This book has five chapters covering peroxisomal diseases, X-linked immunodeficiencies, genetic mutations affecting human lipoproteins and their receptors and enzymes, genetic aspects of cancer, and Gaucher disease. The chapter on peroxisomes covers their discovery, structure, functions, disorders, etc. The chapter on X-linked immunodeficiencies discusses such diseases as agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, animal models, linkage analysis, etc. Apolipoprotein formation, synthesis, gene regulation, proteins, etc. are the main focus of chapter 3. The chapter on cancer covers such topics as oncogene mapping and the molecular characterization of some recessive oncogenes. Gaucher disease is covered from its diagnosis, classification, and prevention, to its organ system involvement and molecular biology.

Advances in Human Genetics

Genic variation within and between the three major races of man, Caucasoids, Negroids, and Mongoloids.

It is estimated that the human haploid genome is composed of 3 × 109 nucleotides and that only 10% of it consists of coding and regulatory sequences.14 If a gene is approximately 104 nucleotides in length, which includes the coding region and the intervening and flanking sequences, this estimate would predict that there are about 3–10 × 104 human genes coding for different protein products. Since gene clustering in humans has become evident (for example, the hemoglobin, immunoglobin, and HLA clusters), these estimated gene products may be grouped in from 3000 to 15,000 clusters.15 Further, based upon genetic and molecular studies of microorganisms, Drosophila, and the mouse, there are perhaps 5 × 104 structural genes estimated in humans,14,106,183 which is in agreement with the number of estimated protein products in the human genome. Mapping the human genome involves partitioning the total number of genes into individual maps representing the 24 different human nuclear chromosomes and linearly ordering them on each chromosome. A similar exercise has mapped the 37 genes encoded in the DNA of the mitochondrial genome.2

Mapping the Human Genome, Cloned Genes, DNA Polymorphisms, and Inherited Disease

Inherited variants of many different enzymes have been discovered by electrophoretic techniques. In general they can be attributed to alleles which originated by mutation in individuals in earlier generations a t the loci coding for the structures of the particular enzymes. Population surveys indicate that such alleles vary very widely in their incidence, some being relatively common and others extremely rare. Up till now attention has mainly focused on the common alleles which give rise to the so-called enzyme polymorphisms. It has been found, for example, that polymorphism due to common alleles which determine electrophoretically distinct enzyme variants appears to occur in human populations at some 25-30% of loci coding for enzyme structure, and that the average heterozygosity per locus for such alleles is around 0.07 (Harris & Hopkinson, 1972). The same general phenomenon has of course also been demonstrated in a variety of other species and the recognition of its widespread occurrence has generated a great deal of discussion and not a little controversy about its fundamental biological significance. However, so far not much attention has been paid to relatively rare alleles which also give rise to electrophoretically detectable enzyme variants. This is no doubt, in part, because although many such variants have been reported, little systematic data on their incidence at different loci has been available. The purpose of the present paper is to present an extensive body of data which gives information about the incidence of such rare alleles over a wide range of loci. We believe that such data may provide an observational base which may help to extend the scope of current discussions about the nature and significance of enzyme polymorphism in particular, and about the character of enzyme diversity among the individual members of natural populations in general.

The incidence of rare alleles determining electrophoretic variants: data on 43 enzyme loci in man.

Two cDNA clones, pDRH1 and pDRH2, containing sequences specific for human HLA-DR antigens were isolated from a bank of cDNA clones made from partially purified HLA-DR mRNA from the human lymphoblastoid cell line Maja. The clones were specific for the Mr 34,000 HLA-DR antigen glycoprotein chain. The identity of these clones was established by (i) their ability to hybridize specifically to HLA-DR mRNA in a positive selection assay; (ii) mRNA species hybridizing to the cDNA clones were expressed in B-cell but not in T-cell or fibroblast cell cultures; and (iii) a nucleotide sequence in the longer clone, pDRH2, could be translated into an amino acid sequence that is identical to the limited NH2-terminal amino acid sequence available for the purified HLA-DR antigen Mr 34,000 chain. Analysis of DNA from human, mouse, and human--mouse somatic cell hybrid lines by Southern transfer of restriction endonuclease digests indicated that the HLA-DR heavy chain is encoded in chromosome 6. This finding is compatible with the location of at least one of the HLA-D/DR heavy chain genes within the HLA region. In addition, the sequences coding for HLA-DR heavy chain appear to be present in only one or a few copies in the genome and to be relatively simple in structure.

cDNA clones coding for the heavy chain of human HLA-DR antigen.

Following some of the early studies reporting the successful establishment of lymphoblastoid cell lines from the peripheral blood of patients with infectious mononucleosis (Pope, 1967; Mumford et al. 1967; Glade et al. 1968), methods have been developed which enable such lines to be derived from peripheral blood cells of healthy or diseased individuals (Moore, Gerner & Franklin, 1967; Diehl et al. 1968; Steel & Edmond, 1971). These cell lines have a number of properties, distinct from other cultures of human origin, which make them extremely useful tools for research. Lymphoblastoid cell lines can be established from relatively small amounts of peripheral blood, a material more readily obtainable than skin or other tissue biopsies. They grow as a free-floating suspension, so that cells can be dispersed and subcultured without prior trypsination. A line derived from the blood of a single individual appears to have an indefinite life-span in citro and will apparently retain its unique genotype in continuous culture for long periods of time (e.g. Conover et al. 1970): this contrasts with primary fibroblast or epithelial cultures which are limited to a fixed number of cell divisions before eventual death (Hayflick & Moorhead, 1961). In our hands, lymphoblastoid cell lines appear to show far less cytogenetic variation than fibroblast lines of comparable age and, once established in culture, can rapidly be grown up into large quantities with comparative ease: a considerable amount of cellular material or unique genotype can therefore be made available for detailed biochemical investigations. The cells can also be laid down in the frozen state at any period of culture, and at any time in the future re-established in culture for further studies. A disadvantage to offset against the attributes listed above follows from the fact that these cell lines are infected with EB virus, a herpes-like virus described by Epstein and Barr (Epstein, Achong & Barr, 1964). The role of EB virus in human disease and its effect on lymphoid cells in vitro is not entirely clear a t present, therefore the cell lines must be used with some degree of caution. The above listed properties of lymphoblastoid cell lines make them particularly favourable tools for studies on cells of human origin, especially in experiments which require large amounts of proliferating materials. Of especial interest to us was the possibility that the cells could be

Genetic studies on human lymphoblastoid lines: isozyme analysis on cell lines from forty-one different individuals and on mutants produced following exposure to a chemical mutagen.

Adenine phosphoribosyl transferase (APRT) catalyses the reaction of adenine with 5-pliosphoribosyl-pyrophosphate to give adenosine-5’-monophosphate and pyrophosphate. It is widely distributed in human tissues. There have been several reports of inherited variation of APRT in man. Kelley et nl. (1968) described a family in which four individuals showed a partial deficiency of the enzyme activity in red cells. The trait appeared to be inherited as an autosomal heterozygous character, and it did not appear to be associated with any obvious abnormality in uric acid production. Henderson et al. ( 1968) reported individual differences in therniostability of red cell APRT, which appeared to represent a common polymorphism involving two alleles, one produciiig a relatively more unstable form of the enzyme than the other. Bakay & Nyhan (1971) described the electrophoresis of APRT in acrylamide gels and reported that usually the enzyme migrated as a single symmetrical zone of activity, and in one individual a faster migrating variant was observed. I n the present paper we describe a method for the electrophoresis of APRT in starch gel, and report the results of a search for APRT variants in Caucasian and Negro populations using this technique. We also report briefly some related studies on the usual form of the enzyme and on certain variants.

A search for electrophoretic variants of human adenine phosphoribosyl transferase.

One hundred and thirty-three clones (60 mutagen treated, 73 controls) of the human male lymphoblastoid cell line F 137 have been examined for the electrophoretic pattern of more than 30 enzymes. In nine instances there was loss of activity of one allele of an X-linked or heterozygous autosomal locus. Seven of these involved the Pep A locus, and in every case the change was from the Pep A 2-1 phenotype to Pep A 2. Cytogenetic analysis of the parent line revealed a number of variants on the modal karyotype. On cloning, there appeared to be some selection for survival of non-modal cells. The proportions of the cytogenetically distinct populations within the bulk culture varied over a period of many months. There was a strong correlation in individual clones between loss of activity of the product of the Pep A1 allele and the presence in the cells of a 9/18 translocation. In addition there was one clone of phenotype Pep A 2 with a deletion of part of the long arm of chromosome 18. The data confirms the assignment of the Pep A structural locus to the distal half of the long arm of chromosome 18 and localizes it with some precision to the qter region. The Pep A 2 phenotype of the clones containing the 9/18 translocation could be the result of a small deletion eliminating the Pep A1 allele but not large enough to be detected cytogenetically. Alternatively inactivation of the Pep A1 allele may have occurred as a position effect resulting from the close association of heterochromatin from the centromere of 9 with the qter region of 18.

Genetic studies on human lymphoblastoid cell lines: isozyme and cytogenetic heterogeneity in a cell line, with evidence for localization of the Pep A locus in man.

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Genetic studies on human lymphoblastoid lines: isozyme analysis on cell lines from forty-one different individuals and on mutants produced following exposure to a chemical mutagen.

A search for electrophoretic variants of human adenine phosphoribosyl transferase.

Genetic studies on human lymphoblastoid cell lines: isozyme and cytogenetic heterogeneity in a cell line, with evidence for localization of the Pep A locus in man.