In this article we will discuss about the functional activities of gene in action.
The functional activity of these genes which are needed in all cell types are known as house-keeping genes and those who are active or the activities of those genes are found only in some specialized cells are known as luxury genes. But from the point of view of the classical geneticist a good gene is one which yields perfect Mendelian ratios.
All the genes are originally straight-forward in their effect. The enormous volume of research after the birth of molecular genetics in the 1950, has filled our gaps in the basic concept of molecular basis of heredity. Apart from the enormous volume of research, the fundamental definition of the gene still holds true.
Still today a gene can be defined as the “stretch of DNA, thousands of base pair long, including translated and untranslated stretches of nucleotides both within and outside the region of amino acid coding sequences, which is delegated to the synthesis of a single polypeptide molecule”.
Before going into the detail discussion about the functional activities of gene, let us consider the recent additions to our knowledge of the gene:
(i) Eukaryotic genes have been found to possess non-coding sequences of DNA, intercalated between coding sequences. Usually the entire length of DNA containing the coding sequences is translated into a long mRNA which is known as pre-mRNA. This pre- mRNA is then suitably spliced after excision of the non-coding introns.
After splicing, the processed nnRNA is translated into proteins. This is the cause for the introduction of the term “split gene” in case of eukaryotic gene. Because it is essential for the subsequent synthesis of protein, RNA splicing is necessary.
(ii) In case of immunoglobulin synthesis two types of protein are necessary which are variable protein and constant protein. It has been found that the portion of DNA responsible for the synthesis of two such protein are separated with each other. This type of orientation of a gene in DNA is known as variable gene.
(iii) In some cases, the same length of polynucleotides can yield more than one gene by the simple shifting of the reading frame. This type of gene is also known as overlapping gene.
(iv) Some specific segments of the DNA that are normal constituents of the genome of an organism which have a common unique structure. These segments of DNA have the ability to join DNA segments which have no common homology and thus are able to mediate various recombinational events as well as other rearrangements within or between DNA molecule are known as transposable element or Tn element or mobile gene or movable gene.
(v) Sometimes some genes are inserted into a DNA via mRNA which is copied from the donor gene (by the process transcription). After transcription the mRNA is processed and, therefore, it becomes intronless. The processed mRNA is then copied into a DNA with the participation of an enzyme reverse transcriptase.
The copied DNA from mRNA is known as cDNA which becomes integrated into the recipient DNA. The cDNA is intronless and exhibits the signs of other mRNA processing events. This type of cDNA gene is known as processed gene. Examples of processed genes that have been characterised already include those for α-globin, human immunoglobulin, λ light chain and human β- tubulin.
(vi) In human genome some portion of DNA in an chromosome is apparently useless i.e. does not serve any specific function but maintain themselves in the genome. These DNA portion is known as “Selfish DNA”. Crick and Orgel consider all DNA—for which no function has been found—to belong to a category of useless DNA or junk DNA.
(vii) Gene families are formed by gene duplication. They are thought to have arisen by duplication of an ancestral gene. A set of duplicated genes that encode proteins with similar but non-identical amino acid sequences is called a gene family and the encoded closely related homologous proteins constitute a protein family. Many protein families contain from several to as many as 20 members, a few family contain hundreds of members like:
(viii) Pseudogenes are also duplicated genes but are nonfunctional, sometimes they may be transcribed into RNA.
(ix) Genes for the tRNA, rRNA and his- tones proteins are known as tandemly repeated genes. These tandemly repeated genes are distinguished from the duplicated genes of the gene family in that the multiple tandemly repeated genes encode identical or nearly identical proteins or functional RNAs.
Most often copies of a sequence appear one after the other in a head to tail fashion over a long stretch of DNA. These tandemly repeated genes are needed to meet the great cellular demand.
Genetic Polymorphism:
In case of multiple alleles that two or more alternative forms of a gene can occur in a particular locus and where these alternatives occur in the population with an appreciable frequency, greater than could be accounted for by new mutation, and this phenomenon is referred to as genetic polymorphism.
Till now, over 60 different biochemical polymorphism have been identified in human population; of these about 30 are enzyme Polymorphism and the rest are non- enzymatic. Probably all these arose through mutation of some kind and the fact that they are relatively common which suggest that they all bestow some subtle advantage through which natural selection can act.
However, only a small percentage have much clinical importance at the present time, and even where an enzyme varient is associated with lower than normal activity, the body often compensates completely. Examples of genetic polymorphisms are ABO, Rh blood group, HLA histocompatibility system and abnormal haemoglobin are described in the next section of the book.
Here, another interesting example is considered and that is alpha-1-antitrypsin, which is an inhibitor of certain enzymes like elastase, collagenase etc. This alpha-1-antitrypsin is present in most of the human blood serum and constitutes 3.5% of the total protein in normal serum.
It has been discovered that some patients with pulmonary emphysema had a deficiency of alpha-1-antitrypsin and it is heritable. This deficiency is due to the presence of a gene Z and some of the alelles, and, till now, 20 different inherited variants of this deficiency already been identified. This polymorphism is known as Pi (Protease inhibitor). Family studies have confirmed that all the Pi types are inherited as intermediate autosomal character.
Following is a portion of different Pi types with concentration of alpha-1-antitrypsin in serum:
Drug Induced Genetic Action:
This aspect of gene action is now gaining importance due to its practical application. This is the recognition of inherited abnormalities which, under natural conditions, may cause little or no discoverable harm, but in which the administration of particular drugs may produce-serious effects.
One of the most interesting example is porphyria variegata, a tolerably harmless condition in the ordinary way, but in which a variety of drugs, notably barbiturates, may cause severe and often fatal reaction. This condition is very common in the white population of South Africa where many thousands of people have inherited the gene from a couple who married in 1688.
Another example is pseudocholinesterase deficiency. Apparently does no harm under natural condition, but does result in marked sensitivity to a muscle-relaxant drug— suxamethonium.
Some other examples are as follows with their inducing drugs:
This branch of gene action is now known as pharmacogen.
Manifold Effects of a Gene:
A single abnormal gene may remarkably produce varied effects. It would seem that major abnormal genes are no respecters of anatomical boundaries, and there is almost no limit to what they can do. Apparently different or unrelated effects are often referred to as pleiotropic.
Most common example is the Arachnodactyly, Marfan’s Syndrome hyper- mobility of joints is due to a dominant abnormal gene. The multiplicity of effects are so often seen in inherited disorders, the involvement, say, of both ectodermal and mesodermal tissues, and the fact that the same individual features are often repeated in several different syndromes as well as of occurring in isolation. Mendelian ratios in pedigree chart indicate that a single gene is involved.
Different Genes may Produce Same Effect:
Similar or indistinguishable effects may be produced by different genes. Many examples are known in animals and plants, but the phenomenon is very common in man. Genes producing apparently identical results are sometimes called mimic genes. Retinitis pigmentosa may be taken as an example.
In this disease there is a very gradual degeneration of the retina, usually commencing in infancy or childhood. The first symptom is usually night- blindness, which is insidious in onset and slowly progressive. There is much variation in degree, the disability may become very severe or it may sometimes be so slight, even in case of long-standing that it is revealed only on examination.
Sometimes retinitis pigmentosa is due to a dominant gene and many pedigrees are on record showing regular transmission through a number of generations. A sex-linked gene sometimes responsible. The majority of instances in most areas, however, are recessive.
Moreover, it is very likely that the recessive gene responsible is not one gene but any one out of several. This is indicated by the rate of consanguinous marriages amongst the parents. The frequency of recessive retinitis pigmentosa in some population is probably of the order of 1 in 4000.
Thus retinitis pigmentosa may be due to at least one dominant gene, a sex-linked gene or to any one of several recessive genes (in this regard it should be remembered that some cases of retinitis pigmentosa may also be non-genetic).
Another good example is the deaf mutism. It is very interesting from the genetic point of view that deaf mutes marrying each other provides opportunities for genetic enquiry and there have been some admirable surveys. There is good evidence that the number of alternative recessive genes is at least five or six. Very rarely deaf mutism may show sex- linked transmission.
Differential Penetrance of Genes:
The effects produced by a gene may be manifold, because the gene is expressing itself against a background of thousands of other genes and of variable environmental influences. The differences between the possessors of the gene, in single or double dose, as is appropriate, may be differences of kind, or of degree, or, of course, of both. Differences in kind are seen very commonly in the complex inherited syndromes.
For example, in case of arachnodactyly with ectopia lentis, there are number of abnormalities; but no single affected person ever exhibits all of them. Some of the abnormalities are very common, some occasional and some are very rare. Similarly, in case of microphthalmia which is due to the presence of a sex-linked gene.
In case of male the presence of this gene cause-blindness, but in some it may produce mental defectiveness, and in some other it may produce normal intelligence. Some sufferers of this gene may produce retinitis pigmentosa while others do not.
The phenotypic effects of a gene may differ in degree. In case of Polydactyly (causative agent is a dominant gene), some affected persons belonging to the same family may have well-developed extra digits on both hands and on both feet, while in others some of the extremities only are abnormal, e.g. the extra digit may be represented by no more than a small nodule.
Therefore it appears that the expressivity of a gene is not always constant or in other words the phenotypic expression of a gene is dependent upon several other factors like environmental condition, nutritional status, age of the bearer of the gene etc.
Gene may not Always Produce an Effect:
Not only a gene can exhibit wide variations of expressions but sometimes a gene may not produce any phenotypic result. For example, in case of Polydactyly, where all four extremities may be abnormal, or three, or two, or one, or, finally, the hands and feet may be entirely normal though the individual does, in fact, possess the concerned gene and it is proved by the birth of polydactylous children.
Following is a pedigree chart of Polydactyly:
