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Biochemical Polymorphisms -- Detection, Distribution, Chromosomal Location, and Applications

John J. Hutton

Department of Medicine
VA Hospital and University of Kentucky
Lexington, Kentucky

The application of starch gel electrophoresis and specific staining procedures has led to the detection of genetically controlled structural variation in enzymes from different strains of mice. Polymorphism at loci controlling the structure of proteins is extensive so that it is frequently easy to find a variant of a specific enzyme. The average mouse in the wild is heterozygous at 10% of loci and the percentage of polymorphic loci in the species is 40% ( 63). Genetic variability among independently derived inbred strains of laboratory mice seems similar to variability observed in the wild. Electrophoretic techniques alone cannot detect all variants, since some amino acid differences resulting from mutation do not cause a change in the electrical charge on the protein ( 55). Other techniques such as comparative measurements of thermal lability of enzymatic activities in different strains ( 14, 30, 40, 45), reactivity of molecules with alkylating agents ( 34), solubility of proteins in phosphate buffers ( 68), enzymatic activity with different substrates ( 43, 82), activity per unit weight of tissue ( 1, 14, 30, 35, 36, 44, 50, 55, 56, 81), and distribution of activity among subcellular organelles ( 1, 44, 56) have been helpful in finding "variants." It is difficult to prove that the variation is caused by changes in the primary amino acid sequence of the protein and not by post-translational modifications such as glycosylation ( 2, 17), or by changes in binding sites for the protein in a membrane of a subcellular organelle ( 44), changes in the concentration of an intracellular stabilizing factor ( 23, 35), or mutation in a regulatory element affecting the rate of synthesis of the protein without affecting structure ( 55, 56). Only in the case of hemoglobin have electrophoretic and solubility variants been proved to result from genetic mutation in structural genes with changes in the amino acid sequences of the α- and β-chains ( 28, 60, 68).

Biochemical variants constitute a distinct class of mutations with internationally recognized rules for choosing appropriate names and symbols of new loci affecting enzymes and other biochemical characteristics of mice ( 13). Rules for identifying chromosomes and their associated genetic linkage groups have also been defined ( 12, 48).

Table 1 lists loci which probably determine the structure of proteins and have been assigned to chromosomes. Prior to 1972 genes that segregated together in breeding experiments were said to be members of the same "linkage group." Linkage groups were identified by number and most could not be assigned to specific chromosomes. Because of recent advances in cytogenetics, genetic linkage groups have now been assigned to chromosomes and chromosome numbers have replaced linkage groups. Loci in Table 1 are listed by chromosomal location. Methods and tissues generally used to detect variants at each locus are given. The list of references is lengthy, but not exhaustive, and makes no attempt to assign priority of discovery. References describe the variants, their distribution among strains, segregation with other markers in breeding experiments, and applications to solution of several fundamental biological problems.

The distribution of alleles at 28 loci on 17 chromosomes is summarized in Table 2. These data can be collated from original articles listed in Table 1 or, with minor additions, from recent reviews ( 6, 74). All strains are inbred except M. m. molossinus. Accumulating representative animals for typing is laborious and the distribution of alleles at loci such as Svp-1, Gdc-1, Glo-1, and Phk is not well described. In the case of Phk the b allele is associated with muscle disease so the standard inbred strains except I/LnJ are probably normal with the a allele. Each of the 20 strains has a unique pattern of alleles. It is easy to see that biochemical typing of strains can serve both to detect genetic contamination in production colonies ( 42) and to estimate whether strains are genetically related. Alleles such as Pgm-2b, Gush, Map-1h, Hbbp, Mod-2a, Es-1a, Got-2a, Apkm, Es-3a, Es-3b, Hbad, Amy-1b, Es-10c, and Gpt-1c are only found in one or two of the strains. Variant alleles at Got-1 and Pgk-1 are present in partially inbred mice recently derived from wild populations ( 6, 7).

In searching for a new variant it is important to examine as many inbred strains as possible, since rare alleles may not be found immediately. A group of inbred strains with no known overlapping pedigrees should be studied first. One "best group" that has been recommended for initial screening includes C57BL/6J, SM/J, SWR/J, AU/SsJ, and PL/J ( 63). To these should be added strains recently derived from wild mice or substrains of M. musculus such as M. m. molossinus and castaneus.

The positions of loci on chromosomes are illustrated in Figure 1. This map should be compared to the human gene map ( 46). All chromosomes except 13, 16, and 18 have at least one polymorphic biochemical locus. Additional loci have been assigned to chromosomes by somatic cell hybridization or studies of gene dosage effects associated with the X chromosome. These include glucose-6-phosphate dehydrogenase ( 9, 21, 41), phosphoglycerate kinase ( 9, 41), and hypoxanthine guanine phosphoribosyl transferase ( 9, 22) on the X chromosome, and thymidine kinase and galactokinase on chromosome 11 ( 9, 39). Centromeres are located at the top of Figure 1 and genetic distances in cM are given where estimates are available. If nongenic DNA is fairly evenly distributed among chromosomes, then the average length of a mouse chromosome should be 60-90 cM ( 48), This means that markers at two loci spaced around 50 cM apart with one 10 to 30 cM from either end of the chromosome would serve in breeding experiments to detect whether a segregating gene was on that chromosome. These conditions are met reasonably well by markers on chromosomes 1, 4, 5, 7, 8, 9, and 11. Other chromosomes are less well marked. It is remarkably easy to design crosses in which alleles at 10 or more biochemical loci are segregating, thereby testing genetic linkages on multiple chromosomes and in some cases meeting conditions for a three-point cross to determine the sequential order of loci ( 5, 37, 79). Polymorphic biochemical variants have many practical advantages when used as markers in linkage analysis. Generally, alleles determining biochemical polymorphisms are codominant and fully penetrant. None has deleterious effects on viability so that segregation ratios are not distorted in breeding experiments. Unfortunately, animals must sometimes be killed to determine their genotype and many of the testing procedures are laborious and expensive. The marker to be tested for linkage may not be found in an inbred strain which can be paired with another to achieve segregation of large numbers of markers.

Four examples of tight genetic linkage of enzymes with similar functions are shown in Figure 1. Each of these may represent the tandem duplication of one or more loci. The structural loci of carbonic anhydrase ( Car-1 and Car-2 on chromosome 3) are within 1.5 cM of one another ( 19). The two isozymes of carbonic anhydrase in the mouse are structurally related to the two human isozymes which share 60% sequence homology. The Amy-1 and Amy-2 loci on chromosome 12 may represent a similar duplication, but there is no information about the amino acid sequence of the two proteins. On chromosome 7 there is the interesting example of very tight linkage of the locus controlling the structure of the y-chain of mouse embryonic hemoglobin with the locus controlling the structure of adult hemoglobin β-chain. The y- and β-chains of hemoglobin are structurally similar ( 28, 68), so the Hbb and Hby loci probably represent tandem duplication of a structural gene. The genes at the two loci have evolved so that one functions in the embryo and the other in the adult. The most extensive area of duplication of structural genes is on chromosome 8. Seven esterases ( Es-1, Es-2, Es-5, Es-6, Es-7, Es-9, Es-11) are clustered within a 12 cM segment ( 57, 78). Three of these loci ( Es-2, Es-5, and Es-11) are within 0.58 cM of one another and probably represent tandem duplication of a single ancestral gene. A similar cluster of four esterase loci is present in the rat, suggesting that an autosomal segment comprising at least 15 cM of the rat and mouse genomes has remained relatively intact with respect to genetic content during rodent speciation ( 82).

Both chromosomal and mitochondrial DNA are present in animal cells and it is not clear which mitochondrial proteins are coded by nuclear as opposed to mitochondrial genes. Through studies of the distribution of electrophoretically distinct isozymes among the subcellular fractions from mice of different inbred strains, structural loci of mitochondrial and soluble forms have been identified and assigned to chromosomes. Figure 2 illustrates variants of mitochondrial glutamate oxaloacetate transaminase. The slow phenotype in the figure is designated GOT-2B, the fast GOT-2A, and the heterozygote GOT-2AB ( 16). GOT-2AB animals possess three distinct bands with the intermediate AB band having stronger histochemical staining activity than either the A or B band alone. The approximate 1A:2AB:1B heterozygous phenotype can be best explained if the A and B subunits hybridize at random as dimers ( 16). Mutant genes for at least four mitochondrial enzymes have been described in the mouse. Mitochondrial glutamate oxaloacetate transaminase is coded by a nuclear locus ( Got-2) on chromosome 8, mitochondrial malic enzyme ( Mod-2) is on chromosome 7, mitochondrial malate dehydrogenase ( Mor-1) is on chromosome 5, and mitochondrial proline dehydrogenase ( Pro-1) is on an autosome and is not linked to the loci of the other mitochondrial enzymes. There is no apparent pattern of association of these four nuclear genes coding for mitochondrial enzymes ( 70, 80).

Variants of isozymes provide powerful tools for analysis of the genetic effects of radiation and chemical mutagens on gametes. It is possible to design experiments measuring mutations affecting the amino acid sequence of specific proteins as well as changes in gene dosage brought about by duplication or deletion of segments of chromosomes, To do this it is necessary to treat a mouse with mutagen and then to mate it to a mouse of another inbred strain which differs in genotype from the treated animal at as many loci as possible. Offspring should be heterozygous at multiple known loci and this heterozygosity can be detected by techniques listed in Table 1. Genetic deletion at a locus is indicated by recovery of only one parental allele, that of the untreated parent. Structural change in an enzyme because of genetic mutation may be detected by changes in electrophoretic pattern or some other property of specific protein in the hybrid offspring. Duplication of a locus may cause changes in the relative activity of isozymes in the hybrid. The value of testing mice heterozygous at multiple biochemical loci is that genetic deletion and duplication can be detected as well as simple changes in amino acid sequence. Searches for specific biochemical variants can be facilitated by use of chromosome inversions to recover specific segments of chromosomes of treated animals ( 62). The map of biochemical loci ( Figure 1) assigns positions of genes and can be used to choose the appropriate inversion.

Using biochemical techniques and screening of heterozygous F1 mice, new radiation-induced mutations were sought at the hemoglobin Hba and Hbb loci ( 69). Five hemoglobin variants were found among 8621 F1 progeny of irradiated animals. In three offspring the genetic contribution from the irradiated father was not expressed with regard to the α-chain. These mice are thought to have deletion of genes controlling the structure of α-chain and may represent mouse α-thalassemias. One of the progeny carried a tandem duplication involving Hbb and one probably carried a double nondisjunction of chromosome 7 ( Hbb and Hby). The finding that major chromosomal aberrations can mimic hemoglobin mutations indicates the need to follow F1 screening with thorough cytogenetic analysis ( 69). Clearly, the availability of maps assigning specific biochemical loci to specific locations on chromosomes makes possible the interpretation of combined biochemical and cytogenetic studies.

Figure 3 illustrates the use of biochemical, coat color, and neurological mutants in the analysis of radiation-induced lethal albino alleles ( 24, 29). The c14Cos and c6H mutations were induced by radiation and both are lethal when homozygous. Homozygotes of c14Cos become hypoglycemic and die perinatally, whereas homozygous c6H is an embryonic lethal. Heterozygous c14Cos/ c6H mice are albino but do not die so c14Cos and c6H are assigned to different complementation groups and are thought to represent different, but overlapping deletions. The Mod-2 locus of mitochondrial malic enzyme is on chromosome 7 one cM from the albino locus ( c) between c and sh-1. The MOD-2 phenotypes of normal, c14Cos/+, c6H/+, and c14Cos/ c6H mice were determined. The Mod-2 allele of c6H was not expressed in the hybrids, whereas the allele of c14Cos was expressed. The c6H deletion appears to extend at least one cM from the c locus and involves the structural gene of a known enzyme. The availability of a genetic map ( Figure 1), tables of distributions of biochemical alleles ( Table 2), and techniques for distinguishing homozygosity from heterozygosity ( Table 1) at loci greatly facilitates analysis of complex mutations.

Genetic variants of polymeric isozymes have been used to analyze a variety of interesting problems in developmental biology. Figure 4 illustrates the use of variants of glucose phosphate isomerase ( Gpi-1). Homozygous Gpi-1b mice are composed of cells of identical genotype ( Figure 4, cell type 1). Homogenates of these cells give a single banded electrophoretic pattern of GPI-1B activity ( Figure 4, cell type 2). Homogenates of these cells give a single banded electrophoretic pattern of GPI-1A activity ( Figure 4, electrophoretic pattern 2). Heterozygous Gpi-1a/ Gpi-1b mice express both the Gpi-1a and Gpi-1b alleles in all cells and since glucose phosphate isomerase is a dimer, the heteropolymer GPI-1AB comprises the major electrophoretic component ( Figure 4, electrophoretic pattern 3). Bands of GPI-1A and GPI-1B activity are also present. Mixtures of homogenates from homozygous Gpi-1a mice with homogenates from Gpi-1b homozygotes give rise to two electrophoretic bands (GPI-1A and GPI-1B, Figure 4, electrophoretic pattern 1 plus 2) without formation of heteropolymer. Formation of heteropolymer requires that the Gpi-1a and Gpi-1b alleles both be active within the same cytoplasm. If somatic cells of genotype Gpi-1a/ Gpi-1a and Gpi-1b/ Gpi-1b are mixed, two results can occur. The cells can form mixtures without cell fusion. Homogenates of mixtures of cells will consist of GPI-1A and GPI-1B enzyme without heteropolymer ( Figure 4, cell type 4, electrophoretic pattern 4). Alternatively, the cells can fuse to form heterokaryons. Both types of Gpi-1 alleles are active within the same cytoplasm. Homogenates of heterokaryons will consist of GPI-1A, GPI-1AB, and GPI-1B enzyme Figure 4, cell type 5, electrophoretic pattern 5).

Whether cell fusion occurs has been examined in several mouse tissues using the principles illustrated in Figure 4 ( 4, 27). Trophoblast differentiation in the mouse embryo is characterized by the formation of giant cells whose nuclei contain as much as 500-1,000 times the haploid amount of DNA. Among the mechanisms proposed are endomitosis, fusion of fetal cells, or fusion of maternal and fetal cells. GPI-1A embryos were transferred to GPI-1B mothers, and chimeric GPI-1A <---> GPI-1B embryos were also made. Fetal tissues were examined for the presence of heteropolymer, GPI-1AB, which would indicate cell fusion. No heteropolymer was found in electrophoretic analysis of trophoblast from either the transferred or chimeric embryos. Trophoblast cells do not functionally incorporate maternal DNA nor do they form syncytial heterokaryons by cell fusion. The multinucleated cells must result from endomitosis. Using identical principles and chimeric mice, individual somites from 8 to 9 day embryos have been found to arise from more than one precursor cell ( 26). Myogenesis occurs by actual fusion of uninucleated myoblasts so that the heteropolymer GPI-AB is present in skeletal muscle ( 26), but not in cardiac muscle or other tissues.

Electrophoretic variants of glucose phosphate isomerase have been used to study the time of paternal gene activation during early embryogenesis of the mouse ( 10). GPI-1A females were mated to GPI-1B males and the hybrid embryos were examined for GPI isozymes during preimplantation stages ( Figure 5). The heteropolymer GPI-1AB, indicating activity of the paternal gene, was first detected in the late blastocyst, day 5. No increase in total GPI activity occurred on day 5 so that quantitative measurement of GPI activity does not detect paternal gene activation.

This review of biochemical polymorphisms has of necessity been brief. Discussion has been limited to structural variants of proteins. Extensive references have been provided in Table 1 with emphasis on the recent literature. The space devoted to uses of variants may seem disproportionate, but this information is not easily collated and the potential importance of protein variants in solution of biological problems is not widely recognized.

ACKNOWLEDGEMENTS

The author acknowledges the assistance of Drs. V.M. Chapman and J.E. Womack in preparing Table 2 and Figure 1. Reference 6 was provided to me prior to publication.

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