CHAPTER 1 CELL AND TISSUE DAMAGE Degenerations and Depositions Cellular Physiology and Pathology 2 Cell Damage 3 Necrasis 46 Necrosis — Autolysis 7 Apoptosis 8 Cell Damage — Hydropie Swelling 9 Cell Damage — Fatty Change 10,11 Cell Damage — Radiation 12 Atrophy 13 Ageing “4 Heredity, Genes and Disease 15,16 Mitosis and Meiosis 17 Genetic Abnormalities and Associated Disorders 18-20 Depositions 21 Amyloid Deposition 22-24 Calcification 25 Endogenous Pigmentation 26-31 Exogenous Pigmentation — Degencrations 32CELL AND TISSUE DAMAGE ET CELLULAR PHYSIOLOGY AND PATHOLOGY ‘The complexity and detail of intra-cellular structure and function and their disorders, as revealed by recent research, is such that only the basic principles can be illustrated. In many respects, cellular pathology mimics organ and tissue pathology, e.g. (a) the various cellular components and activities are closely interdependent (it is of course convenient to describe them separately) (b) all activities are conducted with balancing control mechanisms and (c) very efficient compensation and repair mechanisms exist to minimise damage. Energy Source Production Utilisation 0, + Glucose —= Via MITOCHONDRIA —+ Release —» For all cellular ‘ADP ATP. of energy activities (Oxidative phosphorylation} Defects in source, production and utilisation can be reflected in all aspects of cellular function, Plasma membranes i (1) Contact with ext eg. recognition ain cellular environment receptors : functions: ay eare Any disorder may (2) Passage of complex tonitiontloat chemicals in and out of call by 7 to disease. (a) pinocytosis or phagocytosis (b) selective permeability Lysosomes These membrane-bound organelles contain sage Disorder may lead hydrolytic enzymes and are responsible for to enzyme escape digestion and disposal of complex substances. __or to cellular overloading, e.g. storage disorders. Nucleus ‘The nucleus contains at least 50,000 genes and through them exercises control of all cellular activities, Each gene is responsible for a single specific chemical product, e.g. a protein, an enzyme or a complex lipid. ‘Nuclear damage occurs usually during cell replication and is greatly potentiated by ionising radiation. Repair mechanisms are very effective. Germ cell nuclear damage (1) Severe damage to chromosomal structure Prevention of conception. — Early abortion. (2) Less severe damage affecting groups of Developmental and genes, single genes or DNA sequences within HEREDITARY DISEASES genes and SUSCEPTIBILITY to disease. Stem cell nuclear damage This is acquired during life. ‘The development of cancer is the best example — nuclear changes induced by 2 carcinogens — activation of oncogenes — chain of events leading to malignancy.CELL AND TISSUE DAMAGE CELL DAMAGE Visible changes occur in cells as a result of noxious agents, the degree of change varying with the severity of the damaging process: with minor damage the repair mechanisms within the cell reverse the changes: more severe damage results in cell death. CAUSES OF CELL DAMAGE ‘These are innumerable but are grouped as follows (the individual diseases mentioned are illustrative examples): 1, Reduced oxygen supply — respiratory discase, cardiovascular disease, anaemia 2. Physical agents — mechanical trauma, excessive heat or cold, radiations ‘Chemical agenis — these continue to increase enormously with the complexity of industrial processes Toxins — bacteria, plants, animals e.g. snakes Viruses Abnormal immunological reaction — hypersensitivity states, glomerulonephritis Nutritional deficiencies — vitamin deficiency and malabsorption syndromes Genetic abnormalities — Down's syndrome NECROSIS ‘When, as a result of damage by the various agents mentioned above, cells or groups of cells die while still part of the living body the term necrosis is used. Death of the cell is associated with rapid depletion of intracellular energy systems. Initially there are no morphological changes. What we describe as necrosis is the result of the liberation of intracellular enzymes following upon the disruption of cytoplasmic organelles with the production of oxygen free radicals, disintegration of the nucleus and changes in the plasma membrane, Passage into cell Concentration Group of necrotic cols eee Sonera increases Ia ? a blood used in sg tiagnostic test, oicod j Pee Passage out of cell “A Of" and ENZYMES Loss of PLASMA MEMBRANE BARRIER FUNCTION ‘Necrosis is associated with visible changes: 1, Coagulative necrosis is the classical appearance. 2. Several other descriptive forms where the appearances are modified by additional local factors, particularly the action of released enzymes,CELL AND TISSUE DAMAGE NECROSIS COAGULATIVE NECROSIS This type of necrosis is frequently caused by lack of blood supply and is exemplified well in infarcts of solid organs, e.g. heart, spleen and kidney. Naked eye appearance of kidney Microscopic appearance : Normal kidney Aroa is swollen, firm and pale Normal markings are lost ‘The dead cells retain their 1@ but only indistinctly At light microscopic level the following changes in the cell are seen: 1. The nucleus shows one of two changes (a) Karyolysis (b) Karyorthexis, 2. The cytoplasm becomes opaque and strongly eosinophilic (affinity for the red dye, eosin) efi ci a Translucent dameging “Dy, _- Nucleus fades granular ~~. moet te “4-7 and dissolves Seeker —- ) SKanvouvsis i wo ‘Nucleus with -~"* Be ‘ tonite Sromnin 7 Nucleus shrinks 3nd becomes dense = Nuclous fragments and becomes dense = PYKNOSIS Nucleus fragments At electron microscope (E.M.) level, in addition to the above nuclear changes, disorganisation and disintegration of the cytoplasmic organelles and severe damage to the 4 plasma membrane are seen.CELL AND TISSUE DAMAGE EE NECROSIS COLLIQUATIVE NECROSIS In the brain consistently, and in other tissues when they contain a large amount of fluid and enzyme activity is marked, necrotic areas undergo softening and are filled with pigmented or turbid fluid, with complete loss of structure. An abscess (see p. 42, 43) is an example of colliquative necrosis caused by the enzymatic action of polymorphonuclear leucocytes. GANGRENE This is a complication of necrosis. In certain circumstances necrotic tissue is liable to be invaded by putrefactive organisms which are both saccharolytic and proteolytic. Foul- smelling gases are produced and the tissue becomes green or black due to breakdown of haemoglobin. Obstruction of the blood supply to the bowel is almost inevitably followed by gangrene, e.g. iy Thrombosis or EEE “I Intussusception ~ Strangulated hernia Gangrene also occurs on the skin surface following arterial obstruction. It is particularly liable to affect the limbs, especially the toes in, diseases such as diabetes. ‘ A special type of gangrene follows infection with clostridial organisms (gas gangrene; see p.76).CELL AND TISSUE DAMAGE NECROSIS CASEOUS NECROSIS (CASEATION) ‘The necrotic tissue assumes a cream- cheesy appearance, slightly greasy to the ~\ touch. It is commonly seen in tuberculosis, (see p. 78). FAT NECROSIS Adipose tissue is damaged in pancreatitis and occasionally due to trauma. The special appearances are due to the action of lipases on triglycerides as follows: (released from SOAPS ‘TRIGLYCERIDES fa FATTY ACIDS + Ca* ——— Insoluble necrotic fat) LIPASE usually pancreatic E.g. Appearances in omentum and mesenteries, Naked eye Microscopic Normal fatty tigsue Note loss of nuclei and Opaque white patches cell structure, and deposition of insoluble soaps. FIBRINOID NECROSIS ‘This is a descriptive term in which connective tissues and especially arterial walls are infiltrated by a strongly eosinophilic hyaline material which shows some of the 6 characteristics of fibrin, Any actual necrosis is usually inconspicuous (see p. 221).CELL AND TISSUE DAMAGE NECROSIS - AUTOLYSIS SEQUELS OF NECROSIS 1, When small numbers of cells are involved, the cellular debris is removed by PHAGOCYTOSIS (see p. 38). 2, With larger numbers of dead cells, there is an inflammatory response with organisation and fibrous repair (see p. 44), 3. When the necrotic tissue cannot be completely removed or organised, deposition of calcium may be an additional feature, for example in TUBERCULOUS CASEOUS NECROSIS and the ARTHEROMATOUS AORTA. ‘This feature is important in radiological diagnosis. AUTOLYSIS ‘The process of ‘self-digestion’ begins after the death of the cell (as described above) and proceeds at a rate dependent on the local enzyme content; it is an inevitable sequel of necrosis, However, the term is more commonly applied to the changes which take place in tissues removed from the body and in the whole body after death, In practice, autolysis can be modified or inhibited as follows: (by RerIGERATION (by FxaTION ENZYME activity CHEMICALS added slowed down (e.g, formalin) 1 for HEAT Whole body 1 ‘preserved’ ENZYMES and PROTEINS 4 DENATURED AUTOPSY performed t without undue AVAILABLE for PATHOLOGICAL haste PROCESSINGCELL AND TISSUE DAMAGE a APOPTOSIS APOPTOSIS (formerly called ‘Necrobiosis’) ‘This term has been used for a mechanism of cell death affecting single cells scattered in a population of healthy cells. It differs from necrosis and represents a physiological process by which effete and abnormal cells die and are eliminated. Apoptosis is rapid (completed in a few hours) and is considered in two stages: Stage 1 The dying process (a) Active metabolic changes (b) Cell disintegrates into in the cell cause apoptotic bodies — each cytoplasmic ~~~ |. surrounded and nuclear —__ condensation Plasma membrane ~ by a plesma membrane intact + Some contain nuclear material Stage 2 The eli Phagocytosis by surrounding ~~ _ cells (e.g ~ liver cells, tumour cells) followed by rapid digestion Note 1. The surrounding cells move together to fill the vacant space leaving virtually no evidence of the process. 2. ‘The presence of intact plasma membranes around the apoptotic bodies explains the absence of inflammation. Significance “The process is important physiologically in balancing cell proliferation and elimination. It is associated with: (a) maintenance of the organ size in the adult (b) organ development and modelling in the embryo (©) physiological atrophy and involution It is important in pathological processes particularly associated with organ atrophy and cell elimination (e.g. in tumour growth and leukaemia).CELL AND TISSUE DAMAGE CELL DAMAGE - HYDROPIC SWELLING ‘The various agents which can cause cell necrosis may also cause lesser cell damage which is reversible when the injurious agent is removed. ‘The appearances and effects are considered under these headings: (1) hydropic swelling, (2) fatty change, (3) radiation and (4) atrophy. HYDROPIC SWELLING Hydropic swelling — formerly called Cloudy swelling — proceeds to hydropic vacuolation. Normal tubules Hydropie swelling Hydropic vacuolation Cytoplasm contains Cells swell, watery vacuoles Cytoplasm contains coarse granules ‘The damaged organs become swollen and on section may have a ‘par-boiled’ appearance. Electron microscopic (E.M.) appearances indicate the mechanisms: =~ Mitochon rounded, beaded: cause granularity and eosinophilia. Normal plasma Damaged plasma membrane and membrane: mitochondria diminished ATP a & i eX. 1 NO" wcssisen WATER into of endoplasmic cell reticulumCELL ANO TISSUE DAMAGE CELL DAMAGE - FATTY CHANGE 10 ‘This is accumulation of fat in non-fatty tissues, especially the parenchymatous organs, skeletal muscles and the heart, which have a high metabolic rate. ‘The essential problem is the inability of the non-fatty tissues to metabolise the amount of lipid presented to them, resulting in its accumulation within the cells. The most important causes range from direct cell poisons through clinical conditions associated with reduced cellular energy. CELL POISONS Bacterial, | : Chemical e.g. Chloroform, REDUCED __ Inability to Accumulation Alcohol, cellular — metabolise “> of fat ENZYME fat in cells CLINICAL DISORDERS Anexoria due to anaemia, cardiac failure, respiratory disease. Diabetes mellitus, Chronic malnutrition, activity In normal non-fatty tissues the intracellular fat is not visible by light microscopy using. conventional fat stains. In fatty change, the accumulated fat is visualised using frozen sections and fat-soluble dyes: in routine paraffin sections the fat has been dissolved and is indicated by clear vacuoles, For example, in the LIVER, the increase of deposited fat causes enlargement of the organ. Its distribution varies with the cause, e.g. — (1) Lack of Oxygen — in anaemi (2) Poison, Toxins ete — alcohol, and cardiac Infections, Hepatic a. 2 | failure organic Hepa solvents ile duct —— Fat is found Fats tend to be deposited rearearihe furthest from the arterial blood supply (hepatic arteriole) afferent blood supply (portal around the efferent yrnloed vein (hepatic venul iepatic ein (hepatic venule) —eCELL AND TISSUE DAMAGE CELL DAMAGE - FATTY CHANGE EFFECTS OF FATTY CHANGE Impairment of cellular function is usually due to the pathological process causing the fatty change (¢.g. anoxia in severe anaemia) and not to the physical presence of fat within the cell. In the liver, for example, very large accumulations of fat do not impair basic liver functions. A possible exception is the myocardium in certain circumstances. (a) Rapid or large |= —+ Increased ventricular transfusion pressure Dilatation —. Cardiac + of right heart failure Fatty myocardium —~ Weak muscle fibres (b) Sudden excessive exertion —~+ Rise in blood pressure. —= Temporary left + sided cardiac Fatty myocardium Weak muscle fibres emberrassment OBESITY must be distinguished from intra-cellular fatty change described above, Gross degrees of obesity lead to increased adipose tissue in abnormal sites, e.g. between myocardial fibres. In addition, parenchymal cells are unable to deal with the excessive intake of fat and a degree of fatty change occurs in them. The myocardium is under strain due to the circulatory resistance in the excessive adipose tissues. ‘The main controllable cause of obesity is increased intake of food, but other factors, both. genetic and environmental, exert an influence. The diagram illustrates how the Food/ Energy balance may be upset. oe ta Ny IN EXCESSIVE EXERCISE ENDOCRINE FOOD eae - as PRODUCTION INTAKE ABSORPTION fran pinnae Le eters pwn : ree ecneAsteD ENERGY UTILISATION J ee WS Balance tipped towards OBESITY Effects: Obesity reduces life expectancy mainly due to its association with cardiovascular disease, including HYPERTENSION and CORONARY ATHEROMA, ‘Type II diabetes, osteoarthritis of the lower limb joints, and gall stones are closely associated. 1CELL AND TISSUE DAMAGE ATROPHY ‘This is a simple decrease in cell size or number, resulting in a shrinkage of affected tissues and organs. The most common example is atrophy of old age (see p. 14) Caus General fall in cell (1) Gradual diminution ———~ Reduction in © ———= activity and shrinkage, in blood supply oxygen supply @.9. narrowing of coronary and nutrients arteries — myocardial atrophy Normal Accumulation of lipofuscin around nucleus Lipofuscin (“wear and tear” pigment) is a golden yellow pigment representing undigested lipid material derived from cellular metabolism, (2) Reduced functional activity ———~ Diminished demand Atrophy (disuse atrophy) for nutrition of cells Eg. Obstruction of gland duct Atrophy of gland (3) Interrupted nerve supply —~ Reduced reflex and metabolic acti skeletal muscles after destruction of motor nerves as in poliomyelitis. 8, 8g. atrophy of Loss of structure and shrinkage Reduced metabolic activity in dependent tissues (4) Endocrine deficiency ——- Loss of trophic mechanism ‘Adrenals Eg Pituitary deficiency —- Atrophy of ~ Thyroid Gonads and genital organs, (6) Pressure —= Interruption of blood supply and interference with function, e.g. neoplasm pressing on surrounding tissues. Atrophy is reversible provided the cause is eliminated or deficiencies restored. 13CELL AND TISSUE DAMAGE | AGEING ‘The distinction between ‘true’ ageing and ageing complicated by disease processes may be difficult; since therapy can be directed at the latter the distinction is important in clinical practice, ‘The changes associated with rrue ageing would be seen in a theoretical ‘ideal’ environment (minimal stress). ‘The following diagram is illustrative. The main controlling factors are intrinsic, i. genetic: ? associated with ageing changes in mitochondrial DNA. Very gradual loss of stem cell activity; Atrophy of all cells and tissues leading to loss of functional activity Growth and development DEATH Years 1 18.20 40 60 80 100 In the real environment this theoretical concept of ageing is accelerated and aggravated by ‘wo groups of extrinsic factors: NT gg Increased prevalence of Diminished ability ‘Stress’, particularly to respond to ‘Stress’ — INFECTIONS, particularly DEGENERATIVE DISORDERS diminished (eg. arterial and IMMUNE RESPONSE cardiac disease) ACCIDENTS Oe Rai eet Ageing accelerated and aggravat: associated with incidents and disorders causing DEATH NB. Death is only very rarely, if ever, due to ‘pure’ ageing. It is the result of disease — either a single process or, with increasing age, more often several causes, 14CELLAND TISSUE DAMAGE HEREDITY, GENES AND DISEASE (CELL NUCLEUS AND CHROMOSOMES, Knowledge of the GENETIC influence on disease is expanding very rapidly. The following can only be a brief outline of basic facts: ‘The cell NUCLEUS contains structures, CHROMOSOMES, which transmit hereditary traits from one generation to the next and also control the synthesis of all the proteins in the body. ‘The 46 chromosomes which most human nuclei contain are not identifiable in differentiated cells or cells in the non-proliferating phase of the cell cycle (G.).. The different morphological appearances of nuclei in histological sections indicate to some extent the amount of nuclear activity. Resting cells Active cells Differentiated colls 2.9. small lymphocyte e.g. lymphoblast ‘84g. plasma cell Dense nucleus due Large ‘open’ nucleus Nucleus partly condensed (‘cart to molecular = molecular constituents _-¥ wheo!’) and partly open. Only the condensation. ~~_ extended. air rerriesnentas Yor ea URIOAT | es synthesis are active. Individual chromosomes NOT identifiable. ‘CHROMOSOMES During MITosts the chromosomes condense into specific morphological forms which are identifiable by light microscopy: when colchicine is added to a cell culture, mitosis is arrested at the metaphase: chromosomes are then separable and can be studied. Diagram of a “The following features are specific to each chromosome: tel mere 2) Overall length, (2) postion of centromere (this dictates re the length of each arm) and (3) the pattern of banding. sande Ue u bcahed all ence es Baca tom Mc od ie i Me eee enced i a a yen see gence te) ee Sepa ee identifiable chromosomes, plus 2 sex chromosomes Fiath paiesiaiciledl ar either 2 large X = FEMALE AUTOSOME and consists wt large X and of a PATERNAL and x22 JA" 1 small Y MATERNAL chromosome, or r= MALE 15CELL AND TISSUE DAMAGE HEREDITY, GENES AND DISEASE 16 DEOXYRIBONUCLEIC ACID (DNA) ‘Since Watson and Crick defined the molecular structure of DNA in 1963 there has been a great increase in knowledge of the ‘genetic code’. Each chromosome isa very long single molecule of — (UTED DNA, condensed during mitosis It is extended to its characteristic structure when active: ‘The DOUBLE HELIX | Diagram of a very small part of very long molecule. 2 long spirals of nucleotides [consisting of a ribose (sugar) + phosphate] around a central axis, complementary but running in opposite directions. Extending to millions of base pairs. Joined by purine and pyrimidine base pairs ‘The essential function is to initiate and control the synthesis of proteins from amino- acids. All types of protein (structural proteins, hormones, receptors, intra-cellular messengers etc.) are ENCODED along the molecule, A GENE is the unit of the chromosome responsible for the synthesis of a single SPECIFIC PROTEIN. Genes vary in length but on average occupy about 20,000 base pairs of the molecule, ‘There are about 50,000 genes in all the 46 human chromosomes, not all are active: some are repetitive: some form clusters subserving related activities (e.g. MHC (HLA) locus, see p. 100). ‘There is a complex REGULATION of gene activity involving stop and start signals, promoter and enhancer functions all within the DNA structure. Moder techniques of ‘gene mapping’, in which genes and their functions are identified, are proceeding very rapidly (some 2,000 have now been identified). Diagram of Protein Synthesis An cell nucleus | Ineell cytoplasm NA, molecule 4 Single gene ‘switched on’ | (2) Message to for protein synthesis | 4 RIBOSOMES (1) TRANSCRIPTION ei } DNA synthesises messenger DNA synthesis mestenget “processing amino-acids to “a template for an =r Tpetbmmome exact copy of the code! | @) + further intracellular sequencing the amino- pele entire the processing to definitive { specific protein, pecific prote specific proteinCELL AND TISSUE DAMAGE MITOSIS AND MEIOSIS MITOSIS is the process by which SOMATIC cells proliferate ensuring exact replication of the daughter cells. Following the stimulus to proliferate, the chromosomes condense and replicate exactly, PROPHASE METAPHASE ANAPHASE TELOPHASE All chromosomes All chromosomes Chromatids are 2 daughter cells condense and replicate are aligned along _—‘pulled apart’ are about to form, 2 pars only Exact replicates 3 are shown joined at centro- \ se meres (called ’ CHROMATIDS. y 4 equatorial plate: and become each containing nuclear membrane —_ chromosomes. identical A pe ‘sissies. chromosomes 2S Pa Se MEIOSIS is a complex process occurring during GAMETOGENESIS: it involves the reduction and division of chromosomes in such a way that (1) a random mixture of both parental genes is present in the gamete and that (2) the chances are equal for fertilisation to result in either sex. This simple diagram shows the important results of meiosis. One illustrative AUTOSOME consisting of a pair of —— chromosomes, one from each parent. Primitive germ cells contains 46 chromosomes (ie. 22 autosomes + XX or XY) Cell division without replication, ee ao ao Gametes contain 22 single chromosomes. On fertilisation 22 (2) During MEIOSIS the ae autosomes are restored. sex chromosomes are a 6) br coereereeteicremap similarly distributed - tly Fertilisation (Female) 4 (R)SPeemasewre connalaing ont % female oF an equal number con- (Male) taining one Y. Male Note: In this simplified diagram a preliminary replication before meiosis and mitotic divisions after meiosis are omitted. The chances of error can be seen to be greatly increased. 7CELL AND TISSUE DAMAGE LE GENETIC ABNORMALITIES AND ASSOCIATED DISORDERS Stem een ein egg gn le iin Ee eee iat che eee came oun arc eng re ec eee It is important to distinguish between germ cell and somatic cell abnormalities. cand ota AURORA TTC Fe rr ee idea antral wo verte ee ee ee Abnormal Farhad eicioeg a eccandnamid se si ceatninnt on NEES to next generation re O- — ET hoor iitemsti GAMETE to next generation ABNORMALITIES arising in SOMATIC CELLS ‘These tend to cause restricted effects: they are not transmitted to next generation. SOMATIC TISSUES Proteration =r oOO = e ——> Therefore limited 20, Odeo secs i a cells and stem cells Still surrounded by normal cells TYPES OF GENETIC ABNORMALITIES ‘They range from large, involving whole chromosomes, through parts of chromosomes, to gene clusters and single genes. CHROMOSOMAL ABNORMALITIES Polyploidy — when the chromosomal numbers are increased by an exact multiple of the normal (23) e.g. 23 x 3 = 69 chromosomes. Such nuclei are seen in. hypertrophied muscle cells and ageing liver cells (i.e. somatic cell polyploidy), Such gross chromosomal abnormalities occurring during gametogenesis or at fertilisation are usually incompatible with life and are a common cause of spontaneous abortion. (2) Aneuploidy — where the number of chromosomes is increased usually by one (Trisomy) or decreased by one (MONOSOMY). Early spontaneous abortion is again common: survivors show mental retardation and varied physical abnormalities. Down’s syndrome is a good example of AUTOSOMAL TRISOMY and is due to an extra chromosome (ie. Trisomy 21 — karyotype 47XX + 21 or 47XY + 21), ‘The abnormality occurs in utero after fertilisation of the ovum and is therefore autosomal. Increasing maternal age is a potentiating factor in Down’s syndrome and 18 many other genetic defects.CELL AND TISSUE DAMAGE GENETIC ABNORMALITIES AND ASSOCIATED DISORDERS. ‘CHROMOSOMAL ABNORMALITIES (continued) (3) Structural abnormalities Despite the existence of efficient repair mechanisms structural errors do arise when the long DNA molecules are accidentally broken during the dramatic physical changes occurring at replication. They include, for example, duplication and deletion of gene clusters and single genes: and translocation of fragments of DNA between chromosomes. SINGLE GENE DISORDERS Factors regulating the production of the final specific protein are extremely complex and interacting: 1. In the nucleus In the cytoplasm Activity of other genes (including the RNA — of each step in transcription and protein synthesis movement) ‘ “Therefore GENETIC EXPRESSION very VARIABLE 2, The corresponding genes on each parental chromosome exert important influences on each other. The inheritance of the Rhesus blood group D is illustrative: there are two enhancement = — ‘ promotion single gene activity { detailed control start/stop signals possibilities at the D locus on the chromosome — ‘D’ or ‘d’. The 3 possible combinations give rise to the actual blood group (phenotype) as follows: Homozygous Heterozygous a Genotype DD dd Dd ___, The presence of one D confers the Blood group D. a D blood group D i.e. D is DOMINANT. (phenotype phenotypes) \ The presence of two 4's is required to confer the blood group d, i.e. dis RECESSIVE. ‘This concept is important in inherited single gone disorders. (1) In DOMINANT inheritance any HETEROZYGOUS offspring bearing the abnormal trait will be affected: mating with a normal partner statistically produces 50% of normal offspring and 50% affected. (2) In RECESSIVE inheritance only HOMOZYGOTES for the trait are affected. Such cases ‘usually arise from the mating of 2 heterozygous CARRIERS who, by definition, are themselves unaffected ‘The results of mating are as follows: (A = affected gene, N = normal gene) NN = normal individual: NA = carrier: AA = affected individual Heterozygote——Heterozygote Monozygote Normal Heterozygote Normal NA——— Na aA ————_NN Na————NN NN NA NA AA NA NA NA NA NN NA NA NN Statistically 1 normal, SS 2 are normal, 2 carriers, 1 affected All offspring are carriers. 2 are carriers. 19