New translocations in human lymphocytes: a mutagen monitoring system.

The human lymphocyte is a premier cell for monitoring chromosome aneuploidy. The lymphocyte is easily obtained, can be studied before and after culture, and has been extensively investigated. Assays available for lymphocytes include the scoring of chromosome breaks (subjective and laborious), the analysis of chromosome abnormalities such as increase or decrease in number (versus normal background), dicentrics etc., and the micronucleus test (presumable end-state phenomena). We propose the monitoring of somatic chromosome translocations in human lymphocytes. Background data available from North America indicate that the frequency of de novo chromosome translocations in Halifax, Portland, Denver, and Atlanta is about 1.7 x 10(-3). The most common translocation arising in lymphocytes is between chromosomes 7 and 14 (with a frequency of 4 x 10(-4). All translocations occurring de novo in human lymphocytes tend to appear balanced with no evidence for loss or gain of chromosome material. Cytogenetic laboratories are processing lymphocytes daily. The resultant photographs and karyotypes are all scorable for de novo translocations. Suitable data on exposure to possible mutagenic agents could be collected in advance of these chromosome studies. This would provide a new method for monitoring chromosome changes in the population. The cost of monitoring lymphocyte chromosomes for somatic translocations would be small, since numerous laboratories study lymphocytes rountinely for clinical diagnostic purposes. There may be merit in availing ourselves of easily available data from a very available species: man.

X-chromosome replication in parthenogenic benign ovarian teratomas.

Somatic cells from human females undergo X-differentiation, which curtails expression of most, if not all, of the genes on one X-chromosome. According to the Lyon hypothesis, the designation of whick X will be inactive in eutherian females is random. However, in spite of the obvious biologic importance of X chromosome differentiation, little is known about either the mechanism of this process or the role played by fertilization. Benign ovarian teratomas provide a system for assessing the importance of fertilization in X chromosome differentiation. Biochemical and cytologic data indicate that these teratomas are of germ-cell origin. They are comprised entirely of one of the products of the first meiotic division and are thus parthenogens. In the absence of appropriate recombinational events, ovarian teratomas are consistently homozygous at autosomal loci, even when the host is heterozygous. Analysis of X chromosome replication kinetics provides one additional approach for investigating X-differentiation in individual teratoma cells. We utilized BrdU-dye techniques to study terminal replication patterns in ovarian teratomas and in normal fibroblasts and peripheral lymphocytes from the same individuals. The results confirm that human ovarian teratomas possess a single late-replicating X chromosome. Moreover, the pattern of replication in this X is identical to that in normal fibroblasts, but different from that usually observed in peripheral lymphocytes. Thus, if late replication is an accurate gauge of X-inactivation, the data confirm that X-inactivation can occur without fertilization.

Estimating distances from the centromere by means of benign ovarian teratomas in man.

Under the assumption that benign ovarian teratomas in man arise parthenogenically from a germ cell by suppression of the second meiotic division, the distance of a gene from its centromere can be estimated from the observed proportion of heterozygous teratomas collected from heterozygous hosts. The frequency of heterozygous teratomas of heterozygous hosts is equivalent to the frequency of second division segregation at the gene locus which has been used for centromere-related mapping in fungal genetics for more than 40 years. Mapping functions useful for teratoma-based mapping in man are presented.

Human centromere mapping using teratoma data.

Under the assumption that benign ovarian teratomas arise parthenogenetically from a germ cell by suppression of the second meiotic division, the proportion gamma of heteratomas collected from heterozygous hosts is a measure for the distance between the corresponding gene and its centromere. For proportions gamma less than or equal to 0.3, the mapping function x = gamma/2 applies, where x is the map distance in Morgans.

Editorial: Perinatology begins before conception.

PIP: The liberalization of an abortion law in Oregon has resulted in the decline of fetal deaths and the prevention of maternal mortality. Since then the total population including that in the childbearing years has been steadily on the increase while the known conception rate has been decreasing by about 5% per year. While much progress has been made in identifying high-risk pregnancies and dealing more effectively with them, little progress has been made toward influencing events in the first half of pregnancy. Guerrero and Rojas have examined the outcome of pregnancy using basal temperature records to estimate ovulation time. Their findings have led to the belief that aging of sperm (before fertilization) or aging of eggs (before insemination) increases the probability of spontaneous abortion. In addition, overripeness may also lead to chromosomal abnormalities and to babies with Down's syndrome. However, proof is clearly lacking at this moment; careful testing is presently necessary. If proven true, prevention of such defects would be possible by educating people to juxtapose fertilization as close to ovulation time as possible.^ieng

Somatic rearrangement of chromosome 14 in human lymphocytes.

Ataxia-telangiectasia is a rare genetic disorder associated with immune deficiency, chromosome instability, and a predisposition to lymphoid malignancy. We have detected chromosomally anomalous clones of lymphocytes in eight patients with this disorder. Chromosome banding disclosed that the clones are consistently marked by structural rearrangement of the long arm (q) of chromosome 14. A translocation involving 14q was found in clones obtained from seven of the eight patients whereas a ring 14 chromosome was found in a clone obtained from the other. These findings as well as data obtained by others for patients with ataxia-telangiectasia suggest that structural rearrangement of 14q is the initial chromosomal change in lymphocyte clones of patients with this disorder. Chromosomes of lymphocytes from one of the patients were studied before and after the onset of chronic lymphocytic leukemia. Before leukemia was diagnosed, the patient had a lymphocyte clone with a 14q translocation. This clone appears to have given rise to the leukemic cells. We hypothesize that structural rearrangement of 14q is directly related to abnormal growth of lymphocytes and that it may be a step toward the development of lymphoid malignancies. Increasing evidence, provided by others, for the nonrandom involvement of 14q in African-type Burkitt's lymphoma and other lymphoid neoplasms further strengthens this hypothesis.

Parthenogenic origin of benign ovarian teratomas.

To determine the origin of benign cystic teratomas of the ovary, chromosome-banding studies were done on normal tissues and teratomas from five patients. The normal tissues were heterozygous (+/-) for 17 chromosome polymorphisms at or near the centromere, whereas the teratomas were uniformly homozygous (+/+ or -/-). These findings and those employing electrophoretic variants indicate that ovarian teratomas are parthenogenic tumors that arise from a single germ cell after the first meiotic division.