Genetics

Chapter 8

Genetics

Introduction 

• Genetics is the science of heredity. It includes the study of genes and the inheritance of variation and traits of living organisms. It is an important part of biology and gives the basic rules on which evolution acts.

• The fact that living things inherit traits from their parents is known for a long time. The modern science of genetics seeks to understand the process of inheritance.

• Some of the human diseases are related to genetics. The unit of genetic structure is deoxyribonucleic acid (DNA). DNA is organized in the form of genes. Each gene is responsible for one or a set of functions. Some human diseases are related to a single gene. Some other diseases of genetic origin are related to more than one gene. In a group of persons having the same genetic disease, a similar pattern of genes is observed. In such cases they may respond to a drug in similar fashion. This observation has led to development of personalized medicine. Study of genetics is important for person alized medicine. The principles of personalized medicines can help in reducing adverse reactions to a set of persons with genetic similar ity

• Genetics is the study of genes. It involves knowledge about genes and their functioning. Genes are located inside the nucleus and their sequence carries information. This information determines how living organism inherit various features which are called as phenotypic traits. Genetics identifies which features are inherited and explains how these features pass from one generation to another. In addition to inheritance, it studies how genes are turned on and off to control which substances are made in a cell-gene expression, and how a cell divides mitosis and meiosis.

• Some phenotypic traits like colour of eye are cIear|y visible. Other phenotypic traits like variation in an enzyme may not be easily visible. Traits determined by genes can be modified by environment e.g., height of a person is determined both by genetics and nutrition.

Chromosomes Genes and DNA  

• A chromosome is a DNA molecule with part or all of the genetic ma trials (genome) of an organism. Chromosomes are normally visible under light microscope only when the cell is undergoing the metaphase of cell division. Befo re cell division, every chromosome is copied once during S phase. The copy is joined to the original by a c entromere resulting in an X-shaped structure.

• The original chromosome and the copy are now called as sister chromatids. During metaphase, when a chromosome is in its most condensed state, the X-shaped structure is called as metaphase chromosome. In this highly condensed form chromosomes are identified under light microscope.

• Compaction of the duplicated chromosomes during cell division (mitosis/meiosis) results in a four-arm structure (see figure). The shape of chromosome depends on location of centromere. If the chromatin is located in the center the two arms are equal. If the centromere is located near one of the arms the structure is asymmetrical as shown in the Fig. 8.1. Chromosomal recombination during meiosis and subsequent sexual reproduction plays a significant role in genetic diversity. If these structures are manipulated incorrectly, the cell may undergo mitotic catastrophe and die; or it may unexpectedly evade apoptosis leading to the progression of cancer.

• Nuclear chromosomes are packed by proteins into a condensed structure called as chromatin. This allows very long DNA molecules to fit into tiny cell nucleus. The structure of chromosomes and chromatin varies through the cell cycle. They are even more condensed than chromatin and are an essential unit for cellular division. They must be replicated, divided and passed successfully to their daughter cells to ensure that genetic diversity and survival of the progeny is maintained. They may exist as either duplicated or unduplicated. Unduplicated chromosomes are single double helixes, while duplicated chromosomes contain two identical copies, called as sister chromatids and are joined by a centromere.

• In early stages of mitosis or meiosis, the c hromatin double helix becomes more and more condensed. During this stage transcription stops and genetic material becomes a compact transportable form. The compact form makes individual chromosomes visible. Mitotic metaphase chromosomes are best described by a linearly organized, longitudinally compressed array of consecutive chromatin loops.

• During mitosis micro tubules grow from centrosomes located at opposite ends of the cell and attach to the centromere at specialized structures called as kinetochores, one of which is present on each sister chromatid. A special DNA base sequence in the region of kinetochores provides longer standing attachment in this region. The microtubules then pull the chromatids apart towards the centrosomes so that each daughter cell inherits one set of chromatids. Once the cells have divided, the chromatids are uncoiled and DNA can again be transcribed

DNA 

• The molecular basis for genetics is deoxy ribonucleic acid (DNA). It consists of a chain made from four types of nucleotide sub-units, each composed of a five-carbon sugar, called 2 deoxyr ibose; a phosphate group and one of four bases: Adenine (A), Cytosine (C), Guanine (G) and Thymine (T).

• Two chains of DNA Mist around each other to form a DNA double helix with the phosphate — sugar back bone spiraling around the outside and the bases pointing inwards. In the inner part of helix adenine base pairs with thymine while guanine base pairs with cytosine. The specificity of base pairing occurs because A pairs with T with two hydrogen bonds while C pairs with G with three hydrogen bonds. Thus, two strands in a double helix are complimentary, with their sequence of bases matching such that As of one strand pair with Ts of complimentary strand and Cs of one strand pair with Gs of complimentary strand.

• The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type of nucleic acid which is similar to DNA with the only difference that sugar content in RNA is ribose, unlike deoxyribose in DNA. RNA also contains the base uracil in place of thymine. RNA molecules are less stable than DNA and are typically single stranded. There are two types of RNA: t RNA and m RNA. t RNA is a transfer RNA which has a three-nucleotide sequence called codon at its one end. At another end, t RNA carries one amino acid. Every amino acid has a different t RNA for the purpose of translocation.

• Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose; this is known as 3‘end of the molecule. The other end contains an exposed phosphate group; this is the 5‘end. The two strands of a double helix run in opposite directions. Nucleic acid synthesis, including DNA replication and transcription occurs in the 5’ 3‘direction, because new nucleotides are added via a dehydration reaction which uses the exposed 3’ hydroxyl as a nucleophile.

Gene 

• A gene is a locus or region of DNA which is made up of nucleotides and is the molecular unit of heredity. The transmission of genes to an organism’s offspring is the basis of inheritance of phenotypic traits. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. A set of genes together is called as polygenes. Many biological traits are under the influence of polygenes and gene-environmental interactions. Some genetic traits like colour of eye are instantly visible. Some other traits like blood group may not be instantly visible.

• Genes can acquire mutations in their sequence, leading to different variants known as alleles. These alleles encode slightly different versions of a protein, which cause different phenotypical traits. Usage of the term "having a gene" typically refers to containing a different allele of the same gene. Genes evolve due to natural selection or struggle for existence leading to survival of the fittest amongst alleles.

• The concept of a gene continues to be refined as new phenomena are discovered. Some viruses store their genome in RNA instead of DNA and some gene products are functional non coding RN As. Therefore, a broad, modern working definition of a gene is any discrete locus of heritable, genomic sequence which affects an organism’s traits by being expressed as a functional product or by regulation of gene expression.

• The structure of a gene consists of many elements of which the actual protein coding sequence is often only a small part. These include DNA regions that are not transcribed as well as untranslated regions of the RNA.

• All genes contain a regulatory sequence which is required for their expression. In order to be expressed, genes require a promoter sequence. The promoter is recognized and bound by transcription factors and RNA polymerase to initiate transcription. A gene can have more than one promoter resulting in m RNAs which differ in how far they extend in 5’ end. Promoter regions have a consensus sequence, however highly transcribed genes have strong promoter sequences; while others have weak promoters which bind poorly and initiate transcription less frequently.

• In addition, genes can have regulatory regions upstream or downstream to the open reading frame. These act by binding to transcription factors which then cause the DNA to loop so that the regulatory sequence becomes close to the RNA polymerase binding site. There are enhancer or silencer regions in a gene. Enhancers increase transcription by binding an activator protein which then helps to recruit the RNA polymerase to the promoter. Conversely, silencers bind repressor proteins and make the DNA less available for RNA polymerase.

• The transcribed pre m RNA contains untranslated regions at both ends which contain a ribosome binding site, terminator and start and stop codons. In addition, open reading frames contain untranslated introns which are removed before exons are translated. The sequences at the end of introns dictate the splice sites to generate the final mature m RNA which encodes the protein or RNA product.

Functions of Genes:

Gene Expression:

• In all organisms, two steps are required to read the information encoded in a gene DNA and produce the protein which it specifies.

1. First the gene’s DNA is transcribed to m RNA
2. Second, that m RNA is translated to protein.

• RNA coding genes must still go through the first step but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called as gene expression, and the resulting molecule is called a gene product.

Genetic Code:

• The nucleotide sequence of a gene’s DNA specifies the amino acid sequence of a protein through the genetic code. Sets of three nucleotides, called as codons, each correspond to a specific amino acid.
  
• In addition, a start codon and three stop codons indicate the beginning and end of the protein coding region. For four nucleotides there are 4’ = 64 possible codons. There are 20 standard amino acids. Thus, multiple codons can specify the same amino acid. The correspondence between codons and amino acids is universal amongst all known living organisms.

Transcription:

• Transcription produces a single stranded m RNA, whose nucleotide sequence is complimentary to the DNA from which it is transcribed. The m RNA acts as an intermediate between a gene and fina| protein. The transcription is performed by an enzyme called RNA polymerase, which reads the template strands in the 3’ —+ 5’ direction and synthesizes the RNA from 5‘—+ 3’. To initiate transcription, the polymerase first recognizes and binds to promoter region of the gene. Thus, a major mechanism of gene regulation is blocking or sequester Ing the promoter region, either by tight binding to repressor genes or by organizing the DNA so that the promoter region is not accessible. Translation.
• Translation is the process by which a mature RNA molecule is used as a template for synthesizing a new protein. The process is carried out by ribosomes, large complexes of RNA and protein responsible for carrying out chemical reactions to add new amino acids to a growing polypeptide chain by formation of peptide bonds. The genetic code is read as three nucleotides at a time, in units called codons via interactions with t RNA.

Regulation:

• Genes are regulated so that they are expressed only when the protein is needed, because expression draws on limited resources. A cell regulates its gene expression based on external environment, internal environment and its specific role in a multicellular organism. External environment includes available nutrients, temperature and other stresses. Internal environment includes cell division cycle, metabolism, infection status etc. A specific role includes whether the cell is part of bone, skeletal muscle or smooth muscle etc. gene expression can be regulated at any step: from transcriptional initiation to RNA processing or to post translational modification of the protein.

RNA Genes:

• A typical protein-coding gene is first copied into RNA as an intermediate during manufacture of a protein. In other cases, the RNA molecules are the actual functional products, as in the synthesis of ribosomal RNA and t RNA. Some RNAs known as ribozymes are capable of enzymatic function, and micro-RNA has a regulatory role. The DNA sequences from which such RNAs are transcribed are called as non-coding RNA genes.

Protein Synthesis 

• Protein synthesis is a process through which biological cells generate new proteins. It involves two basic processes: transcription and translation. Transcription involves synthesis of RNA from DNA template. Translation involves assembly of amino acids based on RNA.

• DNA is initially transcribed into a series of RNA intermediates. Last version is used as a template in synthesis of a polypeptide chain. Often proteins are synthesized directly from genes by the help of translating m RNA. However, when a protein is needed at a short notice, a protein precursor is produced. A pro protein is an inactive form of protein containing one or more inhibitory peptides which can be activated with removal of inhibitory sequence e.g., pro insulin is a pro protein which is converted to insulin on demand.

• In protein synthesis, a succession of I RNA molecules charged with appropriate amino acids are brought together with a m RNA molecule and matched up by base pairing through the anti-codons of the t RNA with successive codons of the m RNA. The amino acids are then linked together to extend the growing protein chain, and the t RNA, no longer carrying amino acids are released. The whole complex of processes is carried out by the ribosome, formed of two main chains of RNA, called ribosomal RNA (r RNA), and more than 50 different proteins. The ribosome latches on to the end of an m RNA molecule and moves along it, capturing loaded t RNA molecules and joining together their amino acids to form a new protein chain

Transcription:

• In transcription, a m RNA chain is generated, with one strand of DNA double helix in the genome working as a template. This strand is called template strand. Transcription is divided into three stages: initiation, elongation and termination; each regulated by a |arge number of proteins like transcription factors and coactivators.

• Transcription occurs in the cell nucleus, where the DNA is held. Double helix of the DNA is unzipped by the enzyme helicase, leaving single nucleotide chain open to be copied. RNA polymerase reads the DNA strand from the 3’ prime (3’s) end to the 5’ prime (5‘s) end, while it synthesizes a single strand of m RNA in the 5’ to 3’ direction. The genera| RNA structure is very similar to that of DNA with the exception that thymine of DNA is replaced by uracil in RNA. The single strand of m RNA leaves the nucleus through the nuclear pores and migrates into the cytoplasm.

Pattern of Inheritance

• Organisms inherit their genes from their parents. There are two copies of each chromosome because they inherit one complete set from each parent Mendelian Inheritance.

• It involves two terms: phenotype and genotype. Phenotypes are observable physical and/or behavioral characteristics e.g., colour of eye. Genotypes are particular set of genes. Each gene specifies a particular trait with different sequence of gene, called as alleles, giving rise to different phenotypes. Thus, one genotype can lead to more phenotypes, probably because of environmental alterations.

• Alleles at a locus may be dominant or recessive. Dominant alleles give rise to their corresponding phenotypes when paired with any other allele for the same trait. In case of recessive alleles, they give rise to corresponding phenotype only when paired with another copy of the same allele. If you know genotypes of the organisms, you can determine which alleles are dominant and which are recessive. Mendel‘s work demonstrated that alleles as sort independently in the production of gametes or germ cells, ensuring variation in the next generation. Mendelian inheritance continues to be a good model for many traits determined by single genes. Genetic disorders linked to a single gene follow Mendelian inheritance. It does not include the physical process of DNA replication and cell division. Molecular details of genetics were not known during Mendelian inheritance.

• DNA replication is extremely accurate; however errors can occur. The errors are called as mutations. Small mutations can be caused by DNA replication. It can take different forms. In point mutations a single base is altered. In frame shift mutations a single base is inserted or deleted. Either of these mutations can change the gene either as a missense or nonsense. In case of missense, there is a change in codon to encode a different amino acid. In case of nonsense, there is a premature stop codon leading to incomplete transcription/translation. Large mutations can be caused by errors in recombination to cause chromosomal abnormalities such as duplication, deletion, rearrangement of inversion of large sections of a chromosome. In addition, DNA repair mechanisms can introduce mutational errors while repairing physical damage to molecule. The repair, even with mutation, is more important to survival than restoring an exact copy, e.g. repairing of double strand breaks