Publisher Summary This chapter reviews the studies on tumors derived from human females whose mosaicism is governed by X-chromosome inactivation. Development of the experimental technique used in these investigations depended upon the inactive-X hypothesis and the demonstration that the glucose-6-phosphate dehydrogenase locus in many cases undergoes this type of inactivation. Knowledge of whether neoplasms have a uni- or a multicellular origin and of the ways they subsequently develop may lead to a better understanding of their etiology and pathogenesis. Information relevant to these points can be obtained through the study of tumors arising in organisms with two or more cell types distinguishable by their genetic markers. Tumors with a single cell origin arising in such organisms should consist entirely of one or the other cell type, whereas tumors with multiple cell origin may contain both types of cells. Multiple cell origin implies that the initial tumorigenic event occurs in only a single cell and that this alteration subsequently influences the pattern of growth in neighboring cells, or that tumor initiation as well as all the steps in tumor progression involves more than one cell. This type of origin might occur if the target tissue for the oncogenic factors contained a large number of susceptible cells. Inherited tumors such as multiple trichoepithelioma and neurofibroma are the examples of tumors with multicellular origin; all cells in the tissue of origin have an innate tumorigenic potential.

Use Of Genetic Markers To Study Cellular Origin And Development Of Tumors In Human Females

If benign cystic teratomas (dermoid cysts) of the ovary arise from a germ cell that has undergone meiosis, they should be missing genes which are present in the person. Three independently segregating allelic isozymes in 11 benign cystic teratomas of the human female ovary were compared with normal tissue of the same case. Dermoid cysts from persons heterozygous for these isozymes are frequently homozygous for that particular gene product. One of two dermoid cysts is homozygous for glucose-6-phosphate dehydrogenase, two of four tumors are homozygous for phosphoglucomutase at the PGM1 locus, and two (or more) of eight tumors are homozygous for phosphoglucomutase at the PGM3 locus in women heterozygous for these allelic isozymes. These findings are consistent with the hypothesis that these tumors arise from a germ cell which has undergone meiosis with varying degrees of crossing-over.

https://www.pnas.org/content/pnas/63/3/699.full.pdf

Gene Loss in Human Teratomas

2,6-DIAMINOPURINE* has been used as a selecting agent in animal cell CUItures to obtain variant lines for somatic cell studies (HARRIS and RUDDLE 1960; LIEBERMAN and OVE 1960; BLAIR and HALL 1965). The biochemical basis of DAP resistance appears to be due to a loss of AMP pyrophosphorylase activity needed in the conversion of adenine or its analogue to its phosphorylated derivative (LIEBERMAN and OVE 1960; BLAIR and HALL 1965; KALLE and GOTS 1961). However, in some instances altered specificity of the pyrophosphorylase has been shown to confer resistance to DAP in Salmonella (KALLE and GOTS 1963). In other systems permeability changes have been suggested as the basis of resistance ( PATERSON 1962). Although considerable progress has been made in our understanding of the biochemical basis of drug resistance, the genetic basis of purine analogue resistance is less understood. The application of animal cell hybridization techniques to drug resistance has shown that BUDR and 8AG resistance are recessive. From sensitive hybrids carrying the two markers, it was possible to recover the two parental (BUDR and 8AG resistance) cell types, which is suggestive of a nuclear event underlying drug resistance (LITTLEFIELD 1964a, 1964b). It is known that drug resistant variants occur in discrete independent steps ( LITTLEFIELD 1964c, SZYBALSKI, SZYBALSKA and RAGNI 1962), are stable (HARRIS and RUDDLE 1960; SZYBALSKI and SMITH 1959), and fluctuation tests appear to indicate that variants arise independently of the drug (LIEBERMAN and OVE 1959). A direct demonstration of independence has not been made, and it is the objective of this paper to report the development of a nonselective technique for this purpose.

/pdf/development-of-a-nonselective-technique-for-studying-2-6-1tik07ilbt.pdf

Development of a nonselective technique for studying 2, 6, diaminopurine resistance in an established murine cell line

Six cases of de Lange's syndrome; parental consanguinity in two.

Some of the cells of every human being will grow outside the body as microorganisms. It is possible to show, in a variety of ways, that these cells resemble genetically the individual from whom they were obtained. Over 35 inherited human diseases and anomalies can now be studied in such cell lines.



Human diploid cell strains, biochemically marked by one or more mutant Mendelian genes, have proven particularly useful for the study of gene action in man and for the detection of genetic changes such as mutation and somatic cell hybridization. In addition, the strains have a number of clinical applications, including the antenatal diagnosis of inherited disease.



The failure of cultured human cells to display their phenotype at most loci continues to restrict their use in both genetics and medicine. There are reasons for hoping that this difficulty will eventually be solved, and some experiments bearing on the problem are already feasible.

/pdf/the-action-of-mendelian-genes-in-human-diploid-cell-strains-2qz2mzlopu.pdf

The action of Mendelian genes in human diploid cell strains.

Cell culture techniques and starch gel electrophoresis were utilized in an attempt to detect the presence of autosomal inactivation at the branched chain amino acid decarboxylase locus and the locus controlling phosphoglueomutase activity. Inactivation of the type seen with the X-chromosome was not found. Partial inactivation at a 3 : 1 or greater level could be excluded in the phosphoglucomutase system.

The absence of inactivation at two autosomal loci.

Chromosomes in de lange's syndrome

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The absence of inactivation at two autosomal loci.

Chromosomes in de lange's syndrome