- 1 Pedigree Analysis and its Types with Examples – Patterns of Inheritance and Single-Gene Disorders
- 1.1 The Pedigree and the Method for Construction of a Pedigree
- 1.2 Analysis of Pedigree
- 1.3 Pedigree Analysis Examples
- 1.4 Autosomal Traits Showing Mendelian Pattern of Inheritance
- 1.5 Autosomal Recessive Traits
- 1.6 Autosomal Dominant Defects
- 1.7 Sex Linked Recessive Trait
- 1.8 X-linked Dominant Traits
- 1.9 Thalassemia
- 1.10 Types of Thalassemia and the Cause of Development:
- 1.11 Mode of Inheritance of Thalassemia in the Family:
The study of cellular Biology Topics is essential to understanding the workings of all living organisms.
Pedigree Analysis and its Types with Examples – Patterns of Inheritance and Single-Gene Disorders
Subsequently, after the rediscovery of Mendel’s works, scientists tried to find Mendelian Principles of Inheritance in animals. Bateson in 1902 started works on fowls to observe the transmission of characters. Similarly, interests were shown by different investigators about the inheritance of human characters and Mendelian inheritance of several traits of man was followed through study of the human pedigrees. The first among them is brachydactyly causing malformation of hands and fingers where they appear to be abnormally short (reported in 1905).
However, because of some limitations in studying humans like other experimental animals and plants earlier reports on human inheritance were mainly supported with pedigree analysis. But in the recent scenario study on human inheritance is much more elaborate rather than initially thought of. With the discovery of advanced techniques and tools for genetic studies human species is probably the best-understood organism among all other diverse species in the world. The number of genes, their chromosomal location, the sequences framing a gene in the DNA, the mode of action as well as their pattern of inheritance now are known to us with satisfactory information.
But primarily to understand the mode of inheritance of a character in humans we may depend upon the method of pedigree analysis and with the help of careful pedigree analysis, a character is transmitted whether in a Mendelian pattern or not, can be ascertained. Through only pedigree analysis, a large number of human traits could be tabulated as dominant and recessive genes as well as their chromosomal relationship. As human subjects cannot be taken as experimental material for simply ethical reason pedigree analysis had been a faithful tool to reveal the mystery of transmission of characters in man.
The Pedigree and the Method for Construction of a Pedigree
Pedigree is a symbolic representation of the history of a family. This pedigree in the form of a chart presents the number of generations in a family showing the relationship among the members of the family. Members of the family affected by a particular character may be marked with distinct symbols and modes of inheritance of the same may be followed in the family depending on the available information on the character and thus the genetic character, its nature of expression in man and the mode of inheritance may be ascertained with careful analysis. Thus pedigree analysis may be the alternative way of studying Mendelian inheritance in man in contrast to a designed experimental cross as may be done for plant or other subhuman animal species.
For preparing a pedigree chart or family tree, a set of standardized symbols are used and the symbols are borrowed from genealogy. In the pedigree, a male is represented by a square, a female by a circle, unknown sex by a rhombus, and an affected person by a shaded square or circle. A square and a circle is joined by a transverse line to show the marriage between them. A marriage line connected with a short vertical line indicates a progeny line with which a parallel line may be joined to which all the progeny from the couple may be connected with short vertical lines according to their sequence of birth. The line joining the brothers and sisters of a generation is known as the sib-ship line.
The generations are marked by Roman numerals (I, II, III, etc.) and the progeny from a lineage are marked with Arabic numerals in order of birth. A square or circle or rhombus marked with a number within indicates a number of the same type of individual in a generation. A deceased male or female in the pedigree is shown by an oblique line across the square or circle. Stillbirth in the pedigree is shown by a small square or circle as would be the sex of the member under consideration. Marriage between the related individuals in a pedigree is marked by the double lines parallelly connecting the male and the female. Twins in the family are usually shown by the members in symbols connected by a forked line joined with the sib-ship line. In case the twins are monozygotic the forked lines originate from a single vertical line from the sib-ship line. It is to be remembered that the monozygotic twins are always of the same sex, but the dizygotic twins may differ by their sex.
The individual who is detected for any genetic disorder first in the family is called a proband and the proband is marked with an arrow. Proband being a female is known as proposita and that being a male is called propositus. The symbols ordinarily used in preparing a pedigree chart have been represented on the previous page.
Analysis of Pedigree
For pedigree analysis, some principles related to the inheritance of characters are required to be known. Genes that determine characters in man may show their location on different types of chromosomes namely autosome, X chromosome, and Y chromosome. Based on this fact the nature of inheritance differs from one character to the other. Further, a gene may be dominant or recessive with regard to its expression, and depending upon this property also the mode of transmission of the gene or the related character also differ. Thus some principles for autosomally located recessive character and autosomally linked dominant character may be noticed during their transmission. The same is also true for the sex-linked recessive and sex-linked dominant traits. A distinct mode of inheritance of the Y-linked gene and the related character may also be noticed. The general principles for the different types of characters as mentioned above are pointed out in the following table.
General Principles of Transmission of Characters Linked to Different Types of Chromosomes:
|Chromosomal Relation of the Character||Properties Shown by the Character During Transmission|
|Autosomal Recessive Trait||1. A skip of generation is typically noticed.
2. Unaffected parents may produce an affected child.
3. One parent being affected usually produce unaffected children.
4. Males and females in the family are equally affected by the trait (i.e., there is no sex bias in the expression of the trait)
|Autosomal Dominant Trait||1. Typically skip of generation is usually not noticed in the pedigree for the trait under consideration (i.e., the dominant trait seldom shows a skip of generation).
2. Either of the parents being affected usually shows the production of the affected child.
3. Males and females in the pedigree get equally affected by the trait.
4. Affected son or daughter must have an affected parent.
|Sex Linked Recessive Trait||1. Phenotypic expression of the trait is much more frequent in males than females.
2. Affected male never transmits the trait to his son.
3. Affected male transmits the gene for the character to his daughter who becomes a heterozygous carrier for the trait, but normal by expression.
4. Carrier female transmits the trait normally to 50% of her sons.
5. Criss-cross pattern of inheritance (i.e., grandfather-to-grandson transmission through daughter) becomes prominent in the transmission of the trait in the pedigree.
|Sex Linked Dominant Trait||1. Affected male produces all affected daughters and no affected son.
2. Heterozygous affected female transmit the trait to half of their sons and to all their daughters.
3. No skip of generation is normally observed for the trait.
|Y-linked Trait||1. Being the holandric trait the character is expressed only in males in the pedigree.
2. Affected male always transmits the trait to the male progeny in the total pedigree.
All of the conclusions regarding gene action (dominant/recessive; co-dominant) we have discussed so far have been obtained from analyzing the results of controlled crosses. In some situations, we do not have the opportunity to perform controlled crosses. Rather we need an analysis of an existing population. This is always the case when studying human inheritance. The principles of inheritance as may be observed in the case of different types of traits (mentioned in the Table) are usually noticed in the typical pedigree charts.
Pedigrees as indicated in the figure show how a character linked with autosome or X chromosome may be inherited in a family. The case of dominance and recessiveness for a particular trait also shows a distinctive pattern of inheritance. Hence if the history of a family in description or in a pedigree chart for an unknown genetic defect is known to us we may easily determine the nature of inheritance of the character. With an example, this may be explained. Following is a pedigree of unknown heritable features. By careful analysis, the chromosomal location of the gene for the trait in the family and its nature of expression may be ascertained.
Pedigree Analysis Examples
The above figure represents a pedigree of three generations marked as I, II, and III. Altogether there are seventeen members in the pedigree of which the third generation 4th member (III-4 male) is the proband, i.e., the male member first identified for the genetic defect or genetic trait. In this pedigree I — 1 is an affected male who is married to the normal I — 2 female. The I — 3 male and I — 4 female are husband and wife and they are unaffected by the trait. In the second generation there are seven members as II — 1 female, II — 2 with unknown sex, II — 3 male, II — 4 female, II — 5 female, II — 6 and II — 7 are males. All the members of this generation are unaffected. The II — 3 and II — 4 females become husband and wife and from them, the third generation progeny are produced as III — 1 male, III — 2 female, III — 5 and III — 6 females are unaffected. The III — 5 female and III — 6 female are monozygotic twins. On the other hand, the III — 3 female and III — 4 male are affected by the trait. The III — 4 affected male is the proband in this case.
Out of three generations, only the first and third generations contain the affected individual indicating a skip of generation for the character. Further, the unaffected parents (II — 3 male and — 4 female) produced affected children, one male (III – 4) and one female (III – 3). Hence the character appears to be controlled by a recessive gene. The pedigree also shows that both male and female members are affected by the trait. Hence, there is no sex bias in the expression of the character. Therefore, the character appears to be autosomal by location. Hence, the trait under consideration indicates the autosomal recessive mode of inheritance. Logical analysis and inference may be tabulated in the following manner.
Analysis of pedigree for determination of the mode of inheritance of the trait:
|1. Three generation pedigree contains 17 individuals and out of which there are eight males and eight females. One member (II – 2) is having unknown sex.
2. In the whole pedigree only three individuals are affected by the trait and they are I – 1 male, III – 3 female, and III – 4 male when the III – 4 male is the proband.
3. None of the II generation progeny are affected by the trait. Therefore, there is a distinct skip of generation in the expression of the trait.
4. Further affected parent, the I – 1 male did not produce any affected children and the unaffected parents of the second generation, II – 3 male and II – 4 female, produced two affected children (III – 3 female and III – 4 male).
|Hence, the trait under consideration is surely recessive by nature.|
|1. The trait under consideration is expressed both in male and female members in the pedigree. Therefore, there is no sex bias in the expression of the character.
2. The affected members are I – 1 male, III – 3 female, and III – 4 male, the proband.
|Hence, the trait under consideration is autosomal by location.|
Conclusion: The trait under consideration has a distinct pattern of inheritance which suggests its autosomal recessive mode of inheritance.
(c) Determination of Genotype:
On the basis of the above inference the genotypes of all the members in the pedigree may be determined. Let, the gene controlling the expression of the trait under consideration is ‘a’, then its normal allele may be designated as ‘a+’. Therefore, the genotype of the affected individual will be aa and that of an unaffected individual may be either a+a+ or a+a. Based on the above criteria the genotype of the members in the pedigree may be indicated in the following table.
The genotype of the members in the Pedigree:
Autosomal Traits Showing Mendelian Pattern of Inheritance
In human there are many characters that are controlled by a single gene and their inheritance in the pedigree occurs in a Mendelian pattern. Several such characters are described below.
Autosomal Recessive Traits
Albinism is a genetic defect in men due to which melanin synthesis in the skin does not occur in the affected individual. Because of this, the affected individuals have white skin, white hair, and red eyes. This is the classical albinism commonly known as Occulocutaneous Albinism (OCA) and there is another form of albinism known as OA or Occular Albinism when pigment from the iris will be lost. Due to some enzyme deficiency in the pathway of tyrosine metabolism (tyrosinase) classical albinism is developed and due to this though in the skin melanocytes are present but they lack any melanin. Albinism leads to DNA damage in the skin cells by UV radiation coming from the sun. The persons having melanin in the skin may get some protection from UV radiation. On the contrary melanin deficient albinos are very much prone to DNA damage in the skin cell leading to skin cancer.
The most widely occurring albinism is OCA develops due to a recessive mutation of the autosomal gene and therefore, the albino phenotype appears in the presence of a homozygous condition. The incidence of albinism is 1 in 33000 in Caucasians and 1 in 28000 among blacks in the United States. However, this frequency varies from one population to the other.
2. Cystic Fibrosis
Cystic fibrosis is a disabling and fatal genetic condition in man. The disease results in pancreatic, pulmonary, and digestive dysfunction in the affected individual. The diseased condition is developed due to excessive mucous secretion from the exocrine glands and ducts of the glands are clogged with mucous secretion. Besides various parts of the lung also accumulates mucous and the patient needs removal of mucous from the lung parts. It is a fatal disease and the average life expectancy of the diseased man is about 40 years. The disease is caused by the homozygous condition of one autosomal recessive gene and its incidence is 1 in 200 of the newborn Caucasians. In Asians, its frequency is 1 in 90000.
3. Phenylketonuria (PKU)
Phenylketonuria is a serious genetic disorder in man and it is caused by a recessive mutation of the autosomal gene present on chromosome 12. A PKU patient exhibits severe mental retardation and slow growth leading to early death. They also exhibit low production of thyroxine, adrenaline, and melanin. A defect in phenylalanine metabolism leads to PKU condition when the enzyme phenylalanine hydroxylase required for phenylalanine metabolism is deficient in the patient.
In such a condition phenylalanine in the form of phenyl pyruvic acid is accumulated in the blood which prevents normal brain development in the newborn. If treatment is not given to the patient within one or two months of birth the patient develops severe mental retardation and other associated symptoms. The treatment, in this case, includes a phenylalanine-free diet for the patient up to the age of 10-12 years when brain development in the baby may be almost complete. Because the disease is recessive is nature apparently normal parents (but heterozygotes for the PKU gene) may give birth to a PKU baby and the inheritance pattern of the defects strictly follow the Mendelian rules. The incidence of PKU in the population is about 1 in 12000.
4. Sickle Cell Anaemia
Sickle cell anemia is an autosomal recessive disease that affects haemoglobin thereby affecting oxygen transport in the affected individuals. It was first described by J. Herrick in 1910.
Expression of the Disease:
- Red blood cells assume the characteristic sickle shape instead of a normal disc shape.
- Sickle RBCs are fragile and break easily resulting in anemia.
- Sickle cells are less flexible and are unable to squeeze through blood vessels like normal ones.
- Therefore they tend to clog capillaries resulting in impaired blood circulation and oxygen deprivation.
Oxygen Deprivation: It not only takes place in the extremities but also in the brain, heart, lungs, kidneys, GI, muscles, joints, etc. If not treated conditions might get worse leading to complications like pneumonia, abdominal pain, rheumatism, kidney failure, heart failure, etc.
Cell Dehydration: It is a common characteristic of sickle cell disease that contributes to pathophysiology. Cell dehydration promotes the polymerization and sickling of cells. The Gardos channel (a sensitive calcium-dependent potassium selective channel expressed in erythrocytes) of sickle cells either singly or with the K-Cl co-transport plays a havoc role in cell dehydration.
Sickle Cell Disease & Stress: sickle cell disease has a typical state of nitric oxide (NO) resistance and bioavailability of L-arginine – the substrate for NO synthesis that contributes to endothelial dysfunction and other complications.
Causes Behind Sickle Cell Disease: Molecular de feet (substitution of glutamic acid with valine at 6 positions from the N-terminal end of the beta polypeptide) in the beta-globin chain resulting in the formation of Hb-S. The β-polypeptide sickle cell mutant allele is (3s and its normal allele is βA. Homozygous βAβA makes normal HbA along with normal α-globin chains. Sickle Cell Disease (SCD) happens when 2 normal α-chains and 2 mutant β globin chains are produced. The mutant β-globin genes (PSPS) produce defective β-globin chains.
Sickle Cell Trait: Heterozygous PAPS people produce both normal HbA as well defective Hbs. This is a sickle cell trait. People with sickle cell trait very rarely show symptoms of SCD, but if subjected to heavy exercise or higher altitude, will show oxidative stress and anaemia the haemoglobin will change its shape to become sickle-like
Transmission of Sickie Cell Disease (Inheritance): When the father is normal (HbA HbA) and the mother is a carrier (HbA Hbs) as shown in the checkerboard.
Again if a union takes place between two sickle cell traits, children may be normal, with sickle cell anemia or may carry the sickle cell trait.
Control of SCD: The US FDA has approved three new drugs for prophylaxis and treatment of various complications related to sickle cell disease and they are L-glutamine, Voxelotor, and Crizan lizumab.
A list of some other autosomal recessive genetic defects is given in the following table.
Some Autosomal Recessive Genetic Disorders in Man:
|Name of the Defect||Main Symptoms|
|1. Xeroderma Pigmentosum||Absence of DNA repair enzymes, skin cancer, and early death.|
|2. Falconi Anaemia||Cardiac abnormality, slow growth rate, high incidence of leukemia.|
|3. Galactosemia||Mental retardation, accumulation of galactose in the liver.|
|4. Ataxia Tangiectasia||Degeneration of the nervous system in progressive order.|
|5. Tay-Sachs Disease||Abormal ganglioside metabolism, early death.|
|6. Sickle Cell Anaemia||Abnormal haemoglobin formation in blood, sickling of RBC in low oxygen concentration, the deficient oxygen supply in the peripheral region of the body due to clogging of blood capillaries by sickle-shaped RBC, often heart failure, partial paralysis and sore development on the body surface.|
|7. Orotic Aciduria||Lethargy, delay in behavioural development, some mental retardation, excretion of high levels of orotic acid in urine.|
|8. Severe Combined Immunodeficiency||Defects in immune response due to reduced or absent immunoglobulin, reduced growth, prone to infection and recurrent infection, and early death.|
|9. Hereditary Xanthinuria||Painful debilitating disease due to accumulation of xanthine crystals in muscles, xanthine liberation in urine.|
Autosomal Dominant Defects
The defect leads to dwarfism in man. The body trunk is normal in size but the arms and legs are greatly reduced in size. The head of such a defective person is unusually large in size and the defective individual exhibits good muscular growth. The incidence of achondroplasia in the population is about 1 in 30000. People with achondroplasia have short stature, with an average adult height of 131 cm for males and 123 cm for females.
2. Marfan Syndrome
In this abnormal condition the skeletal system, eye, and cardiovascular system are much affected. The affected individual appears to be tall and thin in stature having long arms and legs. The span of the arms may exceed the height of the individual. In Marfan syndrome the connective tissue surrounding the main aorta arising from the heart becomes weak and therefore, rupturing of the aorta may occur following its enlargement. Therefore, the disease is fatal and in many cases, the affected individual dies at an early age. The disease is caused by an autosomal dominant gene and therefore, the affected person of either sex may transmit the defect to their children in the next generation. The frequency of the disease in the population is about 1 in 10000.
In this defective condition, non-malignant tumors develop on the skin and it is actually benign growth of the nervous system. In some cases, spots on the skin are developed due to abnormal skin pigmentation. The disease is also associated with learning disorders. The gene responsible for the disease is called NF1 and is located on chromosome 17. Due to mutation of the NF 1 gene, loss of control of cell growth occurs leading to the production of small tumours. This disease is caused by a dominant mutation of the gene on chromosome 17 and the incidence of the defect in the population is about 1 in 30000.
A list of several defects in man due to autosomal dominant mutation is given in the following table.
Some Autosomal Dominant Defects Having Mendelian Pattern of Inheritance in Man:
|Name of the Defect||Main Symptoms|
|1. Brachydactyly||Short fingers on the malformed hand|
|2. Camtodactyly||Stiff permanently bent fingers|
|3. Huntington’s Disease||Dementia with progressive degeneration of the nervous system, early death|
|4. Nail Patella Syndrome||Knee caps and nails in the affected individuals absent|
|5. Hypocalcemia||Calcium levels in blood serum increased|
|6. Hypercholesteromia||Cholesterol levels in the blood increased, and heart attack|
|7. Porphyria||Inability to metabolize porphyrin, occasional mental derangement|
Sex Linked Recessive Trait
Colour blindness is the best-known X-linked recessive genetic disorder. The most common form of colour blindness is known as red/green colour blindness when an affected person fails to distinguish between red and green colour. However, the inability to recognize red colour is known as protanopia and that green colour is called deuteranopia. Because the character shows a recessive mode of inheritance and the gene for the defect is X-linked, the character is more prevalent in the male human population.
The genetic locus for protanopia is known as RCP (Red Cone Pigment) and the genetic locus for deuteranopia is called GCP (Green Cone Pigment) and they are present on the long arm of the X chromosome of man and very close by location. There may be one or more copies of GCP on the chromosome but only one copy of the RCP. The genes may produce color-sensitive proteins that may absorb specific light. Both genes are required for normal colour perception in man. Among the two forms of colour blindness, deuteranopia is more prevalent in the population. Colour blindness is reported to affect 8% of the male population in the United States.
Haemophilia is also known as bleeder’s disease and the affected person requires a longer time to achieve clotting of blood and blood clotting may not occur at all in the affected person. Because of this, during any bloodshed even in minor form, the patient suffers from severe blood loss and the patient dies of blood loss unless a treatment is given. Haemophilia may be available in two forms Haemophilia A when the clotting factor VIII is absent and the other is known Haemophilia B when clotting IX is deficient. The second form of haemophilia is also known as Christmas disease.
The genes for both the factors for blood clotting are present on the X chromosome and they show a recessive mode of inheritance. Of the two forms of hemophilia, Haemophilia A is the most common bleeding disorder, and about 1 in 10000 individual suffers from the defect in the human population, while the Second form of haemophilia affects the population with a frequency of 1 in 100000000. Royal family of England was found to be affected by Haemophilia A and many of the descendants of Queen Victoria were affected by the disease.
In the case of ichthyosis skin of the affected individual often resembles a fish scale. Due to a recessive gene present on the X chromosome an enzyme called steroid sulfatase is found to be deficient in this disease. As a result of this dark scales appear on the trunk and the extremities. The incidence of ichthyosis is about 1 in 6000 males in the human population. A list of X-linked recessive disorders is given in the following table.
Some X-linked Recessive Disorders in Man:
|Name of the Genetic Trait||Main Symptoms|
|1. Duchenne Muscular Dystrophy (DMD)||Progressive muscle wasting, a fatal condition leading to early death|
|2. Fabry Disease||Enzyme alpha-galactosidase A deficiency leads to metabolic disorders causing cardiac and renal problems.|
|3. Lesch-Nyhan Syndrome||Deficiency of the enzyme HGPRT (Hypoxanthine Guanine phosphoribosyl transferase) leads to mental retardation, self-mutilation, and early death.|
|4. Glucose-6-Phosphate Dehydrogenase Deficiency||Fatal anemic condition.|
Only a few X-linked dominant defects in humans are known. However, a dominant X-linked gene shows a distinct mode of inheritance when the pattern of inheritance will be identical as found in the case of X-linked recessive disorder. The only difference is that the trait will be expressed in all the generations. The affected heterozygous female may transmit the defect to half of her sons and the affected male may transmit the trait to his daughters only. Hereditary enamel hypoplasia in man is due to a dominant mutation of one X-linked gene.
Several X-linked Dominant Disorders in Man:
|Name of the Genetic Trait||Main Symptoms|
|1. Hypophosphatemia||A type of ricket or bow-leggedness, non-curable with vitamin D supplement due to deficiency of phosphate.|
|2. Hereditary Enamel Hypoplasia||Faulty enamel and dental discolouration.|
|3. Constitutional thrombopathy||Severe bleeding anomaly due to interference with the formation of blood platelets.|
Thalassemia is a type of hereditary blood-related disorder in men for which the amount of haemoglobin in the blood may be severely depleted. In many cases, due to such a disorder, the person affected by the disorder may die. The disease is developed due to some genetic defect and in severe cases an affected person may continue living with a transfusion of blood from time to time. The defect is usually detected in early childhood and in extreme situations the affected child dies in the maternal womb.
The term “thalassemia” is derived from the Greek word meaning ‘sea’. The disease was first detected in areas surrounding the Mediterranean Sea. Because of the prevalence of the disease in these areas, it has been named thalassemia. However, the disease would also be detected in other regions of the world. In the Indian population, the disease also appears to be moderate in its incidence. In South-East Asia and surrounding areas of the Mediterranean Sea, about 20-30% of the total population gets affected by this disease.
Symptoms of Thalassemia:
In our body haemoglobin in circulating blood help us in transporting oxygen to different parts of the body for their smooth functioning. A person affected with thalassemia cannot produce sufficient haemoglobin in the blood and therefore, the affected person suffers from mild to severe anemia consequently a number of complications may be developed with this which may be indicated in the following manner.
Complications Developed in Thalassemia:
|1. Iron Overload||Excessive iron deposition in blood and accumulation of fatal iron level in blood.||Damage to the heart, liver, and endocrine system|
|2. Infection||The risk of infection is increased.||Secondary ailments|
|3. Bone Deformities||Abnormal bone structure, especially in the face and skull. Bones become thin and brittle.||Expansion of bone marrow|
|4. Spleen Enlargement||Splenomegaly and severe enlargement of spleen for removal of damaged red blood cells.||Overload on the skin with regard to its function|
|5. Slow Growth||The rate of growth is slowed down along with delayed puberty.||Ill health because of low growth rate|
|6. Heart Problem||Arrhythmia and congestion in the heart.||Heart failure in severe case|
Types of Thalassemia and the Cause of Development:
The physiological effect of thalassemia is defective haemoglobin production resulting in anemia in the patients. Haemoglobin is formed of four polypeptide chains out of which two are α-chain and two are β-chain. The defect may appear either in the β-chain or in the α-chain which may be the main cause of the disease. However, based on this feature thalassemia may be categorized into several types:
1. α-thalassemia or Alpha thalassemia:
In α-thalassemia due to genetic defect either α-polypeptide is not at all synthesized or its synthesis is depleted. As a result β-polypeptide chain becomes excess in adults and γ-polypeptide chains in newborns. As a consequence unstable tetramers of β-polypeptide chains (called haemoglobin H) may be formed and these haemoglobins have abnormal oxygen dissociation curves resulting anaemia.
For the production of the 2-α-polypeptide chain 2-α-globin genes are present in chromosome no 16. In the normal person, there are 2 pairs of this gene in diploid condition. In defective conditions, either 2-α-globin genes from both chromosomes may be deleted or one gene may be deleted from the homologous chromosomes. If both copies of the gene are deleted from the homologues, it is called α-thalassemia-1 and on the other hand if one copy of the genes on the chromosomes is deleted it is known as α-thalassemia-2. α-thalassemia-1 is severely fatal and the baby usually dies in the maternal womb.
On the other hand, when two copies of the gene are deleted from one of the homologues, it is called a heterozygous state and in a heterozygous state anaemic state will be developed at a low level. The same situation will be developed when one copy of the gene gets deleted from both the homologues (α-thalassemia-1). When out of four copies of the α-globin gene, only one copy of the gene is deleted from one of the homologues, the total gene copies in the affected person becomes three and the anaemia level will be very less and appears to be insignificant.
2. β-thalassemia or Beta thalassemia:
β-thalassemia occurs due to mutation in the P-globin gene cluster in chromosome-11. Due to various types of mutations, the β-polypeptide chain is depleted in the affected person and this may be the cause of β-thalassemia. β-thalassemia may be of various types namely β°-thalassemia or β-thalassemia major, β+-thalassemia or β-thalassemia intermedia, and δ/β thalassemia. Usually, deletion appears to be the principal cause of the development of the defect. However, non-sense, missense, frameshift or defect in RNA processing, etc. may be the cause of the disease in man.
In the case of β°-thalassemia, no β-polypeptide is synthesized in blood and a patient of β-thalassemia major may
be treated with blood transfusion for the survival of the patient for long period. In δ/β thalassemia, though β-polypeptide is not synthesized along with S chain synthesis γ-polypeptide is produced and the Severity of anaemia may be neutralized to some extent. However, in β-intermedia some β-chains are produced and the α-chains may be in excess. The excess α-chains bind with the RBC membrane causing membrane damage.
Besides these main types of thalassemia, δ-thalassemia may be another type of defect when due to mutation of a gene, δ-chain synthesis is depleted. It is noteworthy to mention that in normal adults about 3% of haemoglobin is formed of α and δ chains. But this thalassemia is not of great concern.
Mode of Inheritance of Thalassemia in the Family:
The occurrence of thalassemia is related to the defect in the gene(s) present in the autosomes. The gene for α-thalassemia is present on human chromosome 16 and that for β-thalassemia on chromosome 11. Both thalassemia are inherited in an autosomal recessive fashion, α-thalassemia-1 or a0 thalassemia and β°-thalassemia are fatal when the affected individual is homozygous for the defective gene. But in both cases, the heterozygous condition is not so fatal, and the affected person suffers from little anaemia. When the couples in a marriage are heterozygous for the gene defect they have a fair chance of producing a homozygous defective child. 50% of the children of such couples may be carriers and 25% of the children may be affected by the fatal disease.
Though thalassemia is inherited in a recessive fashion, the defective allele is co-dominant with its normal counterpart. Therefore, the heterozygotic condition develops mild anaemia. The heterozygotic condition also confers some benefit to the carrier individual. It has been reported that the heterozygotes for thalassemia get protection from malarial infection.
Incidence of Thalassemia:
The highest incidence of thalassemia has been observed in the Maldives and the carrier rate is about 18%. In India, 3-8% of the population becomes affected. In Cyprus, the estimated prevalence is about 16%. In Europe, the highest concentration of the disease is found in Greece, the Coastal region of Turkey, and parts of Italy.