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  Section: Genetics » Fine Structure of Gene - at the Genetic Level
 
 
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Gene vs allele : A new concept of allelomorphism

 
     
 
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Fine Structure of Gene - at the Genetic Level  (A New Concept of Allelomorphism)
Gene vs allele : A new concept of allelomorphism 
Fine structure of gene (lozenge in Drosophila, rII in T4 phage)
Cistron, recon and muton

Classical concept
In classical genetics, a distinction was made between gene and allele on the basis of following two criteria.

Recombination test. Recombination was believed to take place between two genes but not between two alleles. In other words, intragenic interallelic recombination was not conceived. For instance; a hybrid aB/Ab between mutants aa (aaBB)and bb (AAbb)for two linked genes A and B could give rise to wild type progeny on a test cross. Since A and B are linked, this would be possible only due to recombination (Fig. 14.1). On the other hand if two mutants a1a1 and a2a2 belonging to same gene A were crossed and F1 (a1/a2)is test crossed (a1a2 x aa)no wild type progeny would be expected (Fig. 14.2). It was thus, earlier believed that different genes or loci could recombine with each other by crossing over but different alleles of a gene could not. This test of allelism is illustrated in Figure 14.3.

Recombination test (a test cross) in which two linked genes in repulsion phase (aB/Ab)recombine and give rise to wild type individuals.
Fig. 14.1. Recombination test (a test cross) in which two linked genes in repulsion phase (aB/Ab)recombine and give rise to wild type individuals.
 
A cross between two mutants of same gene showing lack of recombination as shown by absence of wild type individuals.
Fig. 14.2. A cross between two mutants of same gene showing lack of recombination as shown by absence of wild type individuals.

A test of allelism (classical concept).
Fig. 14.3. A test of allelism (classical concept).
 
Cis and trans arrangements of alleles a and b in heterozygous condition.
Fig. 14.4. Cis and trans arrangements of alleles a and b in heterozygous condition.

Complementation test. It was also shown that mutant alleles of two different genes coming from two parents, thus being in repulsion phase (also known as trans configuration), will complement giving rise to wild type in F1 generation. But the mutant forms allelic to each other, will never complement (Fig. 14.4).

Thus, in its classical concept, the gene recombined as a unit, functioned as a unit and also changed (mutated) as a unit. This concept was consistent with the view of Morgan and his group that genes were like beads on a string, where one bead could change independently and recombine with its neighbouring beads. It will be seen in this section that such a view where genes corresponded to beads on a string was an oversimplification. The first exception to this came, when it was shown that Bar locus in Drosophila controlling size (number of facets) of eye, contained more than one units of function and could undergo intralocus recombination. As will be seen in Organization of Genetic Material 1.  Packaging of DNA as Nucleosomes in Eukaryotes, a concept, of beads on a string or better called as string on beads was revived in connection with chromatin structure and the nucleosome. In this case beads correspond to nucleosomes and not to genes.

Position effect
It was shown early in the present century that due to shift of loci from one position to another, or due to shift of another segment in vicinity of a locus, expression changes. This will be illustrated by following two examples.

Bar eye in Drosophila. In 1925, Sturtevant published results of his study on analysis of Bar eye mutant in Drosophila. It was shown that it was a semi-dominant mutation leading to reduction in number of facets from 779 in wild type (B+/B+)to 358 in heterozygote (B+IB)and to 68 in homozygote dominant (B/B). From homozygous for Bar eye (B/B), mutations to wild type occurred at a frequency of one in 1600, and mutation to an extreme type known as ultrabar (with only 24 facets) also occurred, although with a lower frequency (Fig. 14.5). Pure ultrabar cultures (BU/BU)could also be established. Ultrabar also gave rise to wild type eye with the same rate with which ultrabar was obtained from them. It was observed by Sturtevant that frequency of these events was much higher than what was expected due to spontaneous mutations. Therefore, Sturtevant had to seek an alternative explanation. He formulated a hypothesis and confirmed that new types arose due to unequal crossing over in the region of Bar locus. The technique used for confirming unequal crossing over, involved use of marker genes on either side of Bar locus, so that if crossing over occurred, then these marker genes on either side of Bar locus would also recombine, and will prove the occurrence of recombination. As shown in Figure 14.6, asymmetric pairing of homologous chromosomes may lead to unequal crossing over, which is evident from recombined marker genes (forked bristles = f; fused veins = fu). For instance, fB +/+ B fu, when test crossed with fBfu/fBfu, could give rise to four types

  1. ultrabar, forked bristles and fused veins (fB B fu)
  2. wild type for eye, bristles and veins (+ B+ +)
  3. wild type eye, forked bristles and fused veinsifB+fu)
  4. ultrabar, but wild type bristles and veins (+ BB +)
Position effect, due to duplication at bar locus, on the two sides of which genes f+ (wild allele for forked bristles) and fu+ (wild allele for fused veins) are shown.
Fig, 14.5. Position effect, due to duplication at bar locus, on the two sides of which genes f+ (wild allele for forked bristles) and fu+ (wild allele for fused veins) are shown.
 
Appearance of ultrabar and wild from bar eyed Drosophila, due to unequal crossing over. The evidence for crossing over was available due to recombination in f(forked bristles) and fu (fused veins) genes on the two sides of bar locus (B). (B+)* mean, no bar gene (B) is present or that only one dose of I6A region is found.
Fig. 14.6. Appearance of ultrabar and wild from bar eyed Drosophila, due to unequal crossing over. The evidence for crossing over was available due to recombination in f(forked bristles) and fu (fused veins) genes on the two sides of bar locus (B). (B+)* mean, no bar gene (B) is present or that only one dose of I6A region is found.

Sturtevant also demonstrated that phenotype of flies with two bar genes on one chromosome and none on the other (double bar heterozygous), was different from those with one bar gene on each of the two chromosomes (Figs. 14.7, 14.8). This indicates that position of gene with respect to adjacent regions also influences its expression. This was called position effect. Later C.B. Bridges and his group, through a study of salivary gland chromosomes demonstrated cytologically that Bar character was associated with a repeat of 16A region in X-chromosome (Fig. 14.8) and that ultrabar (double bar) had two such repeats in the same region.


The difference in phenotypes, between homozygous bar and heterozygous ultrabar, although in each case number of 16A segments is same. This illustrates position effect (also see Fig. 14.8).
Fig. 14.7. The difference in phenotypes, between homozygous bar and heterozygous ultrabar, although in each case number of 16A segments is same. This illustrates position effect (also see Fig. 14.8).
 
Different arrangements of segment 16A on X-chromosomes in female Drosophila and resulting phenotypes, showing position effect.
Fig. 14.8. Different arrangements of segment 16A on X-chromosomes in female Drosophila and resulting phenotypes, showing position effect.


The following conclusions can be made from this work : first that gene is not a point, but has its dimensions and that its alleles may differ in size; second, that alleles of a gene or locus may recombine with each other, producing new combinations and third, that phenotypes of a heterozygote in cis configuration (for instance + +/a1a2)and that of a heterozygote in trans configuration (a1 +/+ a2)may differ due to position effect.

Variegated position effect. Another kind of position effect can be illustrated with the help of an example of eye colour in Drosophila. White eye locus is present on X chromosome near tip of the end away from centromere. Further, centromere is flanked on either side with heterochromatin (inert and more condensed chromatin material relative to euchromatin, which is active and less condensed), the remaining region being largely euchromatic, so that white eye locus lies in euchromatin and quite away from heterochromatin. It was shown that when wild type allele of white eye locus i.e. W+, responsible for red eye colour, is transposed to a region near heterochromatin, a mottling of eye is observed (Fig. 14.9). Mottling means that some facets are wild type and some are white giving a variegated appearance. Variegation effects can also be observed, if a gene originally located near heterochromatin is transferred to a position away from it. Such changes in position of genes can result due to structural changes like inversions or translocations in chromosomes.
 
Transposition of W+ due lo inversion from a distal region to a region proximal to heterochromatin on X-chromosome in Drosophila. This leads to variegated position effect.
Fig. 14.9. Transposition of W+ due lo inversion from a distal region to a region proximal to heterochromatin on X-chromosome in Drosophila. This leads to variegated position effect.

Pseudoalleles and complex loci
Earlier in this section, we discussed criteria for allelism, which included lack of recombination and lack of complementation between two mutant alleles of the same gene. In earlier sections, we also defined allelomorphs (or alleles) as alternative forms of same gene. This classical concept of allelomorphism needed change in view of intensive work done after 1940, initially in Drosophila and later in several other organisms.

In Drosophila, a recessive sex linked mutant called lozenge (lz)is responsible for smaller, darker and more elliptically shaped eyes (Fig. 14.10). A number of mutants at this locus were discovered and could be identified due to severity of effect on eye and also due to other phenotypic effects. Ordinarily a fly heterozygous for two lozenge mutant alleles (lz1/lz2)will not yield wild type in its progeny, because wild allele is absent. However in 1940, Oliver discovered wild type flies in progeny of such heterozygotes, with a frequency of one in several thousands. This frequency was still much higher than expected on the basis of spontaneous mutation rates known. In view of this, the results could not be easily explained and the lozenge locus was then thoroughly studied by M.M. Green, a student of Oliver.
 
Wild and lozenge eye phenotypes in Drosophila.
Fig. 14.10. Wild and lozenge eye phenotypes in Drosophila.

Following Sturtevant's technique with Bar locus, Green marked the lozenge locus on either side by marker genes to confirm if the wild type appeared due to recombination. If wild type was the result of recombination, Green expected that marker genes would also recombine. In his experiments, Green observed that not only wild type flies appeared for lozenge, but the marker genes a and b also recombined suggesting that lz1 and Iz2 could recombine (Fig. 14.11). This suggested that two mutants may be separated by a distance within the gene.

Later E.B. Lewis, in 1951 reported results of one of his experiments, where from a cross of apricot eyed and white eyed flies (apricot is an allele of white eye locus), he obtained F1 having intermediate eye colour. In F2, he had expected segregation only for apricot and white, but to his surprise, he recovered at a very low frequency wild type also as earlier shown by Oliver and Green in case of lozenge locus.

In both examples of lozenge and eye colour, mutant alleles apparently recombined and therefore proved to be nonallelic according to the classical concept of allelomorphism described earlier. Since these alleles behaved as non-allelic, Lewis preferred to call them pseudoalleles and the phenomenon as pseudoallelism. Pontecorvo later however argued that since our concept of allelism has changed and that the classical concept of alleles has been modified in view of this work, it is needless to call this phenomenon as pseudoallelism and the elements as pseudoalleles. He, instead, suggested that the phenomenon be called Lewis effect and the mutant elements be called alleles as earlier.
 
Results and interpretation of Green's experiment in Drosophila where female Iz1 /Iz2 was crossed with male Iz |— or lz2|—.
Fig. 14.11. Results and interpretation of Green's experiment in Drosophila where female Iz1 /Iz2 was crossed with male Iz |— or lz2|—.

Position pseudoallelism or cis-trans effect In above experiments of Green and Lewis we tried to demonstrate that intragenic interallelic recombination can take place leading to appearance of wild type (in a very small frequency) in the progeny of a F1 heterozygote for two mutant alleles. If two mutant alleles occupy different positions, showing close linkage rather than same position, then one may expect that F, heterozygote should have a genotype lz1+/+lz2 or apr+/+w and, therefore, should express wild phenotype. Since F1 did not exhibit wild phenotype, we may like to examine the second criterion for allelism i.e. lack of complementation. In view of this criterion, we may explain the absence of wild type in F1 due to lack of complementation. Such a lack of complementation is due to position effect, which can be understood by studying two arrangements of mutant alleles.

For instance in heterozygote for lz1 and lz2, two arrangements are possible (Fig. 14.12), one with both mutant alleles on same chromosome and their wild counterparts on the other homologue (cis), the other with two mutant alleles on two different homologues (trans). For lozenge locus (lz1 and lz2)cis and trans arrangements are shown in Figure 14.12. It is also indicated that in cis position they will express wild type, and in trans configuration, the mutant phenotype. This may presumably be due to position effect, where a mutant allele does not allow adjacent region to express wild phenotype. This difference in phenotypes due to cis and trans arrangements is known as cis-trans effect.
 
Cis and trans configurations of heterozygotes involving two alleles lz1 and lz2 at lozenge eye locus in Drosophila.
Fig. 14.12. Cis and trans configurations of heterozygotes involving two alleles lz1 and lz2 at lozenge eye locus in Drosophila.

An explanation for cis-trans effect was given by E.B. Lewis, who believed in sequential nature of gene product synthesis. According to him, if both mutant alleles are on one chromosome, the other chromosome will be normal and will be able to produce the end product. Such a situation is found in cis arrangement. But in trans arrangement, sequence of steps involved in synthesis will be interrupted due to mutations on either of the two homologous chromosomes, thus leading to a mutant phenotype (Fig. 14.13).
 
Possible explanation at the molecular level in terms of synthesis of polypeptides in cis and trans configurations.
Fig. 14.13. Possible explanation at the molecular level in terms of synthesis of polypeptides in cis and trans configurations.
 
     
 
 
     




     
 
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