Introduction to Genetic diseases

A knowledge of the normal human genetics will facilitate the understanding of genetic diseases. Hence, the student is advised to revise the normal human genetics before reading this chapter. Here, only brief highlights of the normal are given. Genetic diseases are often said to be difficult to students. We have tried to dispel this wrong notion & to make genetic as clear as possible at the cost of brevity. we did in order to facilitate the student’s understanding. 

Genetic information is stored in DNA. The typical normal human cell contains 46 chromosomes {i.e. 23 pairs of chromosomes: 22 homologous pairs of autosomes & one pair of sex chromosomes (XX or XY)}. Members of a pair (described as homologous chromosomes or homologs] carry matching genetic information. I.e. they have the same gene loci in the same sequence; though at any specific locus they may have either identical or slightly different forms, which are called alleles. One member of each pair of chromosomes is inherited from the father, the other from the mother. Each chromosome is in turn composed of a very long unbranched molecule of DNA bound to histones & other proteins. This interaction between the long DNA molecule & the histones decreases the space occupied by the long DNA. I.e. this interaction packages the long DNA into the shorter chromosomes.

Each chromosome contains a single continuous DNA molecule. DNA is composed of two very long complementary chains of deoxynucleotides. The 2 chains (strands) of DNA wind around each other i.e. twist about each other forming a double helix – “the twisted ladder model”.  Each deoxynucleotide, in turn, is composed of a nitrogenous base {i.e. adenine (A), or guanine (G), or cytosine (C), or thymine (T)} bound to deoxyribose & phosphate.

 DNA has two basic functions:

 1.  It codes for the proteins which are important for the metabolic & structural functions of the cell. I.e. it provides the genetic information for protein synthesis.

2.  It transmits the genetic information to the daughter cells & to the offspring's of the individual.

 Hence, the central dogma of molecular biology is:-

Figure 1 : showing the central dogma of molecular biology 

DNA stores genetic information. This is done by the sequence of the nucleotides in the DNA. The portion of DNA that is required for the production of a protein is called a gene. A gene has exons (coding sequences) & introns (intervening sequences). The transcription of a gene is regulated by a promoter region, enhancer region, etc…. The sequence of nucleotides in a gene determines the sequence of amino acids in a specific protein. Three consecutive nucleotides form a code word or codon. Each codon signifies a single amino acid. Since the number of condones (64) outnumbers the number of amino acids (20), most amino acids are specified by more than 1 condon, each of which is completely specific.

To translate its genetic information into a protein, a segment of DNA (i.e. a gene) is first transcribed into mRNA. The mRNA contains a sequence of nucleotides that is complementary to the nucleotides of the DNA. Each DNA triplet codon is converted into a corresponding RNA triplet codon. Then each mRNA codon codes for a specific amino acid. Hence, the sequences of the RNA codons is translated into a sequence of amino acids (i.e. protein). Therefore, the sequence of the amino acids in the protein is determined by the sequence of the codons in the mRNA which in turn is determined by the sequence of nucleotides in the DNA.

In summary, the primary sequence of bases in the coding regions of DNA determines the sequence of amino acids in the protein. Hence, any alteration in the sequence of bases in the normal gene causes an alteration of the protein at a specific point in its sequence. Such alteration is called mutation & is the basis of genetic diseases. Genetic information is transmitted to the daughter cells under two circumstances:

1. Somatic cells divide by mitosis, allowing the diploid (2n) genome to replicate itself completely in conjunction with cell division.

2. Germ cells (sperm & ova) undergo meiosis – a process that enables the reduction of the diploid  (2n) set of chromosomes to the haploid state (1n).When the egg is fertilized by the sperm, the 2 haploid sets are combined, thereby restoring the diploid state in the zygote.

Terminology:-

 -  Hereditary (familial) disorders are disorders derived from one’s parents.

-  Congenital means “born with.”  It may be genetic, for example Down’s syndrome. Or it may not be genetic, for example congenital syphilis. Not all genetic diseases are congenital, for example patients with Huntington’s disease begin to manifest their disease in the 3^rd or 4^th decades. 

-  Genotype means the genetic constitution (genome).

-  Phenotype means the observed biochemical, physiological, & morphological characteristics of an individual as determined by his/her genotype & the environment in which it is expressed. 

-  Allele means one of the alternative versions of a gene that may occupy a given locus.

-  Gene, as already stated, is the portion of DNA that codes for a protein.

References

Bezabeh ,M. ; Tesfaye,A.; Ergicho, B.; Erke, M.; Mengistu, S. and Bedane,A.; Desta, A.(2004). General Pathology. Jimma University, Gondar University Haramaya University, Dedub University.