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DOI: 10.1201/9781003355205-4

C h a p t e r 4

Variant Discovery

4.1  INTRODUCTION TO GENETIC VARIATIONS

Classical genetics began with the works of Gregor Mendel in the 19th century as a field

of biology for studying hereditary in species based on morphology and visible results of

reproductive acts. Very recently, genetics has been greatly instrumented by bioinformatics

that emerged as a logical consequence of the modern progress in molecular biology, infor-

mation technology, and the urgent need for handling genome-scale data. Bioinformatics

has become a key in each step of genetic analysis and it provides standardized framework

for variant discovery and description, which are the essence of the modern genetics.

The general workflow of the research on genetic variation focuses on the analysis and

identification of genetic variants associated with specific phenotypes or populations.

Mutations are the key source of genetic variation within a species. A mutation is any

change in the nucleotide sequences of the genome of a living organism. The basic muta-

tions include base substitution, insertion, and deletion. However, translocation (exchange

of segments between chromosome) and copy number variation (CNV), which is multiple

copies of DNA segment, are also source of genetic variations. These mutations can occur

in parts of the genome. Base substitution is the most frequent one, and it has been thought

that it was a random process and it could occur anywhere in a genome with equal prob-

ability, but now such thoughts began to change after genomic studies in several organisms

showed that mutations are less frequent in important regions of the genome [1]. Therefore,

most genetic studies focus on the mutations that affect genes.

The single base substitution is called point mutation and it can be either transition

(when a purine is substituted with another purine or a pyrimidine is substituted with

another pyrimidine) or transversion (when a purine is substituted with a pyrimidine or

a pyrimidine replaces a purine). The base substitution may have a silent consequence if it

occurs in the third position of a codon and the result is a synonymous codon that codes

for the same amino acid and does not alter the protein sequence. The substitution will have

missense consequence if it results in a nonsynonymous codon that codes for a different

amino acid and alters the protein polypeptide sequence. The consequence of a substitution,