make a relatively small contribution to the rate of this type of human germinal spontaneous mutation. While in vitro somatic-cell mutation rates, such as derived in this study, provide a basis for modeling the contribution of nucleotide substitutions in multihit/clonal theories of carcinogenesis, it is also argued that the complex of events involved in carcinogenesis, including chromosomal rearrangements and mitotic recombination, could have very different individual probabilities. Estimates for the rates of these other types of mutation are needed to provide a better understanding of the manner in which multiple mutations accumulate in malignant cells.

Alleles↗
PubMed1992

Endemic human T cell lymphotropic virus type II infection among isolated Brazilian Amerindians.

Evidence for human T cell lymphotropic viruses (HTLV) was sought in sera and cells collected from adults in 13 isolated South and Central American Indian tribes. Serologic tests identified frequent HTLV-II-like reactivity among the Cayapo and Kraho tribes, who live 330 km apart in Central Brazil. Polymerase chain reaction analyses of viral DNA in cell pellet and plasma fractions confirmed the virus as HTLV-II. Both tribes speak Gé and, at the time of blood collection (1974), subsisted as hunter/gatherers and slash and burn agriculturalists. Further testing of plasma from Cayapo and Kraho of all ages revealed overall HTLV-II prevalence rates of 33.3% and 12.2%, respectively, with increasing prevalence associated with age and female gender. These data reveal for the first time a high prevalence of HTLV-II infection in remote South American Indians with little contact with non-Indians. Thus, HTLV-II is postulated to be an ancient human virus in the New World.

Adult↗
PubMed1992

Microevolution of the Chibcha-speaking peoples of lower Central America: rare genes in an Amerindian complex.

Models are developed for the survival, history, and spread of variant alleles, in order to consider what can, and what cannot, be inferred from this type of data. The high variances of the processes involved, and questions of sampling, place severe limitations on inferences. Nonetheless, by combining information on a number of rare variants observed in a group of interrelated populations, reliable qualitative inferences are possible. These ideas and models are developed in the context of data on five rare variants and six private polymorphisms observed in eight Chibcha-speaking tribes of Costa Rica and Panama. The decline and fragmentation of the Amerindian populations of Central America over the last 300 years create considerable difficulties in attempting inference of past genetic events. However, these tribes have been well studied genetically, anthropologically, and linguistically and thus provide an excellent framework for the study of rare-variant spread.

Biological Evolution↗
PubMed1991

Highly resolving two-dimensional gels for protein sequencing.

Two-dimensional (2D) PAGE, using carrier ampholytes for the first-dimension separation, has provided a tool for the simultaneous analysis of cellular proteins. To extend the utility of 2D PAGE to the preparative level, we have investigated the use of immobilized pH gradients (IPG) for the first-dimension separation. The results we have obtained indicate that as much as 1 mg of cellular protein can be loaded onto a single IPG gel without loss of resolution. Mutant polypeptides previously detected in carrier ampholyte-based 2D gels were equally detectable in IPG-based 2D gels. With IPG gels several hundred cellular polypeptides can be isolated, from as few as 10 gels, in sufficient amount for sequencing with current sequencing technology. We therefore conclude that IPG greatly enhances the prospects for the large-scale sequencing of cellular proteins for the development of 2D gel-related protein data bases and for the identification of new polypeptide gene products, with the attendant implications for a genome sequencing effort.

Amino Acid Sequence↗
PubMed1991

A two-dimensional electrophoresis-related laboratory information processing system: spot matching.

An approach for the computer-assisted analysis of two-dimensional gels has been developed as a part of our laboratory information processing system (LIPS). This approach relies in part on an algorithm for the pairwise matching of protein spots. The matching process initially matches spots based on a cross-correlational measure of how well neighboring spots align. While this first pass correctly determines most spot correspondences and noncorrespondences, it can make errors. Higher accuracy is obtained by monitoring the consistency of spot match decisions in a second pass, which demands that neighboring spot pairs that align spatially must also have been found to match in the first pass. Pairwise comparisons of gels are combined into n-way comparisons by matching spot lists of gels to "master" gel spot lists, which in turn are matched to higher level masters, resulting in a hierarchy of matched spots. After each pairwise match the results are reviewed and corrected with the assistance of a graphical match-editor. Results are given for 19 single-cell-derived lymphoid clones in which the presence of a mutation had previously been established, each processed in duplicate. Only one of 46 spot changes failed to be detected, which demonstrates that the strategy is sensitive and efficient for detecting qualitative spot differences.

Algorithms↗
PubMed1991

Mortality among the offspring (F1) of atomic bomb survivors, 1946-85.

We compare the mortality in the years 1946-85 in a cohort of 31,159 children born to parents one or both of whom were exposed to the atomic bombing of Hiroshima and Nagasaki (a parental gonadal dose greater than or equal to 0.01 Sv) with that in a control group of 41,069 children. The average gonadal dose for the exposed parents was 0.435 Sv. The mean age of the cohorts was 28.8 years. In the greater than or equal to 0.01 Sv dose group 1,253 deaths were observed in the subset of children both of whose parents have been assigned DS86 doses. 3.2% were attributed to cancers, 72.9% to all diseases except neoplasms. These proportions in the 0 Sv dose group were about the same. Based on a linear relative risk model, no statistically significant increase in the mortality attributable to diseases other than neoplasms is noted following parental exposure, the excess relative risk being 0.030 (+/- 0.046) per sievert based on the DS86 doses (RBE of neutrons = 20). For fatal cancer, no statistically significant effect of parental radiation dose was also observed. An analysis based on the full sample, using not only the DS86 dose group but also ad hoc dose group, yields essentially the same results as the analysis restricted to the DS86 dose group.

Adult↗
PubMed1990

Average locus differences in mutability related to protein "class": a hypothesis.

Substantially less genetic variation has been recognized in studies of the proteins of nucleated cells by the technique of two-dimensional polyacrylamide gel electrophoresis than has been encountered in studies of serum transport proteins and erythrocyte enzymes with one-dimensional electrophoresis. Technical factors appear to account for only part of the difference. The two remaining (nonexclusive) explanations are more stringent biological selection against variants of these proteins or lower mutation rates at the loci encoding the proteins visualized with two-dimensional electrophoresis. While the former possibility cannot be rigorously excluded, the evidence suggests the latter hypothesis merits serious consideration. Some consequences of this latter suggestion for genetic monitoring and the interpretation of molecular evolution are mentioned.

Biological Evolution↗
PubMed1990

Malignant tumors during the first 2 decades of life in the offspring of atomic bomb survivors.

The risk of cancer (incidence) prior to age 20 years has been determined for children born to atomic bomb survivors and to a suitable comparison group. Tumor ascertainment was through death certificates and the tumor registries maintained in Hiroshima and Nagasaki. The rationale for the study stemmed from the evidence that a significant proportion of such childhood tumors as retinoblastoma and Wilms tumor arise on the basis of a mutant gene inherited from one parent plus a second somatic cell mutation involving the allele of this gene. Gonadal radiation doses were calculated by the recently established DS86 system, supplemented by an ad hoc system for those children for one or both of whose parents a DS86 dose could not be computed but for whom an ad hoc dose could be developed on the basis of the available information. The total data set consisted of (1) a cohort of 31,150 live-born children one or both of whose parents received greater than 0.01 Sv of radiation at the time of the atomic bombings (average conjoint gonad exposure 0.43 Sv) and (2) two suitable comparison groups totaling 41,066 children. Altogether, 43 malignant tumors were ascertained in the children of exposed parents, and 49 malignant tumors were ascertained in the two control groups. A multiple linear regression analysis revealed no increase in malignancy in the children of exposed parents. However, examination of the data suggested that only 3.0-5.0% of the tumors of childhood that were observed in the comparison groups are associated with an inherited genetic predisposition that would be expected to exhibit an altered frequency if the parental mutation rate were increased. There is thus far no confirmation of the positive findings that Nomura found in a mouse system.

Adolescent↗
PubMed1990

Microevolution in lower Central America: genetic characterization of the Chibcha-speaking groups of Costa Rica and Panama, and a consensus taxonomy based on genetic and linguistic affinity.

There is evidence that Amerindians have continuously occupied the lower Central American Isthmus for as long as 10,000 years. There remains some doubt about the relationships of these original colonizers to the resident peoples of this zone at the time of European contact (approximately A.D. 1500). We present new genetic data for up to 48 genetic loci for 570 members of six Chibcha-speaking tribes of lower Central America--the Boruca, Bribri, Cabecar, and Guatuso of Costa Rica and the Kuna and Teribe of Panama--and delineate the genetic affinities among the various groups (these six tribes and the Guaymi and Bokota) of lower Central America. We convert standard genetic distance metrics into a form that is linear with the effective time since divergence, and we compare the genetic distances with linguistic distances for the same groups (r = .74, P less than .001). Geographic affinity accounts for some of the genetic divergence among groups (r = .49, P less than .084) and for some of the linguistic divergence (r = .53, P less than .037), but the correspondence between geographic position and taxonomic affinity is not high. We combine all of the genetic and linguistic data to construct a synthetic overview taxonomy of the lower Central American Chibcha. Both the genetic and linguistic data exhibit hierarchical organization of tribal groups, showing a general east-to-west pattern of grouping, with greater affinities between close neighbors. The presence of private genetic variants of some antiquity within the region and their absence outside the zone, coupled with the essential absence of the DI*A polymorphism of mongoloid origin that is widespread outside the zone, argue for a relatively isolated development of the Central American Chibcha. Our results do not support the old view of lower Central America as a frontier between more advanced cultures to the north and south. Any such explanation would require recent waves of migration from outside the region, migration that is not compatible with either the genetic or linguistic data or with the archaeological history of the region.

Alleles↗
PubMed1990

Congenital malformations, stillbirths, and early mortality among the children of atomic bomb survivors: a reanalysis.

Of all the data sets pertinent to the estimation of the genetic risks to humans following exposure to ionizing radiation, potentially the most informative is that composed of the cohort of children born to atomic bomb survivors. We present here an analysis of the relationship between parental exposure history and untoward pregnancy outcomes within this cohort, using to the fullest extent possible the recently revised estimates of the doses received by their parents, the so-called DS86 doses. Available for study are 70,073 terminations, but DS86 doses have not been or presently cannot be computed on the parents of 14,770. The frequency of untoward pregnancy outcomes, defined as a pregnancy terminating in a child with a major congenital malformation, and/or stillborn, and/or dying in the first 14 days of life, increases with combined (summed) parental dose, albeit not significantly so. Under a standard linear model, when the sample of observations is restricted to those children whose parents have been assigned the newly established DS86 doses (n = 55,303), ignoring concomitant sources of variation and assuming a neutron RBE of 20, the estimated increase per sievert in the predicted frequency of untoward outcomes is 0.00354 (+/- 0.00343). After adjustment for concomitant sources of variation, the estimated increase per sievert in the proportion of such births is 0.00422 (+/- 0.00342) if the neutron RBE is assumed to be 20. A "one-hit" model with appropriate adjustments for extraneous sources of variation results in an almost identical value, namely, 0.00412 (+/- 0.00364). When the sample is extended to include parents lacking the full array of dose parameters necessary to calculate the DS86 dose, but sufficient for an empirical conversion of the previously employed T65DR dose system to its DS86 equivalent, we find under the linear model that the estimated increase per sievert in untoward pregnancy outcomes is some 31% higher than that published previously, 0.00264 (+/- 0.00277), assuming an RBE of 20, after adjustment for extraneous sources of variation. (Since a dose could not be calculated in 367 of the 70,073 outcomes, the n = 69,706). The corresponding value with the one-hit model is 0.00262 (+/- 0.00294).

Cohort Studies↗
PubMed1990

The children of parents exposed to atomic bombs: estimates of the genetic doubling dose of radiation for humans.

The data collected in Hiroshima and Nagasaki during the past 40 years on the children of survivors of the atomic bombings and on the children of a suitable control population are analyzed on the basis of the newly revised estimates of radiation doses. No statistically significant effects emerge with respect to eight different indicators. Since, however, it may confidently be assumed some mutations were induced, we have taken the data at face value and calculated the minimal gametic doubling doses of acute radiation for the individual indicators at various probability levels. An effort has also been made to calculate the most probable doubling dose for the indicators combined. The latter value is between 1.7 and 2.2 Sv. It is suggested the appropriate figure for chronic radiation would be between 3.4 and 4.5 Sv. These estimates suggest humans are less sensitive to the genetic effects of radiation than has been assumed on the basis of past extrapolations from experiments with mice.

Aneuploidy↗