GENETIC MUTATION

Based on their genetic contribution, human diseases can be classified as :

¨  Monogenic diseases à alterations in a single gene (segregate in families according to the traditional Mendelian principles of inheritance).

¨  Chromosomal diseases à alterations in chromosomes. within an individual's genome, some chromosomes may be missing, extra chromosome copies may be present, or certain portions of chromosomes may be deleted or duplicated.

¨  Multifactorial à complex diseases are caused by variation in many genes, and they may or may not be influenced by environment, responsible for most of the burden on our health care system, include cardiovascular disease, cancer, diabetes, and a number of birth defects and psychiatric disorders.

Types of DNA Mutations and Their Impact

Class of Mutation	Type of Mutation	Description	Human Disease(s) Linked to This Mutation
Point mutation	Substitution	One base is incorrectly added during replication and replaces the pair in the corresponding position on the complementary strand	Sickle-cell anemia
	Insertion	One or more extra nucleotides are inserted into replicating DNA, often resulting in a frameshift	One form of beta-thalassemia
	Deletion	One or more nucleotides is "skipped" during replication or otherwise excised, often resulting in a frameshift	Cystic fibrosis
Chromosomal mutation	Inversion	One region of a chromosome is flipped and reinserted	Opitz-Kaveggia syndrome
	Deletion	A region of a chromosome is lost, resulting in the absence of all the genes in that area	Cri du chat syndrome
	Duplication	A region of a chromosome is repeated, resulting in an increase in dosage from the genes in that region	Some cancers
	Translocation	A region from one chromosome is aberrantly attached to another chromosome	One form of leukemia
Copy number variation	Gene amplification	The number of tandem copies of a locus is increased	Some breast cancers
	Expanding trinucleotide repeat	The normal number of repeated trinucleotide sequences is expanded	Fragile X syndrome, Huntington’s disease

Mutations and the Environment : Ultraviolet (UV) light from the Sun can induce mutations in your skin cells.

Mutations Caused by Chemicals : Eg: benzo pyrene (carcinogen and a component of cigarette smoke) à induce lesions at guanine bases in the tumor suppressor gene P53 at codons 157, 248, and 273. These codons are the major mutational hot spots seen in clinical studies of human lung cancers

Spontaneous Mutations

¨  Depurination à a purine base is lost from a nucleotide through hydrolysis à incorporation of an incorrect base during the next round of replication.

¨  Deamination, or the removal of an amine group from a base. Deamination of cytosine converts it to uracil, which will pair with adenine instead of guanine at the next replication, resulting in a base substitution.

                Repair enzymes can recognize uracil as not belonging in DNA, and they will normally repair such a lesion.

                However, if the cytosine residue in question is methylated (a common modification involved in gene regulation), deamination will instead result in conversion to thymine. Because thymine is a normal component of DNA, this change will go unrecognized by repair enzymes

Mutations and Polymorphisms

¨  A mutation is defined as any alteration in the DNA sequence

¨  “Single nucleotide polymorphism" (SNP) to refer to a single base pair alteration that is common in the population.

                Specifically, a polymorphism is any genetic location at which at least two different sequences are found, with each sequence present in at least 1% of the population.

“Polymorphism" is generally used to refer to a normal variation, or one that does not directly cause disease.

The cutoff of at least 1% prevalence for a variation to be classified as a polymorphism is somewhat arbitrary; if the frequency is lower than this, the allele is typically regarded as a mutation

¨  SNPs are important as markers, or signposts. On average, SNPs are found every 1,000–2,000 nucleotides in the human genome 

(from many references)