Introduction to Genetics[physiology] 2024.pptx

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1. Genetics Dr Onyango K 20/11/23

2. Objectives Understand the basic principles of genetics, structure and functions of chromosomes, and functions of genes/DNA and RNA. Appreciate the application genetics in medicine. Understand the basic principles of recombinant DNA technology, polymerase chain reaction, cloning, mutation and blotting techniques. Learn the genetic basis of cancer and gene therapy. Understand the concept of apoptosis.

3. Understand the mechanism of gene expression and protein synthesis. Explain the process and importance of recombinant DNA technology, polymerase chain reaction and blotting techniques. Describe different types of cancer genes, and the physiological basis of gene therapy. Explain the mechanism and importance of apoptosis.

4. PHYSIOLOGY OF GENETICS Physiology of genomics is a developing branch of medi­cine. It deals with the understanding of the concept of gene and gene therapy in the treatment of genetic disor­ders. Genetics is the science of heredity, dealing with resem­blances and differences of related organisms resulting from the interaction of their genes and the environment.

5. Application of knowledge of genetics to understand the heritable basis of the diseases and to improve the man­agement of diseases through gene intervention, is called medical genetics. Mendel’s work in 1886 that hereditary characteristics are transmitted to offspring by separate units laid the foundation of genetics. Later, Johannied , the Danish botanist in 1909 termed these units as genes and, Morgan, the American geneticist established that the hereditary characteristics are transmitted on chromo­somes.

6. Chromosomes The term chromosome was coined by Waldeyer in 1888. Chromosomes transmit the genetic information from parents to offspring. There are 46 chromosomes in cells of all tissues except gametes that contain 23 chromosomes. Autosomes are present in somatic cells and sex chromo­somes in gametes.

7. Structure of Chromosomes Each chromosome consists of two chromatids that are con­nected at the centromeres (or kinetochore). Each chroma­tid is composed of two chromosomes. Typically, the centromere is not midway between the two ends of chromatids. When chromatid has a short arm and a long arm, the chromosome is called submetacentric .

8. If two arms of the chromatid are of equal length, the chromosome is metacentric, if one arm is too short the chromosome is acrocentric and if centromere lies at one end (each chro­matid has only one arm), the chromosome is telocentric. Chromosomes are distinguishable only during mitosis. In the interphase (between successive mitoses), chromosomes elongate and assume the form of a long thread called chromonemata Though chromosomes are formed mainly by DNA, they also contain RNA, the basic protein histones, complex proteins, organic phosphorous compounds and inorganic salts.

9. DNA Deoxyribonucleic acid (DNA) is found in bacteria, and in nuclei and mitochondria of all eukaryotic cells. DNA is the component of chromosome. Chromosome appears in pairs, except in germ cells. Chromosomes are made up of a mammoth molecule of DNA, which is about 2 m in length.

10. However, DNA is accommodated in the nucleus as most part of it at intervals is wrapped around histone proteins to form nucleosomes . About 25 millions of nucleosomes are present in a nucleus. The complex of DNA and the histone protein is called chromatin. As cell division begins, acetylation of histone loosens the coiling and pairs of chromosomes become visible

11. Chromosome structure

12. Types of chromosomes

13. DNA nucleotide A molecule of DNA is made up of two strands of polynucleotides linked together in the form of a double helix A nucleotide consists of a nitrogenous base, a sugar molecule ( deoxyribose ) and a phosphate molecule. In DNA, the nitrogenous bases are purines (adenine and guanine) and pyrimidines (cytosine and thymine).

14. Nucleotides in DNA from a polymer of polynucleotides through covalent bonds between the sugar molecules. [Nitrogenous bases are often designated by their first letter i.e. A for adenine, T for thymine, G for guanine and C for cytosine]. The purine and pyrimidine bases encode genetic message.

15. Functions of DNA DNA as part of chromosome transmits genetic characteristics(hereditary features) from generations to generations. The base may be adenine,cytosine , guanine or thymine. It possesses information required for the synthesis of RNA and cell proteins (including enzymes).

16. It controls cell division. The Genome; Each chromosome contains only one type of long-chain DNA molecule. DNA is the component of chromosome that carries the genetic message (blueprint of heritable characteristics) of the cell.

17. The total genetic information stored in chromosomes of a cell is known as the genome. The human genome contains about 3 billion nucleotide pairs, and in diploid cells they are organized into 23 pairs of chromosomes (all cells of the body, except the gametes). In each pair, one is derived from the mother and the other from the father. However, in males, the X chromosome is inherited from the mother and the Y chromosome from the father.

18. Y chromosome from the father. The X and Y chromosomes are concerned with the determination of sex, and therefore they are called sex chromosomes. The XX are necessary for development of the female and XY pair is necessary for development of the male. As stated in Lyon hypothesis, in female, one of the two X chromosomes (paternal or maternal derived), is inactivated during embryogenesis. This inactivation is passed to all the somatic cells, while the germ cells in female remain unaffected. That means ovary will have always active X chromosome.

19. The inactive X chromosome in the somatic cells in female lies condensed in the nucleus and is called as sex chromatin. This phenomenon in females helps in nuclear sexing

20. Gametes (sperm and ovum) have half this number of chromosomes, and therefore are said to be haploid cells. During fertilization of an ovum by a sperm, the diploid number is restored, so that each cell carries 23 chromosomes from each parent.

21. Chromosomal abnormalities Chromosomal abnormalities may be either due to the defect in autosomes or in sex chromosomes, and are accompanied by congenital abnormalities. Trisomy 21: The commonest abnormality of autosomal chromosome is the presence of three instead of two chromosomes in the number 21 pair. The condition is known as trisomy 21. The resulting clinical condition is called mongolism, or Down’s syndrome, which is characterized by mental retardation, congenital anomalies and abnormal physical features

22. Turner and Klinefelter syndromes: The common sex chromosomal abnormality in female is Turner syndrome in which one X chromosome is absent (i.e. XO), and in male is Klinefelter syndrome in which an extra X chromosomes is added (XXY). In these conditions, the subject is sterile, and has peculiar physical abnormalities. Klinefelter’s syndrome that occurs in males, presents with gynecomastia , osteoporosis, and testicular atrophy.

23. Turner’s syndrome that occurs in females presents with short stature, webbed neck, small breast size and primary amenorrhea

24. X-linked Disorders: An abnormal gene located in an autosome leads to an autosomal trait; whereas location of abnormal gene in a sex chromosome gives rise to sex-linked traits. However, all the known sexlinked genetic disorders are due to the defective genes located on one X chromosomes, and therefore they are called as X-linked disorders.

25. Very few of them are X-dominant, but most are X-recessive. Therefore, many X-linked disorders do not manifest in females who have normal X chromosome allele. However, sex linked genetic disorders at all times manifest in males as they do not have normal neutralizing X allele.

26. Common examples of X-recessive disorders are: • Hemophilia • G-6-PD deficiency • Nephrogenic diabetes insipidus . Rarely do they manifest in females, such as females with Turner ’s syndrome.

27. Gene expression

28. Components of gene unit

29. Transcription Transcription is the process in which RNA is synthesized from DNA. In this process: The genetic information stored in DNA is transferred to the RNA. During the process of formation of RNA, the relevant part of the DNA double helix unwinds and exposes the gene unit, which is then copied. The DNA strand that directs the synthesis of mRNA through complementary base pairing is called template strand (also called, coding strand or sense strand) and the other DNA strand is called noncoding strand or antisense strand. The enzyme RNA polymerase carries out transcription by binding to a site on DNA called promoter site.

30. Translation This is the process by which genetic message transferred to mRNA from DNA is converted into polypeptide chain containing specific sequence of amino acids. Post-transcription: The mRNA is processed from the primary RNA transcript; the process known as maturation in which released introns join with two adjacent exons . Only the exons and introns contain the genetic code.

31. Gene unit Each gene unit is organized into three components: regulatory DNA sequence (repressor, promoter and operator), exons and introns . Introns are removed during post-transcriptional events and adjacent exons join. Regulatory DNA sequence plays major role in transcription.

32. The regulatory DNA sequences are non-coding sequences that ensure that the gene is transcribed at the right time and in the proper cell. There are three types of regulatory nucleotide sequences per gene. The promoter DNA sequence that contains a sequence of Thymine-Adenine-Thymine-Adenine (T-A-T-A) nucleotides.

33. This acts as the recognition site for the enzyme RNA polymerase to attach with nearby transcription start site before it can move forward to begin transcription of the exons and introns . The promoter separates from the exons and introns by about ten nucleotides known as the operator. The operator should be free of attached molecules for the RNA-polymerase to reach the exons and introns .

34. A repressor nucleotide sequence located ahead of the promoter region is known as 5’ region, which codes for a repressor protein. This protein under certain conditions attaches itself to the operator that prevents the RNA-polymerase from moving towards the structural gene. There is often another regulatory nucleotide sequence at the other end known as 3’ region.

35. Exons are the DNA coding sequences that code for the formation of RNA. Introns are DNA coding sequences inserted at intervals between segments of exons . During the formation of RNA, both the introns and exons are transcribed, but the later one is translated into sequences of amino acids for the synthesis of a specific polypeptide within the ribosome.

36. Protein synthesis Protein synthesis occurs in three major steps. 1. Transcription: The two strands of DNA fiber separate from each other over the area bearing a particular cistron . Thus, the ends of the bases linked to the opposite strand become free. A molecule of mRNA is synthesized as a guide or a template. The code for the sequence in which amino acids are to be linked is passed on from DNA to mRNA. This is called transcription, which occurs under the influence of RNA polymerase.

37. The part of the mRNA strand that bears the code for one amino acid is called codon . The molecule of RNA now separates from the DNA strand and moves from nucleus to cytoplasm, where it attached with ribosome.

38. Amino acid activation and translation: On the ribosome, one side of tRNA attaches to amino acid, and on the other side bears a code for three bases ( anticodon ) that are complementary to the bases coding for its amino acid on mRNA. In the presence of enzyme aminoacyl tRNA synthase , amino acids react with ATP, get activated and attach with specific tRNA . Under the influence of the ribosome, several units of tRNA along with their amino acids become arranged along-side the strand of mRNA. In the sequence determined by the code on mRNA.

39. This is called translation. Translation occurs in three steps: Initiation: translation of mRNA with formation of initiation complex. Elongation: elongation of polypeptide chain by sequential addition of amino acids to the growing end. Termination: termination of polypeptide synthesis evoked by nonsense codon .

40. Post-translational modification: Post-translational modifications such as proteolytic degradation, hydroxylation, glycosylation , etc. make the protein more functional.

41. Regulation of gene expression Gene expression is regulated by following mechanisms. Gene amplification: Enhancement of gene expression can cause drug resistance. For example, amplificationof the gene coding for dihydrofolate reductase causes development of drug resistance by cancer cells to chronic administration of methotrexate. Gene rearrangement: This enhances the generation of antigen specific immunoglobulins. Regulation through transcription factors: Transcription factor regulate interaction of protein with specific segments of DNA. Regulation through mRNA: Modification of mRNA activity is the major mechanism of regulation of gene expression.

42. RNA Ribonucleic acid is made up of a single chain of polynucleotides (polymer of ribonucleotides ). Unlike DNA, which is double stranded, the RNA has a single strand. RNA is present in the nucleus, cytoplasm, ribosome and to some extent in mitochondria. RNA differs from a DNA strand in many aspects such as: 1. RNA chain is much shorter in length than the DNA chains. 2. The sugar-phosphate that forms the backbone contains ribose instead of deoxyribose . 3. The base thymine is replaced by uracil .

43. Types of RNA There are three types of RNA and they have different functions. 1. Messenger RNA: Messenger RNA (mRNA) is formed in the nucleus and enters cytoplasm for protein synthesis. It forms the template that directs the synthesis of protein molecules within ribosomes . 2. Transfer RNA: Transfer RNA ( tRNA ) conveys specific amino acids to the site of protein synthesis. 3. Ribosomal RNA: Nucleolus is the site of synthesis of ribosomal RNA ( rRNA ), which is associated with many proteins to form ribosomes , the protein-synthesizing machine.