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J V Neel

Publications and source records attributed to J V Neel.

At least 91 records · Page 5Linked to original sources
PubMed1988

Estimation of mutation rates based on the analysis of polypeptide constituents of cultured human lymphoblastoid cells.

A subclone of a human diploid lymphoblastoid cell line, TK-6, with consistently high cloning efficiency has been used to estimate the rates of somatic mutations on the basis of protein variation detected by two-dimensional polyacrylamide gel electrophoresis. A panel of 267 polypeptide spots per gel was screened, representing the products of approximately 263 unselected loci. The rate of human somatic mutation in vitro was estimated by measuring the proportion of protein variants among cell clones isolated at various times during continuous exponential growth of a TK-6 cell population. Three mutants of spontaneous origin were observed, giving an estimated spontaneous rate of 6 x 10(-8) electrophoretic mutations per allele per cell generation (i.e., 1.2 x 10(-7) per locus per cell generation). Following treatment of cells with N-ethyl-N-nitrosourea, a total of 74 confirmed variants at 54 loci were identified among 1143 clones analyzed (approximately 601,000 allele tests). The induced variants include 65 electromorphs which exhibit altered isoelectric charge and/or apparent molecular weight and nine nullimorphs for each of which a gene product was not detected at its usual location on the gel. The induced frequency for these 65 structural gene mutants is 1.1 x 10(-4) per allele. An excess of structural gene mutations at ten known polymorphic loci and repeat mutations at these and other loci suggest nonrandomness of mutation in human somatic cells. Nullimorphs occurring at three heterozygous loci in TK-6 cells may be caused by genetic processes other than structural gene mutation.

Cell Line↗
PubMed1988

Population amalgamation and genetic variation: observations on artificially agglomerated tribal populations of Central and South America.

The interpretation of data on genetic variation with regard to the relative roles of different evolutionary factors that produce and maintain genetic variation depends critically on our assumptions concerning effective population size and the level of migration between neighboring populations. In humans, recent population growth and movements of specific ethnic groups across wide geographic areas mean that any theory based on assumptions of constant population size and absence of substructure is generally untenable. We examine the effects of population subdivision on the pattern of protein genetic variation in a total sample drawn from an artificial agglomerate of 12 tribal populations of Central and South America, analyzing the pooled sample as though it were a single population. Several striking findings emerge. (1) Mean heterozygosity is not sensitive to agglomeration, but the number of different alleles (allele count) is inflated, relative to neutral mutation/drift/equilibrium expectation. (2) The inflation is most serious for rare alleles, especially those which originally occurred as tribally restricted "private" polymorphisms. (3) The degree of inflation is an increasing function of both the number of populations encompassed by the sample and of the genetic divergence among them. (4) Treating an agglomerated population as though it were a panmictic unit of long standing can lead to serious biases in estimates of mutation rates, selection pressures, and effective population sizes. Current DNA studies indicate the presence of numerous genetic variants in human populations. The findings and conclusions of this paper are all fully applicable to the study of genetic variation at the DNA level as well.

Alleles↗
PubMed1988

Protein variants in Hiroshima and Nagasaki: tales of two cities.

The results of 1,465,423 allele product determinations based on blood samples from Hiroshima and Nagasaki, involving 30 different proteins representing 32 different gene products, are analyzed in a variety of ways, with the following conclusions: (1) Sibships and their parents are included in the sample. Our analysis reveals that statistical procedures designed to reduce the sample to equivalent independent genomes do not in population comparisons compensate for the familial cluster effect of rare variants. Accordingly, the data set was reduced to one representative of each sibship (937,427 allele products). (2) Both chi 2-type contrasts and a genetic distance measure (delta) reveal that rare variants (P less than .01) are collectively as effective as polymorphisms in establishing genetic differences between the two cities. (3) We suggest that rare variants that individually exhibit significant intercity differences are probably the legacy of tribal private polymorphisms that occurred during prehistoric times. (4) Despite the great differences in the known histories of the two cities, both the overall frequency of rare variants and the number of different rare variants are essentially identical in the two cities. (5) The well-known differences in locus variability are confirmed, now after adjustment for sample size differences for the various locus products; in this large series we failed to detect variants at only three of 29 loci for which sample size exceeded 23,000. (6) The number of alleles identified per locus correlates positively with subunit molecular weight. (7) Loci supporting genetic polymorphisms are characterized by more rare variants than are loci at which polymorphisms were not encountered. (8) Loci whose products do not appear to be essential for health support more variants than do loci the absence of whose product is detrimental to health. (9) There is a striking excess of rare variants over the expectation under the neutral mutation/drift/equilibrium theory. We suggest that this finding is primarily due to the relatively recent (in genetic time) agglomeration of previously separated tribal populations; efforts to test for agreement with the expectations of this theory by using data from modern cosmopolitan populations are exercises in futility. (10) All of these findings should characterize DNA variants in exons as more data become available, since the finding are the protein expression of such variants.

Alleles↗
PubMed1988

Search for mutations altering protein charge and/or function in children of atomic bomb survivors: final report.

A sample of (1) children whose parents had been proximally exposed (i.e., less than 2,000 m from the hypocenter) at the time of the atomic bombings of Hiroshima and Nagasaki and (2) a suitable comparison group have been examined for the occurrence of mutations altering the electrophoretic mobility or activity of a series of 30 proteins. The examination of the equivalent of 667,404 locus products in the children of proximally exposed persons yielded three mutations altering electrophoretic mobility; the corresponding figure for the comparison group was three mutations in 466,881 tests. The examination of a subset of 60,529 locus products for loss of enzyme activity in the children of proximally exposed persons yielded one mutation; no mutations were encountered in 61,741 determinations on the children of the comparison group. When these two series are compared, the mutation rate observed in the children of proximally exposed persons is thus 0.60 x 10(-5)/locus/generation, with 95% confidence intervals between 0.2 and 1.5 x 10(-5), and that in the comparison children is 0.64 x 10(-5)/locus/generation, with 95% intervals between 0.1 and 1.9 x 10(-5). The average conjoint gonad doses for the proximally exposed parents are estimated to be 0.437 Gy of gamma radiation and 0.002 Gy of neutron radiation. If a relative biological effectiveness of 20 is assigned to the neutron radiation, the combined total gonad dose for the parents becomes 0.477 Sv. (Organ absorbed doses are expressed in gray [1 Gy = 100 rad]; where dose is a mixture of gamma and neutron radiation, it is necessary because of the differing relative biological effectiveness of gamma and neutron radiation to express the combined gamma-neutron gonad exposures in sieverts [1 Sv = 100 rem]).

Enzymes↗
PubMed1987

Amino acid substitutions in inherited albumin variants from Amerindian and Japanese populations.

We report an effort to determine the basis for the altered migration of seven inherited albumin variants detected by one-dimensional electrophoresis in population surveys involving tribal Amerindians and Japanese children. An amino acid substitution has thus far been determined for four of the variants. The randomness in the albumin polypeptide of these and the other sixteen independently ascertained amino acid substitutions of albumin and proalbumin thus far established was analyzed; the clustering of eight of these at two positions in the six-amino acid propeptide sequence seems noteworthy. By comparison with other proteins studied by electrophoresis, albumin exhibits "average" variability. It is a paradox that individuals who, for genetic reasons, lack albumin exhibit no obvious ill effects; yet, electrophoretic variants of albumin are no more numerous than are variants of proteins, the absence of which results in severe disease.

Albumins↗
PubMed1987

Frequency and distribution of rare electrophoretic mobility variants in a population of human newborns in Ann Arbor, Michigan.

We have summarized the frequency and distribution of the rare variants encountered during the screening of 258,815 allele products, the products of 51 different loci, in 3242 predominantly Caucasian (88%) newborns. Seventy-nine different rare variants, representing 187 occurrences, were identified. Almost 60% (46 of 79) of the rare variants occurred as singletons while another 20% were seen in two unrelated individuals. No rare variants were detected at 18 loci while no variants, either rare or polymorphic, were detected at 14 loci. More rare variants were identified at loci that were classified as polymorphic and also at loci where the gene products exist as a monomer. A positive relationship was observed between variant frequency, either classes or copies, and subunit molecular mass.

Alleles↗
PubMed1986

Gene flow across tribal barriers and its effect among the Amazonian Içana river Indians.

Demographic information was obtained from 622 individuals of five communities of primarily Baniwa Amerindians living near the Içana river in Brazil. Four of these populations, plus another from the same area, were also studied genetically. The latter investigation included the blood and, in some cases, saliva of 531 subjects, variously tested in relation to 40 genetic systems. Demographically these groups are characterized by young age, high intertribal admixture, low non-Indian admixture, high exogamy but low marital distance and high inbreeding, high fertility but low variance in offspring number, and relatively low mortality. Their gene pool shows a peptidase B variant (PEPB2BAN1) and "private" polymorphism of carbonic anhydrase2 (CA2BAN1) until now observed only among them. Other distinctive characteristics are the low frequencies of LNS (0.08), LNs (0.09), RZ (0.01), RO or r(0.02), ACPA (0.08), GALTD (0.01), and the relatively high prevalences of Gm (0.05) and Gc1 (0.82). TfDchi occurs with a low prevalence (0.01). Genetic distance analysis reveals that the one Baniwa sample by history comprised of minimally admixed individuals is quite similar genetically to the Wapishana, another Arawak-speaking tribe some 900 km to the east, and that the genetic distances between the Baniwa communities reflect the amount of historical admixture in a way that indicates which should be excluded from considerations of intertribal genetic distances. Finally, the genetic relation of the Baniwa to the nearby tribes is examined.

Adolescent↗
PubMed1986

An algorithm for comparing two-dimensional electrophoretic gels, with particular reference to the study of mutation.

An algorithm dedicated to the detection of presumed mutational events involving the polypeptides displayed with two-dimensional polyacrylamide gel electrophoresis has been described. Because of the large number of gels necessary in most studies of mutation, the algorithm has been designed to minimize operator intervention in its execution. The basic principle involves a comparison of the graph structures of the gels of a father, mother, and one or more children, searching for protein spots in the child not found in either parent. These so-called "orphan" spots are considered a probable manifestation of mutation only after other possible causes of such an isolated event have been excluded as rigorously as possible. At present, the analysis of gels prepared from a platelet or erythrocyte lysate yields about 2% "false-positive" findings, i.e., results in the incorrect designation of a unique spot in a child. These errors can be disposed of by technician intervention. In an experiment designed to simulate the occurrence of mutational events, the algorithm operated with 70% accuracy. Most of the "errors" ("false negatives") occurred when the position of the simulated mutant polypeptide coincided in whole or part with that of a preexisting polypeptide, resulting in a class of mutation not detectable by the eye either. With correction for this fact, the accuracy was 84%. Possible improvements in the algorithm which would substantially increase accuracy have been discussed at some length, as have some ideas as to how to manage the large body of data resulting from the operation of the algorithm. A murine experiment designed to validate the approach has been outlined.

Blood Proteins↗
PubMed1986

The rate with which spontaneous mutation alters the electrophoretic mobility of polypeptides.

Studies of a Japanese population, involving a total of 539,170 locus tests distributed over 36 polypeptides, yielded three presumptive spontaneous mutations altering the electrophoretic mobility of the polypeptide. This corresponds to a mutation rate of 0.6 X 10(-5) per locus per generation. The a priori probability that undetected discrepancies between legal and biological parentage might in our test system result in an apparent electrophoretic mutation in this population is calculated to be only 0.3 X 10(-7) per locus per generation. Since electrophoresis only detects about half of the amino acid substitutions due to mutations of nucleotides, the corrected rate for mutations causing amino acid substitutions in polypeptides is 1.2 X 10(-5) per locus per generation. With allowance for synonymous mutations and those resulting in stop codons, the total mutation rate for nucleotide changes in the exons encoding a polypeptide becomes approximately equal to 1.8 X 10(-5) per locus per generation. When the present observations are combined with all of the other available data concerning mutation resulting in electrophoretic variants, the electrophoretic rate drops to 0.3 X 10(-5) per locus per generation, the total locus rate drops to roughly 1.0 X 10(-5), and the nucleotide rate drops to 1 X 10(-8). Even with this lower estimate, given approximately equal to 2 X 10(9) nucleotides in the haploid genome and an average of 10(3) exon nucleotides per polypeptide encoded, the implication, if these exon rates can be generalized, is of approximately equal to 20 nucleotide mutations per gamete per generation. This estimate of the frequency of "point" mutations does not include small duplications, rearrangements, or deletions resulting from unequal crossing-over, transcription errors, etc.

Child↗
PubMed1986

Cytogenetic "rogue" cells: what is their frequency, origin, and evolutionary significance?

Among 102,170 cultured lymphocytes obtained from 9818 individuals from Hiroshima, Japan, aged 9 to 37 years and scored for chromosomal abnormalities, 24 cells that exhibited an extreme degree of damage were encountered. The damage consists of multiple dicentric and even tricentric chromosomes, as well as numerous fragments, many with the appearance of "double minutes." The occurrence of these cells was not correlated with parental exposure to the atomic bomb, age, sex, year, or season. They were nonrandomly distributed by individual. Such cells were originally described in South American Indians and have also been recorded in inhabitants of the United States and the United Kingdom; this appears to be a world-wide phenomenon. Their cause remains unknown, and it is not known whether they occur in other somatic and germ-line cells. Should the latter be the case and should the least damaged of these cells occasionally successfully complete mitosis and meiosis, the possible role of such cells in oncogenesis and evolution must be considered.

Adolescent↗
PubMed1986

The genetic structure of a tribal population, the Yanomama Indians. XV. Patterns inferred by autocorrelation analysis.

Fifteen allele frequencies have previously been determined for 50 villages of the Yanomama, an Amerindian tribe from southern Venezuela and northern Brazil. These frequencies were subjected to spatial autocorrelation analysis to investigate their population structure. There are significant spatial patterns for most allele frequencies. Clinical patterns, investigated by one-dimensional and directional spatial correlograms, were relatively few in number and were moderate in strength. Overall, however, there is a marked decline in genetic similarity with geographic distance. The results are compatible with a hierarchic population structure superimposed on the geography, and generated by a stochastic fission-fusion model of village propagation, followed by localized gene flow. Strong temporal autocorrelations of allele frequencies based on linguistic-historical distances representing time since divergence were also found. There appears to be a stronger relation between geography and linguistic-historical hierarchic subdivisions than between either feature and genetic distances. These findings confirm by different approaches the results of earlier analyses concerning the important roles of both stochastic and social factors in determining village allele frequencies and the occurrence within this tribe of some allele frequency clines most likely due to the operation of chance historical processes.

Alleles↗
PubMed1986

Inherited electrophoretic variants detected in a Japanese population with two-dimensional gels of erythrocyte lysates.

Genetic variation has been studied in erythrocyte lysates from 100 Japanese children and their parents by means of two-dimensional polyacrylamide gel electrophoresis. Fifty-five polypeptides selected without respect to variability were considered suitable for scoring. Genetic variation was encountered in 14 of these polypeptides. Family data show that the segregation of 13 variants is consistent with an autosomal codominant mode of inheritance; the remaining variant exhibits a sex-linked mode of inheritance. Of 8 presumably identical polypeptides found variable in Japanese and/or Caucasians, differences in the occurrence or allele frequencies of polymorphisms were recognized for four. Contrary to the experience of some investigators, the amount of variation and the ethnic differences we are encountering indicate that two-dimensional polyacrylamide gel electrophoresis is a sensitive tool for the study of genetic events.

Alleles↗
PubMed1986

A revised indirect estimate of mutation rates in Amerindians.

We have previously raised the possibility that the mutation rate resulting in rare electrophoretic variants is higher in tribal/tropical-dwelling/nonindustrialized societies than in civilized/temperate-dwelling/industrialized societies. Here, we report the results of examining 11 additional proteins for the occurrence of rare electrophoretic variants in 10 Amerindian tribes, for a total of 8,968 determinations and a total of 17,648 locus tests. When these data are combined with the results of all our previous similar studies of Amerindians, a total of 272,298 polypeptides, the products of 43 different loci, have been examined for the occurrence of rare electrophoretic variants. On the assumption that these variants are maintained by mutation pressure and are essentially neutral in their phenotypic effects, we have calculated by three different approaches that it requires an average mutation rate of 1.3 X 10(-5)/locus per generation to maintain the observed variant frequency. Concurrently, we are reporting elsewhere that a direct estimate of the mutation rate resulting in electromorphs in various studies of civilized industrialized populations is 0.3 X 10(-5)/locus per generation. Although this difference appears to have statistical significance, the nonquantifiable uncertainties to both approaches are such that our enthusiasm for a true difference in mutation rates between the two types of populations has diminished. However, even the lower of these estimates, when corrected for all the types of genetic variation that electrophoresis does not detect, implies total locus and gametic mutation rates well above those which in the past have dominated genetic thinking.

Chromosome Mapping↗
PubMed1986

Genetic analysis of thirty-three platelet polypeptides detected in two-dimensional polyacrylamide gels.

Two-dimensional gel electrophoresis followed by silver-staining was utilized to visualize platelet polypeptides for genetic analysis. A subset of 33 polypeptides that were most suited for scoring was selected. Families consisting of father-mother-child trios were studied. Thirty-six polypeptides of a total of 1,413 scored in children's gels exhibited the combination of a normal and a variant polypeptide. The observed index of heterozygosity of 2.55% is comparable to our previously reported findings for red cell proteins.

Blood Platelets↗
PubMed1985

Two-dimensional gel studies of genetic variation in the plasma proteins of Amerindians and Japanese.

Genetic variation has been studied in plasma samples from 107 Amerindian children and their parents, and 110 Japanese children and their parents by means of two-dimensional polyacrylamide gel electrophoresis. Twenty-three polypeptides were scored; the identity of nine of these is at present still unknown. Genetic variation was encountered in 11 of these polypeptides. We have previously reported that the index of heterozygosity was 6.2 +/- 0.7% for 20 "randomly selected", silver stained polypeptides scored for genetic variation in Caucasoids (Rosenblum et al. 1983b). For technical reasons only 11 of these 20 polypeptides could be routinely scored in preparations from the Amerindian samples. For these 11 polypeptides, the indices of heterozygosity in the three populations were: Amerindians, 4.5 +/- 0.6%; Japanese, 5.7 +/- 0.7%; Caucasoids, 8.0 +/- 1.1%. Even with these relatively small numbers some striking ethnic differences as regards individual polypeptides are apparent.

Adult↗