GENETIC DISORDERS

Pedigree Analysis :

A record of inheritance of certain genetic traits for two or more generations presented in the form of a diagram or family tree is called pedigree.

Parents are shown by horizontal line while their offsprings are connected to it by a vertical line.

The offsprings are also shown in the form of a horizontal line below the parents and numbered with arabic numerals.

Pedigree analysis is study of pedigree for the transmission of particular trait and finding the possibility of absence or presence of that trait in homozygous or heterozygous state in a particular individual.

It is useful for the genetic counsellors to advise intending couples about the possibility of having children with genetic defects like haemophilia, colour blindness, alkaptonuria, phenylketonuria, thalassaemia, sickle cell anaemia (recessive traits), brachydactyly, myotonic dystrophy and polydactyly (dominant traits).

Pedigree analysis indicates that Mendel's principles are also applicable to human genetics with some modifications found out later, like quantitative inheritance, sex linked characters and other linkages.

Symbols used in Pedigree analysis :

Proband is person from which case history starts. If it is male, it is called propositus, if it is female it is called proposita.

Example 8 : In the pedigree given below, indicate whether the shaded symbols indicate dominant or recessive allele. Also give genotype of the whole pedigree.

Solution: Since the shaded symbol appears in all the offsprings, father must be homozygous dominant while the mother homozygous recessive (AA × aa = all Aa) because in all other cases this possibility is absent (Aa × aa = 2Aa + 2aa; aa × AA = all Aa; aa × Aa = 2aA + 2aa). All the members of II generation will, therefore, be heterozygous (Aa). This is further confirmed by marriage of II-1 with homozygous recessive (Aa × aa = 2Aa, 2aa) and bearing children of both the parental types. Marriage of II-3 with the homozygous recessive can produce both recessive and heterozygotes as are present here.

MENDELIAN DISORDERS

Sickle-Cell Anaemia

It is an autosomal recessive disorder. In this disorder, the RBCs become sickle shaped under low O2 concentration.

The affected persons die young.

Other heterozygous for this trait are having normal phenotype and long lived.

The disease is due to base substitution of sixth codon in the gene coding for chain of haemoglobin.

The middle base of a DNA triplet coding for the amino acid glutamic acid is mutated so that the triplet now codes for valine instead.

The mutant haemoglobin molecule undergoes polymerisation under low O2 tension causing the change in the shape of RBC from biconcave disc to elongated sickle like structure.

Fig.: Amino acid composition of the relevant portion of l3-chain haemoglobin:
(a) from a normal individual; (b) from an individual with sickle-cell anaemia.

Thalassaemia

It is recessive autosomal disease caused due to reduced synthesis of or polypeptide of haemoglobin. thalassaemia is a major problem, individuals suffering from major thalassaemia often die before ten years of age.

Phenylketonuria

Recessive autosomal disorder (Chromosome 12) related to phenylalanine metabolism to tyrosine. This disorder is due to absence of a liver enzyme called phenylalanine hydroxylase. Due to lack of this enzyme, phenylalanine follows another pathway and gets converted into phenylpyruvic acid. This phenyl pyruvic acid upon accumulation in joints causes arthritis and if it hits the brain, then it causes mental retardation known as phenyl pyruvic idiocy. These are also excreted through urine because of poor absorption by kidney.

Cystic Fibrosis

It is an autosomal recessive disorder common among Caucasian Northern Europeans. Persons suffering from this disease are having extremely salty sweat. It is due to decreased Na+ and Cl reabsorption in the ducts. Disease is due to a gene present on chromosome 7. Due to a defective glycoprotein, thick mucus develops in pancreas and lungs and formation of fibrous cyst occurs in pancreas.

Huntington's Chorea

It is an autosomal dominant disorder. The gene responsible for this disorder is present on chromosome 4. Disease is characterised by gradual degradation of brain tissue in the middle age and consequent shrinkage of brain.

Alzheimer's Disease

This autosomal recessive disease results in mental deterioration (loss of memory, confusion, anxiety) and ultimately the loss of functional capacities. The disease is due to deposits of -amyloid, a short protein in brain which results in degradation of neurons. It involves two defective alleles located on chromosome number 19 and 21. This disease is common in Down's syndrome.

Myotonic dystrophy is due to a dominant autosomal mutant gene located on the long arm of chromosome 19. Mild myotonia -atrophy and weakness of the musculature of the face and extremities, is most common.

Other Mendelian disorders :

(i) Alkaptonuria (Garrod, 1908) - Due to deficiency of oxidase enzyme.

(ii) Albinism (Chromosome 11) - Absence of tyrosinase

(iii) Tay-Sach's disease (Chromosome 15) - Absence of hexosaminidase B.

(iv) Gaucher's disease (Chromosomes 1) - Due to the inhibition of glucocerebrosidase enzyme action which leads to accumulation of cerebroside.

Other abnormalities due to autosomal dominant gene mutation

(i) Polydactyly - Presence of extra fingers and toes

(ii) Brachydactyly - Abnormal short fingers and toes

Abnormalities due to sex linked (X-linked) recessive gene mutation

(i) Haemophilia A - Due to lack of antihaemophilic-globulin.

Haemophilia B - Due to lack of plasma thromboplastin

(ii) Red-green colour blindness - Daltonism

Protanopia - Red colour blindness

Tritanopia - Blue colour blindness

Deuteranopia - Green colour blindness

(iii) Muscular dystrophy - Due to non-synthesis of protein dystrophin

Deterioration of muscles at an early stage

(iv) Lesch Nyhan syndrome -Deterioration of nervous system

Due to HGPRT deficiency (Hypoxanthin guanine

phosphoribosyl transferase)

CHROMOSOMAL DISORDERS

A. Autosomal abnormalities (Due to mutation in body chromosome)

(i) Down's Syndrome -It occurs due to trisomy of 21st chromosome. The affected individual is short statured with small round head, furrowed tongue and partially open mouth. Palm is broad with characteristic palm crease and mental retardation. Physical and psychomotor development is retarded.

(ii) Edward's syndrome - Trisomy of 18th chromosome

(iii) Patau's syndrome - Trisomy of 13th chromosome

(iv) Cri du chat syndrome - Due to deletion in short arm of 5th chromosome.

B. Allosomal or Sex Chromosomal Disorder

(i) Klinefelter's Syndrome - It occurs due to the trisomy of X-chromosome in male, resulting into a karyotype of 47, (44 + XXY). Individuals have long legs, sparse body hair, small prostrate gland, small testes, reduced mental intelligence and enlarged breasts (Gynaecomastia). Such individuals are sterile.

(ii) Turner's Syndrome - It is caused due to absence of one of the X-chromosome in female i.e. 45 with chromosome complement 44 + XO. Such females are sterile with undeveloped breast, short stature, reduced ovaries & absence of menstrual cycle.

(iii) Super female -AA + XXX, AA + XXXX

(iv) Jacob's syndrome or Super male -AA + XYY, also called as criminal syndrome.

Population Genetics

Hardy Weinberg equation is applied to know the distribution of traits and frequency of autosomal dominant recessive gene distribution in the entire population.

p = Dominant gene/allele

q = Recessive gene/allele

p + q = 1

(p + q)2 = p2 + q2 + 2pq = 1

(p2 + 2pq) = Frequency of dominant trait.

(q2) = Frequency of recessive trait.

Concept Builder

1. Archibald Garrod discovered "Inborn errors of metabolism in humans" -phenylketonuria, alkaptonuria and albinism.

2. Muscular dystrophy and haemophilia causing genes are sex-linked recessive lethal genes.

3. The symptomatic treatment of genetic diseases of man is called Euphenics.

4. Improvement of human race by improving environmental conditions is called Euthenics.

5. Improvement of the future qualities of mankind by selective breeding is called Eugenics.

6. F. Galton -Term "Eugenics".

7. Lejeune -Discovered Cri-du-chat syndrome

8. Darligton (1939) -The genes present in the cytoplasm are called plasmagenes.