One-Gene-One Enzyme Hypothesis | Genetics

In this article we will discuss about:- 1. Meaning of One-Gene-One Enzyme Hypothesis 2. Significant Steps in the Elaboration of One Gene-One Enzyme Hypothesis 3. Present Position.

Meaning of One-Gene-One Enzyme Hypothesis:

These are the genes and not the traits that are inherited. So the basic question is how the gene functions to elaborate a pheno­type. The question is actually twofold. One aspect is concerned with the biochemical nature and activity of the gene and the other aspect is a developmental one, i.e., how a particular biochemical unit creates a particular trait.

The best supported hypothesis of how a gene produces its effects is called the ‘one gene-one enzyme’ hypothesis. According to it the gene controls the production of one enzyme. The enzyme, in turn, re­gulates a specific metabolic reaction.

In the development of a particular phenotype, a number of metabolic reactions occur in a stepwise fashion, each of these steps is regulated by a specific enzyme and each of these enzymes is in turn produced under the direction of a specific gene.

Significant Steps in the Elaboration of One Gene-One Enzyme Hypothesis:

Alcaptonuria. In 1909, A. E. Garrod, an English physician, investigated a condition known as Alcaptonuria in which the urine blackens upon exposure to air and carti­lage tissue becomes black and hardened. Family pedigrees showed Alcaptonuria to be inherited by a recessive gene.

He found that in Alcaptonuria the substance res­ponsible for the blackening of the urine was Homogentisic acid which oxidises upon exposure to air and postulated that Homo­gentisic acid in normal persons is metabolised (i.e., broken down chemically) but not in persons with Alcaptonuria.

He pro­posed that the normal metabolism of the acid to a simpler chemical substance was under the control of an enzyme. Thus biochemi­cally, according to Garrod, Alcaptonuria results from the absence of an enzyme to metabolise Homogentisic acid.

Garrod also showed that the Alcapto­nuria trait behaved genetically as a re­cessive allele and it occurs only with a homozygous recessive genotype.

Albinism:

Garrod also found a consistency with his hypothesis of genes regulating enzymes in his studies in Albinism. Albinism had been recognised as hereditary and is under the control of a recessive gene a. The trait appears in genotype bearing aa.

He pos­tulated that albinism results from a failure on the part of the amino acid, Tyrosine to become metabolised to melanin, a black pigment. Absence of melanin pigment re­sults in the condition known as Albinism. Paralleling his conclusions on Alcaptonuria, Garrod advocated that an albino lacks the appropriate gene which produces the en­zyme for the conversion of Tyrosine to melanin.

Thus in his studies with Alcaptonuria and Albinism, Garrod arrived at the hy­pothesis of gene action in which genes regulate or control the presence and work­ing of enzymes.

Garrod’s views were not accepted in his own time. In the present-day knowledge, however, the view that genes regulate the presence of enzymes and thereby in­directly control metabolic reactions is accepted.

Work on Neurospora:

The ‘one gene-one enzyme hypothesis’ was restated in 1941 by Beadle and Tatum on the basis of the result of work on the fungus, Neurospora crassa. The bread mould, Neurospora can be cultured on a medium containing certain inorganic salts, a carbo­hydrate like table sugar and vitamin Biotin.

As Neurospora can synthesize all its biochemical requirements from a minimal medium, it is reasonable to assume from the gene-enzyme hypothesis that a change in a gene would result in the plant’s in­ability to make one of its particular re­quirements or in other words, a given metabolic pathway of the plant would be blocked or interrupted by a change in a gene.

Beadle and Tatum were able, by X-ray treatment, to produce mutants which differed from the normal wild type only in their inability to synthesise certain amino acids.

One mutant required the addition of arginine to its normal growth medium, another mutant had to be supplied with arginine and citrulline while a third mu­tant required arginine, citrulline and or­nithine for normal growth. Ornithine and citrulline are in fact steps in the biochemical synthesis of arginine.

It becomes apparent then that at each stage blockage can be caused by a sepa­rate non-allelic mutant gene. This sugge­sts that there is an enzyme for each reac­tion controlled by its own gene. Thus,

Mutation of any one of these genes causes an enzyme deficiency which results in the blockage of the sequences. For their work, Beadle and Tatum were awarded Nobel prize in 1958.

Sickle-Cell trait:

Linus Pauling and others have done work on ‘Sickle-cell trait’—a disease occurr­ing among Africans. The term Sickle-cell refers to the peculiar sickle or crescent shape of the red blood cells of affected person.

People who are homozygous for sickle-cell gene suffer not only from anaemia but also from such conditions as kidney damage, spleen enlargement and skin lesions and early death. In heterozygous condition, the persons sometimes suffer from anaemia.

Thus in the sickle-cell trait blood of the genotype is heterozygous having both Hb_A (normal) and Hb^s (mutant) alleles and the haemoglobin consists of a mixture of both kinds.

Pauling and Itano showed that the Hb^S haemoglobin comes out of the solu­tion when oxygen content is low and also that the normal haemoglobin and sickle- cell haemoglobin respond differently to an electric field—normal haemoglobin moves as a negative ion and sickle-cell haemo­globin as a positive ion.

V. M. Ingram, in correlated studies, has been able to demonstrate the actual differ­ences between the molecules of the two kinds of haemoglobin. He showed that normal haemoglobin had the amino acid glutamic acid in certain positions and that a different amino acid valine was found in these positions in sickle-cell haemoglobin.

Thus normal haemoglobin (and hence normal R.B.C.) is converted by the substi­tution of certain amino acid (valine) to an abnormal haemoglobin which causes sickling of R.B.C. It is known that amino acids form chains—the Polypeptides— which are collectively referred to as proteins, the change in a gene at the sickle- cell locus results in a very specific change in a protein by the substitution of one amino acid for the other.

Thus this piece of research is particularly significant in correlating chemical changes with gene changes and therefore-throwing some light on the way gene gives information for protein synthesis.

Another point of interest in sickle-cell trait study is that the heterozygous condi­tion known as sickle-cell trait confers a benefit on its victims in malarial regions giving immunity against the’ Plasmodium trophozoites causing malignant malaria. This selection value probably accounts for the high frequency of sickle-cell trait in tropical Africa.

Present Position of One Gene-One Enzyme Hypothesis:

Much research is being carried out to find the connection between protein differ­ences and gene differences. Many experi­ments have been performed with micro­organisms which are most suitable. The fungus Neuropora is normally able to synthesise Adenine but various mutants can only grow if adenine is added to the culture medium.

If two of these non-allelic adenine requiring mutants (which are of compatible strains) are cultured in the same medium their hyphae fuse and form Heterokaryons. In the mycelia thus formed, two kinds of nuclei mingle and the new ‘growth becomes independent of Adenine. This is known as complementation since each supplies an enzyme missing in the other.

Most allelic mutants do not show com­plementation, but in a few rare cases they do and this suggests that the gene can no longer be regarded as an entity. The lozenge trait in Drosophila shows that the gene at the lozenge locus on the chromo­some regulates not only the eye-size but also the eye-facets. In addition, the same gene affects the amount of eye pigment and reduces fertility in homozygous re­cessive females.

The several effects of a single gene on different traits are refer­red to as Pleiotropism. The lozenge gene, shows pleiotropism in affecting the three different aspects of the eye (size, facet, pigment) and also fertility. Thus it is more likely that a gene consists of smaller subunits of func­tion.

These subunits have been termed cistrons. It is likely that a cistron deter­mines one polypeptide chain and a refor­mulation of the one gene-one enzyme hypothesis has been made. The present reformulated hypothesis is one cistron-one polypeptide.

Some unsolved problems of gene action:

In a cell there are many genes. But only a few of the genes in a particular cell are active at any one time. The question that arises what calls them into action and how- are the other genes held in check? One of the proteins bound to the DNA in the chromosome is histone. It is suspected that histone may play a part in suppressing gene activity until it is required.

The existence of two fundamental types of genes have been postulated by Jacob and Monod. These genes have been termed as Structural and Controlling genes. The structural genes according to them specify amino acid sequence, while the controlling genes regulate the activity of the structural genes in the DNA.

A set of genes is thought to be active only when its controlling gene, the ‘Operator’ is active. The operator in turn may be controlled by a ‘Regulator gene’ which is sensitive to chemical changes in the internal environment of the cell. The whole concept is hypothetical in nature but it may be a starting point for further research in the line.

Genetic code:

Research in the field of elucidation of genetic code is yet to cross its infancy and it is not proper to give any detailed account of the genetic code. However, a summary of the present state of knowledge and hypothesis is given below.

The linear sequence of bases or base pairs in the segment of the DNA that we call gene, appears to form a code for the linear sequences of amino acids in a corresponding polypeptide chain. There are twenty known amino acids and only four bases or base pairs in the DNA. It is thought that each amino acid is coded for by at least a triplet of nucleotide pairs.

Such a code would then give 4³ = 64 possible symbols or codons. The 64 codons are too many for twenty amino acids, so it seems more likely that a doublet code is present which could only give 4² or 16 possible codons. Each base pair can only belong to only one codon and there is no overlapping. This is suggested-Jay the fact that a single mutation causes a change in a single amino acid.

Work on artificial polymerisation of amino acids has ‘shown that a triplet sequence of any three bases can bring about specific amino acid formation but in no case it has been found that all four bases are needed for the formation. Some of the possible codons postulated in Nirenberg’s work are given in Table Genetics-5.