**3. Type of polymorphisms**

The human genome comprises 6 billion nucleotides of DNA packaged into two sets of 23 chromosomes, one set inherited from each parent. The probability of polymorphic DNA in humans is great due to the relatively large size of human genome. Genomic variability includes a wide range of variations from single base pair change, many base pairs, and

Single nucleotide polymorphisms are the most common type of genetic variations in humans [3], due to their abundance across the human genome; single nucleotide polymorphisms (SNPs) have become important genetic markers for mapping human diseases, population genetics, and evolutionary studies. SNPs have become very important since technologies for DNA sequencing have become feasible and widely available. Advance continues at a rapid

A major step forward in genome identification is the discovery of about 30–90% of the genome which is constituted by regions of repetitive DNA which are highly polymorphic in nature [5]. Polymorphic tandem repeated sequences have emerged as important genetic markers and initially, variable number tandem repeats (VNTRs) were used in DNA fingerprinting. In recent years, evidence has been accumulated for the involvement of VNTR repeats in a wide

Throughout the past years, scientists have believed that genes strictly came in two copies in a genome. However, with the recent advancement in molecular technology, discoveries have revealed substantial segments of DNA, ranging in size from thousands to millions of DNA bases that could vary in copy number. Such copy number variations (or CNVs) encompass gene copies, newly discovered CNVs are important sources of genomic diversity [7, 8].

The development and use of DNA-based molecular markers is one of the most significant developments in the field of molecular genetics that facilitate the study of genetic variations

This chapter reviews the DNA-based genetic markers and their application in medicine, with a particular emphasis on common DNA-based genetic markers, including single nucleotide

Genomic variability at DNA level can be present in many forms including: single nucleotide polymorphisms, variable number of tandem repeats (e.g., mini- and microsatellites), transposable elements (e.g., Alu repeats), structural alterations, and copy number variations. It can occur in the nucleus or mitochondria. Two major sources: (1) mutations that may result as chance processes or have been induced by external agents such as radiation and (2) recombination. Once formed, it can be inherited, allowing its inheritance to be tracked from parent

The genomes of humans may be divided into different parts based on known functional properties; the coding and noncoding regions mostly do not code for protein [2, 9]. The coding

repeated sequences [2].

26 Genetic Diversity and Disease Susceptibility

spectrum of pathological states [6].

in health and diseases [5].

to child [3].

polymorphisms and short tandem repeats (STRs).

**2. Polymorphisms at DNA level**

rate [4].

#### **3.1. Single nucleotide polymorphisms**

Single base change is "high-density natural sequence variations in human genome" [14]. SNPs are mostly formed when errors occur (substitution, insertion and deletion). SNPs are prominent sources of variation in human genome and serve as excellent genetic markers. Some regions of the genome are richer in SNPs than others. SNPs may occur within gene sequences or in intergenic sequences. SNPs mostly are located in noncoding regions of the genome and have mostly no direct known impact on the phenotype of an individual but their role till now remains elusive, and depending on where SNPs occurs, it might have different consequences at the phenotypic level [3].

#### **3.2. Insertion/deletion polymorphisms**

It is a type of DNA variation in which a specific nucleotide sequence of various lengths ranging from one to several 100 base pairs is inserted or deleted. Indels are widely spread across the genome. Some authors consider one base pair as SNPs or repeat insertion/deletion as indels.

#### **3.3. Polymorphic repetitive sequences**

DNA repeats can be classified as interspersed repeats or tandem repeats. This can comprise over two-thirds of the human genome [15]. Interspersed repeats are dispersed across the genome within gene sequences or intergenic and include retro (pseudo) genes and transposons. Tandem repeats or variable number tandem repeats (≥2 bp in length) that are adjacent to each [16] can involve as few as two copies or many thousands of copies. Centromeres and telomeres largely comprise tandem repeats. Despite increasing evidence on the functionality of DNA repeats, their biologic role is still elusive and under frequent debate [11]. Tandem repeats are organized in a head-to-tail orientation; based on the size of each repeat unit, satellite repeats can be further divided into macrosatellites, minisatellites, and microsatellites [17]. Some of these repeats are described as follows: macrosatellites, with sequence repeats longer than 100 bp, are the largest of the tandem DNA repeats, located on one or multiple chromosomes [11], minisatellites, stretches of DNA, are characterized by moderate length patterns, 10–100 bp usually less than 50 bp [9, 18], and microsatellites also known as short tandem repeats (STRs) repeat units of less than 10 bp, [3].

Single nucleotide polymorphisms within a coding sequence cause genetic diseases including sickle cell anemia. SNPs responsible for a disease can also occur in any genetic region that can *eventually* affect the expression activity of genes, for example, in promoter regions. SNPs in the noncoding region of the gene, though their effect is still debatable, most of the genome mostly consists of regulatory elements that control gene expression, but these regions have remained largely unexplored in clinical diagnostics due to the high cost of whole genome sequencing and interpretive challenges. Clinical diagnostic sequencing currently focuses on identifying causal mutations in the exome, where most disease-causing mutations are known

DNA Polymorphisms: DNA-Based Molecular Markers and Their Application in Medicine

http://dx.doi.org/ 10.5772/intechopen.79517

29

Another important group of SNPs is the one that alters the primary structure of a protein

However, some SNPs are not causative, some SNPs are in close association with, and therefore segregate with, a disease-causing sequence so, the presence of SNP correlates with the presence or an increased risk of developing the disease; these SNPs are useful in diagnostics,

Single nucleotide polymorphisms can be used as genetic markers for constructing high genetic maps and to carry out association studies related to diseases because of their abundance and the availability of high throughput analysis technologies. SNPs have become an important

There are numerous strategies that can be implemented to new single nucleotide variant (SNVs) discoveries; the most common and well-known method is by direct sequencing and in comparison to a puplic or other sequence date base [25, 26] or locus specific amplification of target genomic region followed by sequence comparison [27, 28]; prescreening prior to sequence determination is needed. SNV detection encompasses two broad areas: (1) scanning DNA sequences for previously unknown polymorphisms and (2) screening (genotyping) individuals for known polymorphisms. Scanning for new SNVs can be further classified to two different types of approaches, the first one being the global (or random approach) and the other one being the regional (targeted approach) [14]. There are certain methods which have been developed for using SNVs randomly in the genome; "such as representation shotgun sequencing [14, 29], primer-ligation-mediated PCR [14, 30] and degenerate oligonucleotide–

Haplotypes are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual

Microsatellites are short tandem repeats (STRs), repeat units, or motifs of less than 10 bp; because of high variability, microsatellite loci are often used in forensics, population genetics, and genetic genealogy. Significant associations were demonstrated between microsatellite

SNPs and may therefore provide increased diagnostic accuracy in some cases [32].

involved in drug metabolism; these SNPs are targets for pharmacogenetics studies.

application in the development and research of genetic markers [14].

disease prediction, and other applications [3].

to occur.

primed PCR" [14, 31].

**4.2. Microsatellites (short tandem repeats)**

variants and many diseases [15].

#### **3.4. Structural and copy number variations**

Structural and copy number variations (CNVs) are another frequent source of genome variability [6, 19, 20]. The term CNVs therefore encompasses previously introduced terms such as large-scale copy number variants (LCVs) [19], copy number polymorphisms (CNPs) [20], and intermediate-sized variants (ISVs) [21]. Some currently used terms are structural variations; a genomic alteration (e.g., an inversion) that involves segments of DNA > 1 kb, copy number polymorphisms; a duplication or deletion event involving >1 kb of DNA [22], intermediatesized structural variant; and a structural variant that is ∼8–40 kb in size, this can refer to a CNVs or a balanced structural rearrangement (e.g., an inversion) [21].
