Introduction to genetics (Unit - I)for B.Sc. Nursing Students

Genetics for B.sc Nursing Students

1. INTRODUCTION TO GENETICS

2. During mid 19 th Century, Gregor Mendel observed that certain features pass from parents to their children/offspring. A child usually looks like their parents and is due to inheritance of certain characteristics from parents to children . This transmission of characteristics from parents to children is known as heredity. The basic unit of heredity is gene, which consist of portion of DNA molecules. The term gene was coined by Johannsen in 1909. INTRODUCTION

3. GENETICS Genetics is the study which deals with the science of genes, heredity and its variations in living organism. Gregor Mendel is the father of Genetics The term Genetics was coined by William Bateson

4. GENE ALLELES Dominant Recessive Chromosomes Terminologies

5. Gene

6. Gene is defined as a segment of DNA (Deoxyribonucleic Acid) which carries the genetic information. Gene is the basic physical and functional unit of heredity DNA has also segment which do not contain gene. The human genome contains about 30000 – 40000 genes and each gene varies in size. Gene

7. Alleles

8. An allele is one of two, or more, forms of a given gene variant. Each allele determines a single inherited characteristics in an individual. Alleles

9. CHROMOSOMES

10. Chromosomes are thread-like structures located inside the nucleus of animal and plant cells. Each chromosome is made of protein and a single molecule of deoxyribonucleic acid (DNA). Passed from parents to offspring, DNA contains the specific instructions that make each type of living creature unique. The term chromosome comes from the Greek words for color (chroma) and body (soma). Scientists gave this name to chromosomes because they are cell structures, or bodies, that are strongly stained by some colorful dyes used in research. Chromosomes

11. PRACTICAL APPLICATIONS OF GENETIC IN NURSING

12. Nurses came across individuals or families affected by the genetic diseases. Nurses are a vital links between patients and health care services. Nurses should have a basic sound knowledge of genetics. The important role of nurses in genetic include - Role of Nurse in Genetics

13. Interviewing patients or individuals with suspected genetic disorders Taking a detailed clinical history along with relevant family history (over three generations) from patients or parents of child with genetic disorder. Refer those with genetic disorder to the concerned doctor. Genetic Counseling and Interviewing

14. Provide health education related to genetics and genetic testing. Drawing and interpreting a pedigree chart. Ability to recognize the possibility of a genetic disorder based on the pedigree chart. Assessment of a genetic risk especially in conjugation with genetic testing options. Planning, Screening or Gene Based Testing Programs

15. Follow up of positive newborn screening test. Monitoring individuals with genetic disorders Working with families under stress due to a genetic disorder. Monitoring

16. Developing an individualized plan of care and services of affected patient. Participating in public education about genetics. Maintain the privacy and confidentiality of the patients genetic information. Care

17. Genetic Aspect When a genetic condition is identified, it leads to stress and shock in the individuals and his family. The nurses have a major role in counseling, reducing their fears, getting the consent for genetic testing and arranging the tests and offering post test advice. About Transmission of genetic condition within families If an individual is identified to have a genetic condition, nurses should educate the family members, who are likely to affected and advice counseling and screening for them. Educational Role

18. Educate how genetics and environmental factors influence health and disease. Nurses should be able to identify the Mendelian patterns of inheritance of genetic conditions in families in the form of a pedigree (family tree) Educational Role

19. Impact of Genetic Conditions on Families

20. Impact of Genetic Conditions on Families Guilt – Parents with genetic disorder tend to feel guilty, when they come to know that they might have passed on a condition to a child. Depression – When an individual comes to know that he/she has a genetic condition and the decision not to have a children or decision to terminate a pregnancy, may result in depression or loss of peace of mind.

21. REVIEW OF CELLULAR DIVISON : Meiosis & Mitosis

22. CELL DIVISION Genetic Information is passed from parent to all descendent cells through cell division namely mitosis. There are two cell division – Mitosis (Somatic Cell Division) Meiosis (Germ cell Division)

23. CELL CYCLE The Cell Cycle is defined as the series of events that take place in a cell leading to its division and duplication (replication). Major Phases of Cell Cycle Cell cycle consists of two major phases namely Interphase Phase Mitotic Phase

24. Resting G0 phase The term “post-mitotic” is sometimes used to refer to both quiescent and declining cells. Non proliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time.

25. CELL CYCLE INTERPHASE It is the period between successive mitosis of the cell cycle. The interphase is sub divided in to three phases – G1 phase S phase G2 phase

26. G1 Phase The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis called G1 (G indicating Gap). It is also called the growth phase. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of the same species.

27. S PHASE The S phase starts when DNA synthesis, when it is complete, all of the chromosomes have been replicated. E.g. each chromosomes has two (sister) chromatids During this phase, the amount of DNA in the cell has effectively doubled Rate of RNA transcription and protein synthesis are very low during this phase.

28. S PHASE

29. G2 PHASE Cell continues to grow and if a problem occurs in DNA replication, it will be repaired. Cell will prepare for mitosis. Cell synthesizes proteins needed for cell division

30. MITOSIS (M Phase) Mitosis is the final phase of cell cycle in which two identical (daughter cells) are produced. Mitosis is defined as the process of somatic cell division to form two identical daughter cells, each with the same chromosomes complement as the parent cell. Characteristics features It produces two genetically identical “daughter cells” having complete set of genetic information. These daughter cells have exactly the same number of chromosomes (i.e. 46) as the original parent cell. The daughter cells are diploid because they contain 46 chromosomes (i.e. 2N= 2 X 23)

31. MITOSIS (M Phase) Estimated (10% of cycle) Includes 2 parts : 1) Mitosis Prophase Metaphase Anaphase Telophase 2) Cytokinesis

32. MITOSIS (M Phase) Estimated (10% of cycle) Includes 2 parts : 1) Mitosis Prophase Metaphase Anaphase Telophase 2) Cytokinesis

33. PROPHASE Duration (15 min) Chromosomes condense (get thicker) and coil, they become visible under light microscope. The two sister chromatids of each chromosomes attach at a point called centromere. Spindle fibers begin to form from two centrosome, and they will start moving apart.

34. PROPHASE

35. METAPHASE Duration (20 min) Chromosomes reach their most highly condensed state. The spindle fibers begin to contract to the centromeres of the chromosomes, which are now arranged along the middle of the spindle.

36. METAPHASE

37. ANAPHASE 3 Min The centromere of each chromosome splits, allowing the sister chromatids to separate. The chromatids are then pulled by the spindle fibers toward opposite sides of the cell. The two sets of chromosomes are identical.

38. ANAPHASE

39. TELOPHASE (10 min) New nuclear membranes are formed around each of the two sets of 46 chromosomes. The spindle fibers disappear. Chromosomes become thinner. Cytoplasm starts dividing by contractile ring. At the end, we will have two diploid daughter cells, which are identical.

40. TELOPHASE

41. CYTOKINESIS The division of the cytoplasm and organelles Begin in anaphase and completed by the end of telophase . This is the last stage of mitosis. It is the process of splitting the daughter cells apart. Each daughter cells contains the same number and same quality of chromosomes

42. TELOPHASE

43. MEIOSIS It is defined as special form of germ cell division that produces reproductive cells in which each daughter cells receives half the number of chromosomes i.e. 23 Site of Meiosis – Occurs in only in germ cell of the gonads Sperm in Males Ova in females

44. MEIOSIS

45. DIFFERENCE

46. MEIOSIS STAGES Like Mitosis Interphase of the cell cycle includes G1,S,G2 Phases. Interphase is followed by Meiosis. Meiosis consists of two successive stages – Meiosis I Meiosis II

47. PHASES OF MEIOSIS I PROPHASE I METAPHASE I ANAPHASE I TELOPHASE I

48. PROPHASE I During prophase I, DNA is exchanged between homologous chromosomes in a process called homologous recombination. This often results in chromosomal crossover. The paired and replicated chromosomes are called bivalents or tetrads. The process of pairing the homologous chromosomes is called synopsis. At this stage, non-sister chromatids may cross-over at points called chiasmata

49. PROPHASE I

50. METAPHASE I Metaphase 1 is the second phase of Meiosis The tetrads from prophase I line up in the middle of the dividing cell randomly Spindle fibers attach to the tetrads from both ends of the cell 24

51. METAPHASE I

52. ANAPHASE I Anaphase I begins when the two chromosomes of each bivalent separate and start moving toward opposite poles of the. In anaphase I the sister chromatids remain attached at their centromeres and move together toward the poles.

53. ANA PHASE I

54. TELOPHASE I The homologous chromosome pairs reach the poles of the cell. The homologous chromosome pairs complete their migration to the two poles A nuclear envelope reforms around each chromosome set, the spindle disappears, and cytokinesis follows

55. TELOPHASE I

56. MEIOSIS II The Second division in the meiotic process is termed as equational division because events in this phase are similar to those of mitosis. Meiosis II Differs from mitosis how ? Answer - Number of Chromosomes has already been halved in Meiosis I and the cell does not begin with the same number of chromosomes as it does in Mitosis

57. PHASES OF MEIOSIS II Mitotic division of 2 haploid cells to produce 4 haploid daughter cells. Prophase -2 Metaphase -2 Anaphase 2 Telophase

58. Difference Between Mitosis & Meiosis

59. NUCLEIC ACIDS

60. NUCLEIC ACIDS Nucleic acids are the macromolecules present in all living cell. Nucleic Acids are of two types – DNA (Deoxyribonucleic Acid) RNA (Ribonucleic Acid)

61. DNA (Deoxyribonucleic Acid)

62. DNA (Deoxyribonucleic Acid) James Watson and Francis Crick first proposed the structural model of DNA in 1953. They got the Nobel Prize for their work in 1962. Proposed Double Helix model for structure of DNA- remarkable proposition was base pairing between two strand of polynucleotide. Comparable to twisted ladder.

63. NUCLEOTIDES Each DNA (and also RNA) strands consists of chain of nucleotides. Each nucleotide chain is made up of three main components – Nitrogenous base – These bases are classified into two types – Purines – The purines bases are Adenine (A) and Guanine (G). Pyrimidines – The pyrimidine bases are Thymine (T), Cytosine (C) and Uracil (U) (Uracil takes place of Thymine in RNA). Deoxyribose Sugar – It is a pentose sugar with 5 carbon atoms Phosphate molecules

64. BONDS BETWEEN NUCLEOTIDES The two nucleotides chain of DNA are held together by two types of molecular forces. Hydrogen Bonds These are formed between the nitrogenous bases on opposite nucleotide strands. They are always between a purines and pyrimidine nitrogenous base only. Adenine base on one strand always pairs with thymine on the other strand (A-T or T-A) Guanine base on one strand pairs with cytosine on the other hand. (G-C or C-G) PHOSPHATE DIESTER BONDS These bonds are between sugar molecules

65. CLASSIFICATION OF DNA Depending on the types of DNA Sequence Single copy DNA Sequence – In this type nucleotide sequences are present only once without any repetition of nucleotide. They account for 50-60 % of human DNA. Moderately repetitive DNA Sequence – In these the nucleotide sequences are repeated many times and constitute about 25-40 % of human DNA. Most of them have no function. High repetitive DNA Sequences – It is characterized by repetition of nucleotides several times (Hundreds to millions). These are non coding sequences and constitute about 10-15% of Human DNA.

66. FUNCTION OF DNA It is the genetic material, therefore responsible for carrying all the hereditary information. It has property of replication essential for passing genetic information from one cell to its daughters or from one generation to next. Crossing over produces recombination Changes in sequence and no. of nucleotides causes Mutation which is responsible for all variations and formation of new species. It controls all the metabolic reaction of cells through RNAs and RNA directed synthesis of proteins.

67. GENE

68. GENE The gene is the Functional unit of Heredity. Each gene is a segment of DNA that give rise to a protein product or RNA. A gene may exist in alternative forms called alleles. Chromosome in fact carry genes. Each chromosome consists of a linear array of genes.

69. GENE STRUCTURE Each gene consist of a specific sequence of nucleotides. Gene may be silent or active. When active the genes direct the process of protein synthesis. Genes do not code for proteins directly but my means of genetic code. The genetic code consists of a sequence codeword called codons. A codon for an amino acid consists of a sequence of three nucleotides base pairs called triplet codon

70. REGION OF GENE

71. INITIATOR AND STOP CODONS The boundaries of a gene is known are known as start and stop codons. The start codons tells when to begin protein production and stop (termination) codons tells when to end the protein production.

72. CODING REGION The nucleotide sequence between the start and stop codons is the core region known as coding region. This region is divided in to two main segment namely exons and introns. Exon – This region codes for producing a protein Introns – These are the regions between exons and do not code for a protein. (Non coding region)

73. REGULATORY REGION These are also non coding regions which control gene expression. Promoters – These are the regions which bind to transcription factors either strongly or weakly. Enhancers – These are the regions which can enhance the effect of weak promoter. Silencers – These are the regulatory regions that can inhibit transcription.

74. RNA

75. RNA The RNA is chiefly presents within the ribosomes and nucleolus. RNA differs from DNA in three main ways: RNA is single stranded The sugar residue within the nucleotide is ribose rather than Deoxyribose. Specific pyrimidine base Uracil is used in place of Thymine.

76. Types of RNA The two major types of RNA are : Coding RNA (m-RNA) Non Coding RNA (nc-RNA)

77. m- RNA m-RNA contains a coding RNA Sequence. It carries the message from the DNA to the ribosomes in the cytoplasm required for protein synthesis. It contains both exons and introns similar to DNA. During protein synthesis the introns (non coding sequences) are cut and removed resulting in smaller m-RNA.

78. NON Coding RNA These do not code for proteins. Transfer RNA – It conveys the message carried by the m-RNA to the ribosomes. Ribosomal RNA (r-RNA) – They play a significant role in the binding of m-RNA to ribosomes and protein synthesis. Micro-RNA (mi-RNA) – The miRNA play a role in normal development.

79. PROTEIN SYNTHESIS

80. STEPS IN PROTEIN SYNTHESIS Several steps are involved in the synthesis of protein. The genetic information in cells flows in one way: DNA Specifies the synthesis of RNA RNA Specifies the synthesis of Amino Acids. The two main steps in protein synthesis are transcription and translation.

81. TRANSCRIPTION Transcription is a process in which genetic information is transmitted from DNA to RNA . It is the first step in protein synthesis and occurs in the nucleus. When the genes are active, proteins called transcription factors are produced. These transcription factors binds to promoter or enhancer region of genes Transfer of the genetic information from DNA –dependent RNA polymerase (Transcriptase) It produces a new complimentary copy of the whole gene and is known as primary RNA molecule. The primary RNA molecule undergoes splicing in which introns are removed from exons, to produce single-stranded messenger ribonucleic acid (mRNA) molecule. The mRNA migrates from the nucleus to the cytoplasm and is used as a template for protein synthesis.

82. TRANSLATION Translation is the transmission of the genetic information from mRNA to form protein. In the cytoplasm, mRNA to form protein. In the cytoplasm, mRNA attaches to ribosomes, which is the site of protein production. During translation, smaller RNA molecules known as transfer RNA (tRNA) bind to the ribosome. The tRNA deliver amino acid to the ribosomes and synthesizes a linear chain of amino acids called a polypeptide (primary protein) and later forms proteins.

83. CHROMOSOMES – SEX DETERMINATION

84. SEX DETERMINATION Sex determination is the process of sex differentiation by which whether a particular individual will develop into male or female sex. The sex chromosomes are responsible for determination of separate sexes. Sex expression is governed by chromosomes and genes. In unisexual animals, chromosomes are of two types, autosomes and allosomes. Autosomes – Chromosomes which do not differ in morphology and number in male and female. Allosomes or sex chromosomes – Chromosomes which differ in morphology and number in male and female and contain genes that determine sex.

85. SEX DETERMINATION Human body cells have 46 chromosomes arranged in 23 pairs. There are 22 pairs of autosomes and one pair of sex chromosomes (allosomes). Female have a perfect pair of sex chromosome XX. Male have mismatches pair of sex chromosome XY. Both male and female contain equal amount of chromosome 23 pair Out of 23 pair: 22 pairs are autosomes 1 pair is sex chromosome.

86. MENDELLIAN THEORY OF INHERITENCE

87. MENDELLIAN THEORY OF INHERITENCE The Law of Inheritance were derived by Austrian Monk named Gregor Mendel. He conducted hybridization experiments in garden pea and proposed certain laws which were known as Mendelian law of Genetics. Mendel suggested that the genes occurs in pairs one of which recessive and the other one is dominant . He stated that genes can be paired in three different ways for each trait: AA, aa, Aa. The capital “A” represents the dominant factor and lowercase “a” represents the recessive “Aa will occur roughly twice as often as each of the other two as it can be made in two different ways “Aa” , “aA”.

88. MENDELLIAN THEORY OF INHERITENCE Mendelian inheritance is a set of primary statements about the way certain characteristics (e.g. color of hair, eye, skin etc.) are transmitted from parent to their offspring. Mendel Law’s of Inheritance Law of Dominance Law of Segregation Law of Independent Assortment

89. LAW OF DOMINANCE In heterozygous individual a character is represented by two contrasting factors called the alleles. The one that can express its effect is called as dominant. The other allele, which does not show its effect in the heterozygous individual is called the recessive allele.

90. LAW OF SEGREGATION Mendel stated that the genes normally occurs in pairs in ordinary cells of the body and each one is derived from each parent. During the formation of gametes (sex cells) the two co-existing copies of a gene separates (segregate) from each other. The resultant gamete (sperm or oocyte) receives only one of the two alleles present in the parent. These alleles may behave as dominant or recessive characters. The law of segregation states that every individual has two alleles of each gene and when gametes are produced, each gamete receives one of these alleles.

91. LAW OF SEGREGATION

92. LAW OF INDEPENDENT ASSORTMENT Mendel’s second for different law states that genes for different traits-for example, seed shape and seed color- are inherited independently of each other. This conclusion is known as law of independent assortment. Genotype RrYy - the alleles R and r will separate from each other as well as from the alleles Y and y.

93. ALLELES

94. ALLELES Chromosomes have many genes. Specific genes are located at a specific place on every chromosomes and this location is known as locus. An allele is one of two, or more, forms of a given gene variant. Each allele determines a single inherited characteristics in an individual. For example – if a gene on a particular chromosomes codes for a characteristics such as hair color, another gene at the same position on homologous chromosomes also codes for hair color. However these two alleles need not to be identical: one might produce red hair and the other might produce blonde hair.

95. TYPES OF ALLELES Mono Allelic – Single allele Di-Allelic – Two Allele Multiple Alleles – E.g. Blood group, hair texture, skin color. Etc.

96. CATEGORIES OF ALLELES Alleles can be categorized as dominant and recessive. Dominant alleles are those which is expressed. Recessive alleles are those which are unexpressed. Co dominant means both alleles of a gene pair exert an observable effect and are thus equally dominant. (E.g. AB Blood group)

97. GENOTYPE Your genotype is a way of expressing the two alleles that you hold for a particular gene Human eye color is controlled by one gene in particular, for which there are only 2 available alleles. B – codes for phenotypically Brown eyes (dominant) b – codes for phenotypically blue eyes (recessive) You need only 1 copy of a dominant allele for it to be expressed You need 2 copies of a recessive allele for it to be expressed BB = Brown eyes bb = Blue Eyes Bb =Brown eyes

98. GENOTYPE When one possesses identical alleles on the maternal and paternal chromosome, this is referred to as a homozygous genotype. e.g. BB = homozygous dominant e.g. bb = homozygous recessive Having two different alleles is a heterozygous genotype. E.g. Bb = Heterozygous The allele for Brown eyes (B) is dominant The allele for Blue eyes (b) is recessive

99. PHENOTYPE The expression of a gene is determined by the combination of dominant and recessive alleles possessed by the individual. Trait that is easily seen (observed trait) is called the phenotype. The ABO blood group system represents not only a gene with multiple alleles, but also a system of codominance. Phenotypic expression is not always visible, it can be physical, biochemical or physiological.

100. BLOOD GROUPING

101. ABO Blood Grouping An excellent example of multiple alleles is the ABO Blood Group System In ABO there are at least four alleles A1, A2, B and O. These alleles control the production of antigens on the surface of red blood cells. An individuals can have any two of these four alleles. These two alleles in an individual may be same or different and the blood group of individual is determined by two of these alleles. For example – AA, A1B, OO, A2O. The A and B alleles are equally dominant to each other. If an individual inherits A allele from one parent and B allele from other parent, the blood group will be AB. The O allele is recessive to both A and B alleles.

102. ABO Blood Grouping If An individual who inherits an A allele from one parent and O allele from other parent the genotype of AO and the blood group will be A. If An individual who inherits an B allele from one parent and O allele from other parent the genotype of BO and the blood group will be B. If An individual who inherits an O allele from one parent and O allele from other parent the genotype of OO and the blood group will be O. A group has two subgroups namely A1 and A2.

103. MECHANISM OF INHERITENCE Mode of inheritance is defined as the manner in which a particular genetic trait or disorder is passed from one generation to the next.

104. Single Gene or Monogenic Disorders/Mendelian Disorders Genetic Disorders that results from mutations in single gene are called as Single gene or Monogenic Disorders. This type of inheritance is called as Mendelian Inheritance. Defective gene is responsible for the single gene may be found in the autosomes or the sex chromosomes. When the defective gene is found on an autosome, the mode of inheritance is said to be of autosomal inheritance I f it is on the sex chromosomes, it is said to show sex linked inheritance

105. Single Gene or Monogenic Disorders/Mendelian Disorders Genes are inherited in pairs-one gene from each parent. However, the inheritance may not be equal, and one gene may overpower the other in their coded characteristic. The gene that overshadows the other is called the dominant gene The overshadowed gene is the recessive one. There are four patterns of Inheritance for Mendelian Disorders Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive.

106. AUTOSOMAL DOMINANT PATTERN OF INHERITANCE Location of mutant gene: These are found on autosomes. Required number of defective genes: Only one copy of the mutant (abnormal) gene is required for effects. Autosomal dominant disorder is expressed in heterozygotes (i.e. one copy of the mutant gene and one copy of normal gene). Sex affected: The mutant gene is found on one of the autosomal chromosomes. Hence, both males and females are equally affected.

107. AUTOSOMAL DOMINANT PATTERN OF INHERITANCE Pattern of inheritance: Every affected individual has an affected parent. Normal members of a family do not transmit the disorder to their children. Risks of transmission to children (offspring): Affected males and females have an equal risk of passing on the disorder to children. When only one parent is affected and other is normal: There is usually a 50% chance of passing the disease onto children. When both parents are affected: There is 75% chance of children being affected and a 25% chance to be normal

108. AUTOSOMAL DOMINANT PATTERN OF INHERITANCE

109. AUTOSOMAL RECESSIVE PATTERN OF INHERITANCE Location of mutant gene : These genes are located on autosomes. Required number of defective gene : Symptoms of the disease appear only when an individual has two copies of the mutant gene. When an individual has one mutated gene and one normal gene, this heterozygous state is called as a carrier. In the carrier state, the product of the normal gene is able to compensate for the mutant allele and hence the patients are asymptomatic. Pattern of inheritance : For a child to be at risk, both parents must be having at least one copy of the mutant gene. Almost all inborn errors of metabolism are autosomal recessive disorders. Sex affected : Females and males are equally affected.

110. AUTOSOMAL RECESSIVE PATTERN OF INHERITANCE When both parents are heterozygous for the condition : Heterozygous parents carry one mutated gene and normal gene. When two heterozygotes mate, 25% of the children will be affected, 50% will be unaffected heterozygotes and 25% will be normal.

111. AUTOSOMAL RECESSIVE PATTERN OF INHERITANCE When one parent is affected and the other is normal : All the children will be unaffected heterozygotes.

112. AUTOSOMAL RECESSIVE PATTERN OF INHERITANCE When one parent is affected and the other is heterozygote : The chances are that 50% of children will be unaffected heterozygotes and 50% homozygously affected.

113. AUTOSOMAL RECESSIVE PATTERN OF INHERITANCE When one parent is normal and the other is heterozygote: This may result in 50% unaffected heterozygote carriers and 50% normal children.

114. X LINKED PATTERN OF INHERITANCE Almost all sex-linked Mendelian Disorder are X-linked. Males with mutations affecting the Y-linked genes are usually infertile. Expression of an X-linked disorder is different in males and females. Though X-linked disorders may be inherited either as dominant or recessive, almost all X-linked disorders have recessive pattern of inheritance. Females: They inherit one X chromosome from each parent (46 XX). The clinical expression of the X-linked disease in a female is variable, depending on whether it is dominant or recessive. Females are rarely affected by X-linked recessive diseases; however they are affected by X-linked dominant disease. Males: They inherit only one X chromosome from mother and Y chromosome from father (46 XY). Males have only one X. chromosome and gene mutation affecting X chromosome is fully expressed even with one copy, regardless of whether the disorder is dominant or recessive.

115. X LINKED RECESSIVE TRAIT This pattern of Inheritance constitutes a small number of clinical conditions. Location of mutant gene : Mutant gene is on the X chromosomes and there is no male to male transmission. Required number of defective gene: One copy of mutant gene is required for the manifestation of disease in males, but two copies of the mutant gene are needed in females. Sex affected: Males are more frequently affected than females; daughters of affected male are all asymptomatic carriers. Pattern of inheritance: Transmission is through female carrier (heterozygous).

116. X LINKED RECESSIVE TRAIT Risks of transmission to children (offspring): When male is normal and female is a carrier: About 25% of children may be normal male, 25% normal female, 25% female carrier and 25% may be male sufferer.

117. X LINKED RECESSIVE TRAIT Risks of transmission to children (offspring): When male is affected and female is normal : An affected male does not transmit the disorder to his sons since he donates only a normal Y chromosome to his son. Thus, all his sons will be normal. An affected male always donates one copy of his abnormal X-chromosome to all his daughters and thus all daughters will be asymptomatic carriers.

118. X LINKED RECESSIVE TRAIT Risks of transmission to children (offspring): When male is affected and female is a carrier: There are chances of 25% of children being female carrier, 25% affected female, 25% normal male and 25% affected male.

119. X LINKED RECESSIVE TRAIT Risks of transmission to children (offspring): When male is normal and female is affected: 50% of children will be female carriers and 50% may be male sufferers

120. X LINKED DOMINANT DISORDERS They are very rare, e.g. vitamin D resistance rickets. Location of mutant gene: It is located on the X chromosome and there is no transmission from affected male to son. Required number of defective gene: One copy of mutant gene is required for its effect. Often lethal in males and so may be transmit ted only in the female line. Often lethal in affected males and they have affected mothers. There is no carrier state. These are more frequent in females than in males.

121. X LINKED DOMINANT DISORDERS Risks of transmission to children (offspring): When female is affected and the male is normal: They transmit the disorder to 50% of their sons and 50% of their daughters.

122. X LINKED DOMINANT DISORDERS Risks of transmission to children (offspring): When male is affected and the female is normal: They transmit to all their daughters but none to their sons.

123. X LINKED DOMINANT DISORDERS Risks of transmission to children (offspring): When both male and female are affected: All the females will be affected and half of males will be affected

124. CHROMOSOMAL ABERRATIONS Chromosomal aberrations, or abnormalities, are changes to the structure or number of chromosomes, which are strands of condensed genetic material. Humans typically have 23 pairs of chromosomes, of which 22 pairs are autosomal, numbered 1 through 22. The last pair of chromosomes are sex chromosomes, which determine an individual’s sex assignment. At birth, most people with XY sex chromosomes are assigned male, and most individuals with XX are assigned female. In general, each parent contributes one set of chromosomes to their offspring, which collectively make up the 23 pairs of chromosomes. A change to any of the chromosomes, in number or structure, creates a chromosomal aberration and may cause medical disorders.

125. CHROMOSOMAL ABERRATIONS The chromosomal aberrations/disorders may be broadly classified as Numerical chromosomal aberrations Structural chromosomal aberrations Both may involve either the autosomes or the sex chromosomes.

126. NUMERICAL CHROMOSOMAL ABERRATIONS Normal cells are diploid containing 46 chromosomes, 22 pairs of autosomes and 1 pair of sex chromosomes. The total number of chromosomes may be either increased or decreased. The deviation from the normal number of chromosomes is called as numerical chromosomal aberrations.

127. TYPES OF NUMERICAL CHROMOSOMAL ABERRATIONS NUMERICAL CHROMOSOMES ABERRATIONS Aneuploidy Monosomy Trisomy Tetrasomy Polyploidy Triploidy Tetraploidy Different Cell Lines: Mosaicism

128. ANEUPLOIDY It is defined as a chromosome number that is not a multiple of 23 (the normal haploid number). It is caused by either loss or gain of one or more chromosomes. Aneuploidy may result from nondisjunction or anaphase lag. Trisomy: Numerical abnormalities with the presence of one extra chromosome are referred to as trisomy. It may involve either sex chromosomes or autosomes. For examples, patients with Down's syndrome have three copies of chromosome 21(47 XX, +21), hence Down's syndrome is often known as trisomy 21. Others are Patau syndrome (trisomy 13) and Edward's syndrome (trisomy 18).

129. ANEUPLOIDY Monosomy: Numerical abnormalities with the absence or loss of one chromosome are referred to as monosomy. It may involve autosomes or sex chromosomes. Monosomy of autosomes is almost incompatible with survival because of loss of too much genetic information. Example for monosomy of sex chromosomes is Turner syndrome, in which the girl is born with only one X-chromosome (45 XO) instead of normal XX (46 XX).

130. POLYPLOIDY Polyploidy is chromosome number that is a multiple greater than two of the haploid number (multiples of haploid number 23). Triploidy is three times the haploid number (69), tetraploidy is four times the haploid number (92). Polyploidy is incompatible with life and usually results in spontaneous abortion.

131. DIFFERENT CELL LINES Changes in chromosome number in an individual may not necessarily be present in all cells but may be found in some cells. Mosaicism is defined as the presence of two or more populations of cells with different chromosomal complement in an individual. Mitotic errors during early development. occasionally give rise to mosaicism. It can involve sex chromosomes or autosomes.

132. STRUCTURAL CHROMOSOMAL ABRERRATION A second type of chromosomal aberrations is due to alterations in the structure of one or more chromosomes. They may occur either during mitosis or meiosis. Structural changes in chromosomes can be balanced or unbalanced. Balanced aberration is generally harmless, because there is no loss or gain of chromosomal material. In unbalanced aberrations, chromosomal material is either gained or lost.

133. TYPES OF STRUCTURAL CHROMOSOMAL ABRERRATION STRUCTURAL CHROMOSOMES ABERRATIONS Translocations (exchange) Balanced Reciprocal Robertsonian Translocation Inversions Paracentric Pericentric Isochromosomes Deletions (loss) Ring Chromosomes Insertions

134. TRANSLOCATION It is a structural alteration be tween two chromosomes in which segment of one chromosome gets detached and is transferred to another chromosome. There are two types of translocations – Balanced reciprocal translocation Robertsonian Translocation

135. Balanced reciprocal translocation It is characterized by single breaks in each of two chromosomes with ex change of genetic material distal to the break. There is no loss of genetic material.

136. Robertsonian Translocation It is a translocation between two acrocentric chromosomes. The breaks occur close to the centromeres of each chromosome. Transfer of the segments leads to one very large chromosome and one extremely small one. The small one is because of fusion of short arms of both chromosomes which lack a centromere and is lost in subsequent divisions. This loss is compatible with life.

137. INVERSION It involves two breaks within a single chromosome, the affected segment inverts with reattachment of the inverted segment. The genetic material is transferred within the same chromo some. There are two types of inversion namely Paracentric Pericentric. Paracentric inversions result from breaks on the same arm (either the short arm or the long arm) of the chromosome. Pericentric inversions results from breaks on the opposite sides of the centromere where both the short and long arms are involved.

138. INVERSION

139. ISOCHROMOSOME They are formed due to faulty centromere division. Normally, centromeres divide in a plane parallel to long axis of the chromosome. If a centromere divides in a plane transverse to the long axis, it results in pair of isochromosomes. One pair consists of two short arms and the other of two long arms.

140. DELETION It is the loss of a part of a chromosome. It is of two types namely: interstitial (middle) and terminal (rare). Interstitial Deletion - It occurs when there are two breaks within a chromosome arm. This is followed by loss of the chromosomal material between the breaks and fusion of the broken ends of the remaining portion of the chromosome. Terminal Deletion - It results from a single break at the terminal part in a chromosome arm, producing a shortened chromosome bearing a deletion and a fragment with no centromere. The fragment is then lost at the next cell division.

141. RING CHROMOSOME It is a special form of deletion. Ring chromosomes are formed by a break at both the ends of a chromosome. There is deletion of the acentric fragments formed due to break and end-to-end fusion of the remaining centric portion of the chromosome at the cut ends resulting in a ring chromosome. The consequences depend on the amount of genetic material lost due to the break. Loss of significant amount of genetic material will result in phenotypic abnormalities.

142. INSERTION It is a form of nonreciprocal translocation in which a fragment of chromosome is transferred and inserted into a nonhomologous chromosome. Two breaks occur in one chromo some which releases a chromosomal fragment. This fragment is inserted into another chromosome following one break in the receiving chromosome, to insert this fragment.

143. MUTATIONS A mutation is defined as a permanent change in the genetic material (DNA) which results in a disease. The term mutation was coined by Muller in 1927. Causes Spontaneous mutation: Majority of mutations occurs spontaneously due to errors in DNA replication and repair. Induced mutation: Mutations can be caused due to exposure to mutagenic agents like chemicals, viruses, and ultraviolet or ionizing radiation. If the genetic material change/variant does not cause obvious effect upon phenotype, it is termed as polymorphism. A polymorphism is defined as genetic variation that exists in population with a frequency of >1%.

144. CLASSIFICATION OF MUTATIONS Depending on the Cell Involved Mutations are divided into two types: Germ cell mutations: Mutations that affect the germ cells are transmitted to the progeny/ descendants and can give rise to inherited diseases. Somatic cell mutations: Mutations involving the somatic cells can produce cancers and some congenital malformations. These mutations are not inherited and are known as de novo mutations.

145. CLASSIFICATION OF MUTATIONS Depending on the Nature Numerical mutation: There is either gain or loss of whole chromosome (trisomy/monosomy). These usually develop during gametogenesis and are known as genomic mutations. Structural Chromosomal Mutations The rearrangement of genetic material causes structural change. Structural mutations may be visible during karyotyping or submicroscopic. The submicroscopic gene mutations can result in partial or complete deletion of a gene or more often, a single nucleotide base.

146. CLASSIFICATION OF MUTATIONS Point Mutation - When a nucleotide base is replaced by a different nucleotide base within a gene, it is known as point mutation. Majority of point mutation occur in the coding region of a gene and cause failure of translation and synthesis of the particular gene product. Frame Shift Mutation - This is due to insertion or deletion of one or more nucleotides. If the number of nucleotide bases inserted or deleted is not a multiple of 3, the code will be changed. They are known as frameshift mutation. When deletions involve a large segment of DNA, the coding region of a gene may be entirely removed.

147. Frame Shift Mutation

148. CLASSIFICATION OF MUTATIONS Trinucleotide repeat mutation: The DNA contains several repeat sequences of three nucleotides (trinucleotide). When they are repeated directly adjacent to each other (one right after the other), they are known as tandem repeats. When the repetitive trinucleotide sequences reach above a particular threshold, they can expand (amplify) or contract. The amplification is more common. These trinucleotide-repeat mutation are dynamic (i.e. the degree of amplification increases during gametogenesis).

149. MUTATIONS WITHIN NONCODING SEQUENCE Transcription of DNA is initiated and regulated by promoter and enhancer sequences. Point mutations or deletions of these regulatory regions result in either marked reduction or total lack of transcription.

150. DEPENDING ON FUNCTIONAL EFFECT Mutations in DNA can lead to either change in the amino acid sequence of a specific protein or may interfere with its synthesis. The consequences vary from those without any functional effect to those which have serious effects. Loss-of-function (LOF) mutations: These mutations cause the reduction or loss of normal function of a protein. It is usually due to deletion of the whole gene but may also occur with a nonsense or frameshift mutation. Gain-of-function mutations: These are usually due to missense mutations. In gain of-function mutation, the protein function is altered in a manner that results in a change in the original function of the gene. Lethal mutations: These lead to death of the fetus.