Some ethical issues at the population level raised by 'soft' eugenics, euphenics, and isogenics.

It is argued that at the population level there are three central genetic developments raising ethical issues. The first is the emergence of 'soft' eugenics, due primarily to the increasing ability to detect carriers of genetic diseases, to monitor their pregnancies, and to provide the option to abort a fetus predisposed to major genetic disease. The second development is the recognition of the extent to which many serious diseases of adult life are due to a disturbance of ancient genetic homeostatic mechanisms due to changing life style, raising the question of whether a society that increasingly pays the medical bills should attempt to impose healthier standards of living on its members. Such an attempt at 'euphenics' may be thought of as the antithesis to eugenics. The third development relates to recognition of the need to regulate the size of the earth's population to numbers that can be indefinitely sustained; this regulation in a fashion (isogenic) that will preserve existing genetic diversity.

Analysis of human peripheral blood T cells and single-cell-derived T cell clones uncovers extensive clonal CpG island methylation heterogeneity throughout the genome.

Methylation of cytosine residues in CpG dinucleotides is generally associated with silencing of gene expression. DNA methylation, as a somatic event, has the potential of diversifying gene expression in individual cells of the same lineage. There is little quantitative data available concerning the extent of methylation heterogeneity in individual cells across the genome. T cells from the peripheral blood can be grown as single-cell-derived clones and can be analyzed with respect to their DNA methylation patterns by restriction landmark genomic scanning. The use of the methylation-sensitive enzyme NotI to cut and end-label DNA fragments before their separation in two dimensions provides a quantitative assessment of methylation at NotI sites that characteristically occur in CpG islands. We have undertaken quantitative analysis of two-dimensional DNA patterns to determine the extent of methylation heterogeneity at NotI sites between peripheral blood single-cell-derived T cell clones from the same individual. A total of 1,068 NotI-tagged fragments were analyzed. A subset of 156 fragments exhibited marked methylation heterogeneity at NotI sites between clones. Their average intensity among clones correlated with their intensity in uncultured, whole-blood-derived T cells, indicating that the methylation heterogeneity observed in clones was largely attributable to methylation heterogeneity between the individual cells from which the clones were derived. We have cloned one fragment that exhibited variable NotI-site methylation between clones. This fragment contained a novel CpG island for a gene that we mapped to chromosome 4. The methylation status of the NotI site of this fragment correlated with expression of the corresponding gene. Our data suggest extensive diversity in vivo in the methylation and expression profiles of individual T cells at multiple unrelated loci across the genome.

JC virus DNA is present in the mucosa of the human colon and in colorectal cancers.

JC virus (JCV) is a polyoma virus that commonly infects humans. We have found T antigen DNA sequences of JCV in the mucosa of normal human colons, colorectal cancers, colorectal cancer xenografts raised in nude mice, and in the human colon cancer cell line SW480. A larger number of viral copies is present in cancer cells than in non-neoplastic colon cells, and sequence microheterogeneity occurs within individual colonic mucosal specimens. The improved yield of detection after treatment with topoisomerase I suggests that the viral DNA is negatively supercoiled in the human tissues. These results indicate that JCV DNA can be found in colonic tissues, which raises the possibility that this virus may play a role in the chromosomal instability observed in colorectal carcinogenesis.

The JC and BK human polyoma viruses appear to be recent introductions to some South American Indian tribes: there is no serological evidence of cross-reactivity with the simian polyoma virus SV40.

In an effort to understand the unusual cytogenetic damage earlier encountered in the Yanomama Indians, plasma samples from 425 Amerindians representing 14 tribes have been tested for hemagglutination inhibition antibodies to the human JC polyoma virus and from 369 Amerinds from 13 tribes for hemagglutination inhibition antibodies to the human BK polyoma virus. There is for both viruses highly significant heterogeneity between tribes for the prevalence of serum antibody titers >/=1/40, the pattern of infection suggesting that these two viruses only relatively recently have been introduced into some of these tribes. Some of these samples, from populations with no known exposure to the simian polyoma virus SV40, also were tested for antibodies to this virus by using an immunospot assay. In contrast to the findings of Brown et al. (Brown, P., Tsai, T. & Gajdusek, D. C. (1975) Am. J. Epidemiol. 102, 331-340), none of the samples was found to possess antibodies to SV40. In addition, no significant titers to SV40 were found in a sample of 97 Japanese adults, many of whom had been found to exhibit elevated titers to the JC and BK viruses. This study thus suggests that these human sera contain significant antibody titers to the human polyoma viruses JC and BK but do not appear to contain either cross-reactive antibodies to SV40 or primary antibodies resulting from SV40 infection.

An association, in adult Japanese, between the occurrence of rogue cells among cultured lymphocytes (JC virus activity) and the frequency of "simple" chromosomal damage among the lymphocytes of persons exhibiting these rogue cells.

Data from a previous study of the cytogenetic effects, in cultured lymphocytes, of exposure to the atomic bomb in Hiroshima have been reanalyzed to determine the relationship between the occurrence of "rogue" cells in an individual and the frequency of "simple" chromosomal damage in the nonrogue cells of the same individual. Rogue cells are cells with complex chromosomal damage, currently believed to be a manifestation of the activity of a human polyoma virus termed "JC." Among a total of 1,835 persons examined, there were 45 exhibiting rogue cells. A total of 179,599 cells were scored for simple chromosomal damage. In both the exposed and the control populations, there was an absolute increase of approximately 1.5% in the frequency of simple chromosomal damage in the nonrogue cells of those exhibiting rogue cells, when compared with the frequencies observed in those not exhibiting rogue cells, which is a statistically significant difference. It is argued that this phenomenon, occurring not only in lymphocytes but possibly also in other cells/tissues, may play a contributory role in the origin of malignancies characterized by clonal chromosome abnormalities. Unexpectedly, among those exhibiting rogue cells, there was a disproportionately greater representation of persons who had received relatively high radiation exposures from the bomb. The reason for this is unclear, but it is tempting to relate the finding to some lingering effect of the exposure (or the circumstances surrounding the exposure) on immunocompetence.

Syndrome X: is it for real?

The term syndrome X has been applied to the association of hypertension, non-insulin-dependent diabetes mellitus (NIDDM), android obesity, insulin resistance, and dyslipidemia. In this paper, based on population samples from Tecumseh, Michigan, and Hiroshima, Japan, characterized by persons > or = 40 years of age, we examine the validity of regarding this constellation of traits as a true syndrome, i.e., an array of traits with a single, unifying pathophysiology underlying its components. Data were not available on insulin resistance and dyslipidemia, and obesity was expressed as body mass index (BMI) without the division into android and non-android types. The four ethnic-gender data sets were analyzed on the basis of two age classes, age > or = 40 years and age > or = 50 years, and two obesity classes, BMI > or = 27 and > or = 30. A simple chi 2 test of goodness-of-fit under a model of independence revealed non-random associations between hypertension, NIDDM, and BMI which were in part attributable to an excess of persons with all three traits. However, when the four data sets were subjected to separate log-linear analyses of the three-way association tables, none of the three-factor interaction terms (i.e., syndrome X) was significant. High significance was, however, observed in the two-factor interaction term for BMI*hypertension. It is concluded that the significant association between these three traits is driven by the BMI*hypertension interaction, and there is no evidence in these data sets of a significant role for a syndrome X. Genet.