DNA Variant

1 Chapter 1 Genetic Polymorphisms Dhafer A.F. Al-Koofee and Shaden M.H. Mubarak Abstract It is amazing to know that around 99.9% of the individuals genome among per-sons is alike, and only 0.1% of it differs in chromosome. This variance is accountable for the diversity in phenotypes and receptiveness of them to environmental effects. DNA Variants are happening in numerous formulas. Mutations might be definite as order variants which happen in less than 1% of the populace, whereas the extra prevalent variant is identified as polymorphisms. More than 1% of the greatest public hereditary variants are known as single nucleotide polymorphisms (SNPs). In human genome, SNPs considered as plentiful figure of genetic variation, and their importance in contribution to many disease, drug efficacy, and side effects in addition to may represent a prophylaxis. SNPs represent a specific location at which more than one nucleotide is established and only two alleles at a SNP locus. More than 100 million SNPs have been recognized in human, in average each 300 nucleotide on usual. The gene which has more than one allele is a normal result of SNP. SNPs are not restricted to coding sequence, but may be associated with non-coding region. Many techniques are used to analyze SNPs and involve two phases, one for allele recognition and another for detection. Keywords: SNP, allele frequency, point mutation, VNP, chromosome, gender, gene, VNTR, CNV, STR 1. Introduction Genetics terms returns to origin from Greek genetikos meaning “genitive,” which in turn derives from genesis meaning “origin” [1, 2]. Genetics in general is a branch of biology related to survey of genes, genetic variation, and even hered-ity in living systems [3–5]. The study of inheritance pattern that influences genes on human nature and occurs in human beings is called human genetics.

During the last years, the recent advance of molecular technologies revealed new discoveries of DNA polymorphisms. DNA polymorphisms are endless, and more dis -coveries continue at a rapid rate. Mapping the human genome requires a set of genetic mark -ers. DNA polymorphism serves as a genetic marker for its own location in the chromosome; thus, they are convenient for analysis and are often used as in molecular genetic studies. Keywords: copy number variations, genetic polymorphism, microsatellite, minisatellite, molecular markers, single nucleotide polymorphisms (SNPs), variable number tandem repeats (VNTRs) 1. Introduction Genetic polymorphism is the existence of at least two variants with respect to gene sequences, chromosome structure, or a phenotype (gene sequences and chromosomal variants are seen at the frequency of 1% or higher), typical of a polymorphism, rather than the focus being on rare variants [1]. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 repeated sequences [2]. 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.

• The specific order of nucleotides within DNA forms the basic units of genetic information. It is organised into chromosomes. Typically, every human cell contains 46 chromosomes (or 23 chromosome pairs). The chromo- somes are a series of individual genes, wherein diploid cells contain two copies of each. • Genetic variation reflects DNA sequence alterations, due to random mating or damage. This variation is referred to as ge- netic polymorphisms or mutations. Genetic polymorphisms are common forms of genetic heterogeneity, whereby dif- ferent forms of a given allele are common in a population. Genetic mutations refer to more uncommon alterations. • Transcription (or gene expression) refers to the process whereby information encoded in the genes is converted into mRNA sequence. Translation refers to converting mRNA se- quence information into a protein, which may in turn affect metabolism. Some, but not all, transcriptional and transla- tional elements are converted into observable phenotypes. • There are several tools used to investigate molecular as- pects of nutrition: animal models, organoids, cell/tissue culture models, molecular cloning, CRISPR/Cas9, RNAi, gene expression analysis (polymerase chain reaction [PCR], DNA microarrays and sequencing), proteomics, sta- ble isotopes, and metabolomics. • Genetic variability is relatively simple to characterise. Understanding the interaction with the environment, of which food is one complex element, is the challenge. The resultant gene–environment interactions can determine nutrient requirements, the metabolic response to food and nutrient intake and/or susceptibility to diet-related diseases. • Nutrients and non-nutrient food components can interact with the genome to modulate gene, protein and metabolite expres- sion. These interactions between nutrition and the genome are referred to as molecular nutrition or nutrigenomics.

48 CH2 DNA, GENOMES AND GENETIC VARIATION a mutation. If the new version is shared by more than 0.1% of the total pop- ulation then this new version is termed a polymorphism (many forms). 2.5.1 Genetic variation of repetitive DNA VNTR and STRs are regions of DNA that result in polymorphisms. Although these two types of variation are different, how the polymorphisms occur is similar. When DNA replicates to make a new cell, the DNA splits apart and a new copy is made by an enzyme. During the process of splitting apart these repetitive fragments can become unstable and loops are created in a free sin- gle strand. These loops in the new strand can either increase or decrease the length of the locus depending on how many repeat units were gained or lost. When this alteration in repeat number occurs in spermatozoa or ova, then a new form (a new allele) can be passed on to the next generation. Almost all repetitive DNA loci, by their very nature, have little effect on the individual. If an organism contains 150 repeats at MS1, a minisatellite, on one chromo- some and 350 repeats on the other, then there is no alteration to the func- tion of the cell compared to another person containing 250 and 275 repeats. Equally none of the STR types shown in Figure 2.3 adversely affect the indi- vidual. This type of variation for both VNTR and STRs regions appears to have no effect on the individual (phenotype) and as such is not under any selection pressure to remain constant. The use of repetitive DNA is the major means of linkage of a biological sample to an individual, population or geo- graphical origin. The use of this technology will be discussed in more detail in Chapter 5. 2.5.2 Single base changes leading to genetic variation Another type of genetic variation is when a change occurs at a single base; such changes are termed a single nucleotide polymorphism (SNP).

4.1.4 H OW M UCH V ARIATION ? The quantity of genetic variation in the human genome is something that until recently has been the realm of many con fl icting estimates. Empirical studies quickly identi fi ed that, on average, comparison of chromosomes between any two individuals will generally reveal common SNPs (> 20% minor allele frequency) at 0.3 to 1 kb average intervals, which scales up to 5 to 10 million SNPs across the genome [6]. The availability of a complete human genome has allowed increasingly accurate estimates of the number of potentially polymorphic mini- and microsatellites, as VNTRs over a certain number of repeats can be reliably predicted to be polymorphic. 94 In Silico Technologies in Drug Target Identification and Validation Breen et al. [7] completed an in silico survey of potentially polymorphic STRs in the human genome and identi fi ed over 100,000 potentially polymorphic microsat-ellites. Other forms of variation such as small insertion deletions are more dif fi cult to quantify, although they are likely to fall somewhere between the numbers of SNPs and VNTRs. 4.1.5 S INGLE N UCLEOTIDE V ARIATION : SNP S AND M UTATIONS Terminology for variation at a single nucleotide position is de fi ned by allele fre-quency. In the strictest sense, a single base change, occurring in a population at a frequency of less than 1%, is termed an SNP. When a single base change occurs at less than 1%, it is considered to be a mutation. However, this de fi nition is often disregarded; instead, single nucleotide “mutations” occurring at less than 1% in general populations might more appropriately be termed low-frequency SNPs. The term mutation is often used to describe a variant identi fi ed in diseased individuals or arising somatically in tissues, with a demonstrated role in the disease phenotype. Mutation databases and polymorphism databases have generally been delineated by this de fi nition.