Basis of Inheritance

Discoverers and Discoveries Related to Genetics

Father of Genetics Gregor John Mendel
Father of Modern Genetics - Bateson
Father of Drosophila Genetics - Thomas Haunt Morgan
Father of Indian Genetics M.S. Swami Nathan
Father of Human Genetics Garrod
Father of Radiation Genetics - H. J. Muller

The hereditary material is present in the nucleus of the cell, whereas protein synthesis takes place in the cytoplasm.

 

DNA structure

For genes to be composed of DNA, it is necessary that the latter should have a structure sufficiently versatile to account for the great variety of different genes and yet, at the same time, be able to reproduce itself in such a manner that an identical replica is formed at each cell division. In 1953, Watson and Crick, based on x-ray diffraction studies by themselves and others, proposed a structure for the DNA molecule that fulfilled all the essential requirements. They suggested that the DNA molecule is composed of two chains of nucleotides arranged in a double helix. The backbone of each chain is formed by phosphodiester bonds between the 3' and 5' carbons of adjacent sugars, the two chains being held together by hydrogen bonds between the nitrogenous bases, which point in toward the center of the helix. Each DNA chain has a polarity determined by the orientation of the sugar-phosphate backbone. The chain end terminated by the 5' carbon atom of the sugar molecule is referred to as the 5' end, and the end terminated by the 3' carbon atom is called the 3' end. In the DNA duplex, the 5' end of one strand is opposite the 3' end of the other, that is, they have opposite orientations and are said to be antiparallel. The arrangement of the bases in the DNA molecule is not random. A purine in one chain always pairs with a pyrimidine in the other chain, with specific pairing of the base pairs: guanine in one chain always pairs with cytosine in the other chain, and adenine always pairs with thymine, so that this base pairing forms complementary strands. For their work Watson and Crick, along with Maurice Wilkins, were awarded the Nobel Prize for Medicine or Physiology in 1962.

The Cell

 

Within each cell of the body, visible with the light microscope, is the cytoplasm and a darkly staining body, the nucleus, the latter containing the hereditary material in the form of chromosomes. The phospholipid bilayer of the plasma membrane protects the interior of the cell but remains selectively permeable and has integral proteins involved in recognition and signaling between cells. The nucleus has a darkly staining area, the nucleolus. The nucleus is surrounded by a membrane, the nuclear envelope, which separates it from the cytoplasm but still allows communication through nuclear pores. The cytoplasm contains the cytosol, which is semifluid in consistency, containing both soluble elements and cytoskeletal structural elements. In addition, in the cytoplasm there is a complex arrangement of very fine, highly convoluted, interconnecting channels, the endoplasmic reticulum. The endoplasmic reticulum, in association with the ribosomes, is involved in the biosynthesis of proteins and lipids. Also situated within the cytoplasm are other even more minute cellular organelles that can be visualized only with an electron microscope. These include the Golgi apparatus, which is responsible for the secretion of cellular products, the mitochondria, which are involved in energy production through the oxidative phosphorylation metabolic pathways, and the peroxisomes and lysosomes, both of which are involved in the degradation and disposal of cellular waste material and toxic molecules.

DNA: The Hereditary Material

Composition
Nucleic acid is composed of a long polymer of individual molecules called nucleotides. Each nucleotide is composed of a nitrogenous base, a sugar molecule, and a phosphate molecule. The nitrogenous bases fall into two types, purines and pyrimidines. The purines include adenine and guanine; the pyrimidines include cytosine, thymine and uracil. There are two different types of nucleic acid, ribonucleic acid (RNA), which contains the five carbon sugar ribose, and deoxyribonucleic acid (DNA), in which the hydroxyl group at the 2 position of the ribose sugar is replaced by a hydrogen (i.e., an oxygen molecule is lost, hence 'deoxy'). DNA and RNA both contain the purine bases adenine and guanine and the pyrimidine cytosine, but thymine occurs only in DNA and uracil is found only in RNA. RNA is present in the cytoplasm and in particularly high concentrations in the nucleolus of the nucleus. DNA, on the other hand, is found mainly in the chromosomes.


Replication
The process of DNA replication provides an answer to the question of how genetic information is transmitted from one generation to the next. During nuclear division the two strands of the DNA double helix separate through the action of enzyme DNA helicase, each DNA strand directing the synthesis of a complementary DNA strand through specific base pairing, resulting in two daughter DNA duplexes that are identical to the original parent molecule. In this way, when cells divide, the genetic information is conserved and transmitted unchanged to each daughter cell. The process of DNA replication is termed semiconservative, because only one strand of each resultant daughter molecule is newly synthesized.DNA replication, through the action of the enzyme DNA polymerase, takes place at multiple points known as origins of replication, forming bifurcated Y-shaped structures known as replication forks. The synthesis of both complementary antiparallel DNA strands occurs in the 5' to 3' direction.
One strand, known as the leading strand, is synthesized as a continuous process. The other strand, known as the lagging strand, is synthesized in pieces called Okazaki fragments, which are then joined together as a continuous strand by the enzyme DNA ligase DNA replication progresses in both directions from these points of origin, forming bubble-shaped structures, or replication bubbles. Neighboring replication origins are approximately 50 to 300 kilobases (kb) apart and occur in clusters or replication units of 20 to 80 origins of replication. DNA replication in individual replication units takes place at different times in the S phase of the cell cycle, adjacent replication units fusing until all the DNA is copied, forming two complete identical daughter molecules.

Chromosome Structure

The idea that each chromosome is composed of a single DNA double helix is an oversimplification. A chromosome is very much wider than the diameter of a DNA double helix. In addition, the amount of DNA in the nucleus of each cell in humans means that the total length of DNA contained in the chromosomes, if fully extended, would be several meters long! In fact, the total length of the human chromosome complement is less than half a millimeter. The packaging of DNA into chromosomes involves several orders of DNA coiling and folding. In addition to the primary coiling of the DNA double helix, there is secondary coiling around spherical histone 'beads', forming what are called nucleosomes. There is a tertiary coiling of the nucleosomes to form the chromatin fibers that form long loops on a scaffold of non-histone acidic proteins, which are further wound in a tight coil to make up the chromosome as visualized under the light microscope, the whole structure making up the so-called solenoid model of chromosome structure.

Gene Structure

The original concept of a gene as a continuous sequence of DNA coding for a protein was turned on its head in the early 1980s by detailed analysis of the structure of the human β-globin gene. It was revealed that the gene was much longer than necessary to code for the β-globin protein, containing non-coding intervening sequences, or introns, that separate the coding sequences or exons. Most human genes contain introns, but the number and size of both introns and exons is extremely variable. Individual introns can be far larger than the coding sequences and some have been found to contain coding sequences for other genes (i.e., genes occurring within genes). Genes in humans do not usually overlap, being separated from each other by an average of 30 kb, although some of the genes in the HLA complex have been shown to be overlapping.

Telomeric DNA

The terminal portion of the telomeres of the chromosomes contains 10 to 15 kb of tandem repeats of a 6-base pair (bp) DNA sequence known as telomeric DNA. The telomeric repeat sequences are necessary for chromosomal integrity in replication and are added to the chromosome by an enzyme known as telomerase.

Transcription

The terminal portion of the telomeres of the chromosomes contains 10 to 15 kb of tandem repeats of a 6-base pair (bp) DNA sequence known as telomeric DNA. The telomeric repeat sequences are necessary for chromosomal integrity in replication and are added to the chromosome by an enzyme known as telomerase.

 


In any particular gene, only one DNA strand of the double helix acts as the so-called template strand. The transcribed mRNA molecule is a copy of the complementary strand, or what is called the sense strand of the DNA double helix. The template strand is sometimes called the antisense strand. The particular strand of the DNA double helix used for RNA synthesis appears to differ throughout different regions of the genome.
Before the primary mRNA molecule leaves the nucleus it undergoes a number of modifications, or what is known as RNA processing. This involves splicing, capping, and polyadenylation.
During and after transcription, the non-coding introns in the precursor (pre) mRNA are excised, and the non-contiguous coding exons are spliced together to form a shorter mature mRNA before its transportation to the ribosomes in the cytoplasm for translation. The process is known as mRNA splicing. The boundary between the introns and exons consists of a 5' donor GT dinucleotide and a 3' acceptor AG dinucleotide. These, along with surrounding short splicing consensus sequences, another intronic sequence known as the branch site, small nuclear RNA (snRNA) molecules and associated proteins, are necessary for the splicing process.
The 5' cap is thought to facilitate transport of the mRNA to the cytoplasm and attachment to the ribosomes, as well as to protect the RNA transcript from degradation by endogenous cellular exonucleases. After 20 to 30 nucleotides have been transcribed, the nascent mRNA is modified by the addition of a guanine nucleotide to the 5' end of the molecule by an unusual 5' to 5' triphosphate linkage. A methyltransferase enzyme then methylates the N7 position of the guanine, giving the final 5' cap.
Transcription continues until specific nucleotide sequences are transcribed that cause the mRNA to be cleaved and RNA polymerase II to be released from the DNA template. Approximately 200 adenylate residues-the so-called poly(A) tail-are added to the mRNA, which facilitates nuclear export and translation

Translation

Translation is the transmission of the genetic information from mRNA to protein. Newly processed mRNA is transported from the nucleus to the cytoplasm, where it becomes associated with the ribosomes, which are the site of protein synthesis. Ribosomes are made up of two different sized subunits, which consist of four different types of ribosomal RNA (rRNA) molecules and a large number of ribosomal specific proteins. Groups of ribosomes associated with the same molecule of mRNA are referred to as polyribosomes or polysomes. In the ribosomes, the mRNA forms the template for producing the specific sequence of amino acids of a particular polypeptide.
In the cytoplasm there is another form of RNA called transfer RNA, or tRNA. The incorporation of amino acids into a polypeptide chain requires the amino acids to be covalently bound by reacting with ATP to the specific tRNA molecule by the activity of the enzyme aminoacyl tRNA synthetase. The ribosome, with its associated rRNAs, moves along the mRNA, the amino acids linking up by the formation of peptide bonds through the action of the enzyme peptidyl transferase to form a polypeptide chain.
Many proteins, before they attain their normal structure or functional activity, undergo post-translational modification, which can include chemical modification of amino-acid side chains (e.g., hydroxylation, methylation), the addition of carbohydrate or lipid moieties (e.g., glycosylation), or proteolytic cleavage of polypeptides (e.g., the conversion of proinsulin to insulin). Thus post-translational modification, along with certain short amino-acid sequences known as localization sequences in the newly synthesized proteins, results in transport to specific cellular locations (e.g., the nucleus), or secretion from the cell.

The Genetic Code

The triplet of nucleotide bases in the mRNA that codes for a particular amino acid is called a codon. Each triplet codon in sequence codes for a specific amino acid in sequence and so the genetic code is non-overlapping. The order of the triplet codons in a gene is known as the translational reading frame. However, some amino acids are coded for by more than one triplet, so the code is said to be degenerate. Each tRNA species for a particular amino acid has a specific trinucleotide sequence called the anticodon, which is complementary to the codon of the mRNA. Although there are 64 codons, there are only 30 cytoplasmic tRNAs, the anticodons of a number of the tRNAs recognizing codons that differ at the position of the third base, with guanine being able to pair with uracil as well as cytosine. Termination of translation of the mRNA is signaled by the presence of one of the three stop or termination codons. The genetic code of mtDNA differs from that of the nuclear genome. Eight of the 22 tRNAs are able to recognize codons that differ only at the third base of the codon, 14 can recognize pairs of codons that are identical at the first two bases, with either a purine or pyrimidine for the third base, the other four codons acting as stop codons

Mutations

A mutation is defined as a heritable alteration or change in the genetic material. Mutations drive evolution but can also be pathogenic. Mutations can arise through exposure to mutagenic agents, but the vast majority occur spontaneously through errors in DNA replication and repair. Sequence variants with no obvious effect upon phenotype may be termed polymorphisms.
Somatic mutations may cause adult-onset disease, such as cancer, but cannot be transmitted to offspring. A mutation in gonadal tissue or a gamete can be transmitted to future generations unless it affects fertility or survival into adulthood. It is estimated that each individual carries up to six lethal or semilethal recessive mutant alleles that in the homozygous state would have very serious effects. These are conservative estimates and the actual figure could be many times greater. Harmful alleles of all kinds constitute the so-called genetic load of the population.


Types of Mutation

Class Group Type Effect on Protein Product
Substitution Synonymous Silent Same amino acid
  Non-synonymous Missense Altered amino acid-may affect protein function or stability
    Nonsense Stop codon-loss of function or expression due to degradation of mRNA
    Splice site Aberrant splicing-exon skipping or intron retention
    Promoter Altered gene expression
Deletion Multiple of 3 (codon)   In-frame deletion of one or more amino acid(s)-may affect protein function or stability
  Not multiple of 3 Frameshift Likely to result in premature termination with loss of function or expression
  Large deletion Partial gene deletion May result in premature termination with loss of function or expression
    Whole gene deletion Loss of expression
Insertion Multiple of 3 (codon)   In-frame insertion of one or more amino acid(s)-may affect protein function or stability
  Not multiple of 3 Frameshift Likely to result in premature termination with loss of function or expression
  Large insertion Partial gene duplication May result in premature termination with loss of function or expression
    Whole gene duplication May have an effect because of increased gene dosage
  Expansion of trinucleotide repeat Dynamic mutation Altered gene expression or altered protein stability or function