The origin of genetic diseases: Overview on DNA and mutation

The origin of genetic diseases: Overview on DNA and mutation

A knowledge of the normal human genetics will facilitate the understanding of genetic diseases. 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 and 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.

The origin of genetic diseases: Overview on DNA and mutation

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 and other proteins. This interaction between the long DNA molecule and 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 and phosphate.


DNA has two basic functions:

1. It codes for the proteins which are important for the metabolic and 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 and to the offsprings of the individual.
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) and 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 condons outnumbers the number of amino acids, 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.

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 and 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.


These are the bases of genetic diseases. Are defined as permanent changes in the primary nucleotide sequence of DNA regardless of its functional significance. Occur spontaneously during cell division or are caused by mutagens such as radiation, viruses, and chemicals. Can occur in germ line cells (sperm or oocytes) or in somatic cells or during embryogenesis. Germline mutations can be passed from one generation to the next and thus cause inherited disease. Somatic mutations do not cause hereditary disease but they may cause cancer (because they confer a growth advantage to cells) and some congenital malformations. Mutations that occur during development (embryogenesis) lead to mosaicism

Categories of genetic diseases

Genetic diseases generally fall into one of the following 4 categories: A. Mendelian disorders b. Chromosomal disorders c. Multifactorial disorders d. Single gene diseases with nonclassic patterns of inheritance Mendelian disorders Each mendelian disorder is caused by a single mutant gene. Affects transcription, mRNA processing, or translation leading to abnormal protein or decreased protein as the result may affect any type of protein and cause disease.

Chromosomal disorders (Cytogenetic disorders)

Are caused by chromosome and genome mutations (i.e. abnormal structure & number of chromosomes respectively). Are not uncommon. They are found in 50% of early spontaneous abortuses, in 5% of stillbirths, & in 0.5 -1% of live born infants. May, therefore, be suspected in the following clinical situations: Spontaneous abortion, stillbirth, abnormal live births and infertile couple.

Disorders with multifactorial inheritance

Are more common than mendelian disorders. They result from the combined actions of environmental factors and 2 or more mutant genes having additive effects (i.e. the greater the number of inherited mutant genes, the more severe the phenotypic expression of the disease). The disease clinically manifests only when the combined influences of the genes and the environment cross a certain threshold. Include such common diseases as; Diabetes mellitus, Hypertension, Ischemic heart disease, Gout, Schizophrenia, Bipolar disorders, Neural tube defects, Cleft lip/ cleft palate, Pyloric stenosis, Congenital heart disease and many other Single gene disorders with nonclassic inheritance


These are rare, can be classified into the following categories:

A. Diseases caused by mutations in mitochondrial genes. E.g. Leber hereditary optic neuropathy

B. Diseases associated with genomic imprinting. E.g. Prader-Willi syndrome, Angelman syndrome

C. Diseases associated with gonadal mosaicism. Gonadal mosaicism can explain unusual pedigrees seen in some autosomal dominant disorders such as osteogenesis imperfecta in which phenotypically normal parents have more than one affected children. This cannot be explained by new mutations. Instead, it can be explained by gonadal mosaicism

D. Disorders caused by triplet repeat mutations. E.g. Fragile X syndrome


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