Tag Archive for Bioinformatics

Dogmas

Francis Crick developed the model of protein synthesis which he called the central dogma (1958) which states that DNA makes RNA makes protein. The dogma emphasises the unidirectional pathway from DNA (the archives of genetic material) by transcription converted to mRNA and then converted into specific amino acid sequences of proteins by translation.

Another step can be added: Amino acid sequences determine protein structure. Most proteins adopt specific 3D conformations dictated by their amino acid sequences alone. Protein structure determines protein function.

This one-way flow requires Darwinian natural selection at the protein level to be a mechanism of evolution – as opposed to direct selection of DNA sequence changes. This is achieved through mutation which generates variation (which changes individual DNA sequences) but does not move a population to a better-adopted state.

The ribosome makes possible the connection between heritable genetic information (as a nucleic acid) and the agents of biochemical activity (proteins). Selection acts as the functions produced by the proteins, and RNAs encoded in the genome and on the regulatory mechanisms.

Some genetic change is non-selective: neutral evolution or genetic drift. Drift is especially important in small populations. The result of both selection and drift are inherited alternations in genomes – including both changes in sequence and changes in allele frequencies. The changes change the nature and expression patterns of the proteins and RNAs in individuals of a population.

What are Proteins ?

Proteins are biological macromolecules that provide 3D structures shaped for many different individual functions. These functions include:

  • Structural Proteins: These proteins include keratins (found in hair and in the skin), the cytoskeleton and coats of viruses.
  • Enzymes: These proteins catalyse the reactions of the metabolism and the replication and transcription of DNA.
  • Antibodies: Antibodies are proteins that recognise and repel invading pathogens and inactive toxins ;
  • Regulatory Proteins: These control the transcription of genes ;
  • Sensors: Sensors detect and implement signals generated within our body and those from the environment we live in;
  • Transporters and pumps : Control the traffic into and out of cells and organelles;
  • Transducers : These are motor proteins that convert chemical to mechanical energy (e.g. for muscle contraction, kinesins and dyneins of intracellular transport, ATP synthases.

A Kinesin in action

 

Proteins: Structure and Function

 

Proteins create the structures for the wide-range of functions by varying the common underlying chemical scheme. They are linear polymers (a macromolecule composed of many repeated sub-remits) that have the same polypeptide backbone. Along the backbone is a variable sequence of side-chains that distinguishes the different proteins. The side-chain at any position is one-of-twenty canonical chemicals which make possible a common synthetic mechanism: ribosomes assemble proteins under the direction of messenger RNA (mRNA) sequences.

The three-dimensional structures of proteins are inherent in their amino acid sequences : natural proteins fold spontaneously to from individual ‘native’ structures.

The polypeptide chain is flexible, and can assume many different spatial conformations which bring into proximity different constellations of sidechains. These constellations interact with one another and with solvent (a substance that dissolves a solute). One of these conformations creates a set of stable interaction which leads to the protein’s native state at equilibrium.

The range of protein structures and functions depends on the variety in the properties of the sidechains. The 20 natural sidechains vary in size and other physiochemical properties.

  • some are polar or charged
    • they can participate in hydrogen bonding or electrostatic interactions with other residues or solvent;
  • charged atoms occur at or near ends of (relatively) long and flexible sidechains;
  • atoms close to backbone are non-polar;
  • two sidechains with positive and negative charge can form a soft bridge;
  • sidechains can be non-polar :
    • Large aliphotic sidechains are hydrophobic (do not like water);
    • The clustering of hydrophobic sidechains on the inside of proteins provides the thermodynamic force for protein-folding.

Source: Introduction to Protein Science – Arther M Lesk

The nature of genetic code

Three bases constitute a codon, that stand for one amino acid. Out of the 64 possible 3-base codons, 61 specify amino acids while the other 3 are stop signals. The ribosomes scan a messenger RNA 3-bases at a time and bring in the corresponding amino acids to link to the growing protein chain. When they reach a stop signal, they release the completed protein.

Genetic Code

Genetic Code

 

How genes direct the production of polypeptides

Gene expression is the process by which a gene product (RNA or polypeptide) is made. Two steps (transcription and translation) are required to make a polypeptide from the instructions in a DNA gene.

 

In transcription, an enzyme called RNA polymerase makes a copy of one of the DNA strands (an RNA copy).

 

In translation, this RNA (messenger RNA or mRNA) carries the genetic instructions to the cell’s protein factories called ribosomes. The ribosomes “read” the genetic code in the mRNA and put together a protein according to its instructions.

 

Ribosomes already contain molecules of RNA (ribosomal RNA or rRNA). Experience shows that ribosomes are non-specific translation machines that can make an unlimited number of different proteins, according to the instructions in the mRNAs that visit the ribosomes.

 

The process of translation

The process of translation

One gene, one polypeptide rule

Transcription and Translation

Gene Replication

DNA is a double helix – two DNA strands wound around each other. The bases of each strand are on the inside of the helix, and a base on one strand pairs with one on the other in a very specific way. DNA has only four different bases:

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Wherever we find an A in one strand, we always find a T in the other; wherever we find a G in one strand, we always find a C in the other. The strands are complementary. If we know the base sequence of one, we automatically know the sequence of the other.

The process of replication takes one strand (after they come apart) and enzymes build new partners for them using the old strands as templates following the Watson-Crick base-pairing rules. This process is called semi-conservative replication since one strand of the parental double helix is conserved in each of the daughter double helices.

A Schematic Diagram of DNA Replication

A Schematic Diagram of DNA Replication

The relationship between genes and proteins

All living things carry out countless chemical reactions and that these reactions are catalysed (accelerated) by proteins called enzymes. Many of these reactions take place in sequence, so that one chemical product becomes the substrate (starting material) for the next reaction. These sequences of reactions are called pathways, and the substrates within a pathway are called intermediates.
Mutagens are used to introduce mutations into genes and then observe the effects of these mutations on biochemical pathways.
Most genes contain the information for making one polypeptide. Genes do more than one thing:

  • first, they are replicated faithfully;
  • second, they direct the production of RNAs and proteins;
  • third; they accumulate mutations and so allow evaluations.
Experiments that establish relationships between genes, proteins, cells and functions.

Experiments that establish relationships between genes, proteins, cells and functions.

http://www.bx.psu.edu/~ross/workmg/TxnRNAPolCh10_files/image002.png

Pathway for Gene Expression

From DNA to Protein

From DNA to Protein

Genetic Recombination and Mapping

Genes on separate chromosomes behave independently in genetic experiments whereas genes on the same chromosomes behave as though they are linked. However, genes on the same chromosome usually do not show perfect genetic linkage. The offspring that have a new combination of alleles that are not seen in the parents are called recombinants.

Recombinants are produced due to crossover between homologous chromosomes (i.e. carrying some alleles of the same genes) during meiosis (gamete formation). Recombination is the process that brings together a new combination of alleles. Genetic mapping (or genetic linkage) is the tendency of alleles that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction.

Genes whose loci are nearer to each other are less likely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be genetically linked (the nearer two genes are to one chromosome, the lower is the chance of a swap occurring between them and the more likely they are to be inherited together). If two loci recombine with a frequency of 1%, they are said to be one centimorgan apart. These rules apply both to eukaryotes (organisms whose genetic material is confined to a nuclear compartment) and to prokaryotes (organisms whose genetic material is not confined to a nuclear compartment).

The cell nucleus has a mixture of compounds called nucleins. The major component of nuclein is deoxyribonucleic acid (DNA), with a related compound called ribonucleic acid (RNA). Both DNA and RNA are long polymers – chains of small compounds called nucleotides. Each nucleotide is composed of a sugar, a phosphate group and a base. The chain is formed by linking the sugars to one another through their phosphate groups.

Protein is made of chain composed of links called amino acids. The amino acids in proteins are joined by peptide bonds, so a single protein chain is called a polypeptide.

Example of Genetic Linkage

Genetic Linkage

Cellular Structure

schematic of plant and animal cell structures

Schematic of plant and animal cell structures

  1. The nucleus is a discrete structure within the cell that contains genetic material, DNA.
  2. DNA is usually present in a cell as a network of fibers, called chromatin.
  3. During mitosis, DNA molecules form the condensed chromosome structure by coiling and supercoiling around specialized proteins.
  4. The centrosome is a structure composed largely of microtubles. Paired centrosomes organise the formation of spindle fibers during mitosis.
  5. The endoplasmic reticulum (ER) is a network of membranes throughout the cell; cells have both smooth and rough ER.
    1. The rough ER is studded with ribosomes, giving it a rough appearance.
    2. The bound ribosomes of the ER synthesize proteins destined for secretion from the cell or that are to be incorporated into the membrane or into specific vacuoles.
    3. The smooth ER synthesizes lipids, phospholipids and steroids. It also carries out the metabolism of carbohydrates, detoxification of natural metabolism products and of alcohol and drugs, steroid metabolism and attachment of receptors on cell membrane proteins.
  6. The Golgi apparatus is a continuation of the membrane network of the ER. The Golgi apparatus is part of the endomembrane system. It packages proteins into membrane-bound vesicles inside the cell before the vesicles are sent to their destination. It is of importance in the processing of proteins for secretion, containing a set of glycosylation enzymes that attach various sugar monomers to proteins or they transfer through the apparatus.
  7. Ribosomes that are free in the cytosal synthesize proteins that remain in the cell and are not transported through the endoplasmic reticulum and Golgi apparatus.
  8. The mitochondrion is the site of energy production in the cell. It consists of a double membrane system. The outer membrane is smooth and the inner membrane has convoluted folds. It can divide independently of the cell and contains its own double standard DNA.

 

Chromosome Theory of Inheritance

The notion that chromosomes carry genes is the Chromosome Theory of Inheritance. Genes are observable objects in the cell nucleus.

 

The Phenotype is an observable characteristic of an organism. Most chromosomes, called autosomes, occur in pairs in a given individual. The X chromosome is an example of a sex chromosome.

 

Each gene has its place on a chromosome, called the locus.

 

Diploid organisms (such as human beings) have two copies of all chromosomes (with the exception of sex chromosomes). Thus they have two copies of most genes. The two copies can either be the same alleles, in which case the organism is homozygous, or different alleles, in which case the organism is heterozygous.

 

The genotype is the allelic constitution of the organism.

 

The wild-type genotype is the most common (generally accepted standard) phenotype of an organism. This is sometimes called the standard type. Mutant alleles are generally recessive, though not always.

 

Diagram of Chromosome Theory of Inheritance

Chromosome Theory of Inheritance

DNA Structure

DNA is a complex, double-stranded polysaccharide composed of a backbone containing phosphate groups bonded to deoxyribose sugar.

Two phosphate groups are covalently bonded to each ring-shaped sugar. One is linked to the third carbon (3′) and the other to the fifth carbon (5′), forming what is called a 3′-5′ glycosidic bond. This confers directionality to each nucleoside. The physical torsion on the molecule due to this structure causes DNA to twist and form a double helix.

DNA Structure

DNA Structure

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