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Genetic Variation

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G
Genetic Variation
Ritu and Bhagyalaxmi Mohapatra
Cytogenetics Laboratory, Department of Zoology,
Institute of Science, Banaras Hindu University,
Varanasi, UP, India
Synonyms
Gene polymorphism; Mutations
Definition
Genetic variation (GV) is defined as the subtle
genomic differences among individuals within or
between populations that makes each or a group
of organisms different from others.
Introduction
Variations are found throughout the genome of an
organism. However, these variations are not evenly
distriibuted. Instead, some regions are “hot spots”
of variability like CpG islands, and some other
parts are stable enough that don’t show variation
(Mugal and Ellegren 2011; Xia et al. 2012) at all
among the individuals. Variation in the genetic
material of an organism is depicted in its pheno-
type. Almost every trait of an individual is affected
# Springer International Publishing AG 2018
J. Vonk, T. K. Shackelford (eds.), Encyclopedia of Animal Cognition and Behavior,
https://doi.org/10.1007/978-3-319-47829-6_20-1
by genetic variation. Variations in the eye color and
hair color, ear lobes, height etc. are due to the
genetic differences between individuals.
Genetic Variation Drives Evolution
Genetic variation is an important evolutionary
force as it provides the diversity within and
between populations. Genetic variability makes
an organism more adapted to its environment.
Variations result in different forms of a gene
(called alleles). For example, if a gene “A” is
mutated to “a” and if the new allele (a) has some
selective advantage for the individual either
through fitness or fecundity, then the mutated
allele will be transmitted to the next generation
over a period of time. On the other hand, if the
new allele is deleterious, then it would be selec-
tively eliminated as the offspring carrying it will
not survive. Preexisting advantageous mutations
when selected will result in observation of new
phenotypes. This process is called natural selec-
tion (Darwin 1859). Natural selection brings
about changes in the gene frequency. Over few
generations, this would result in speciation.
Hence, disturbance in genetic equilibrium or
Hardy-Weinberg equilibrium, i.e., change of fre-
quency of alleles in a population would lead to
evolution.
2 Genetic Variation
Sources of Genetic Variation
Mutations, gene flow, and sexual reproduction are
three primary sources of genetic variation.
Mutations
Mutation is a process which produces altered
DNA sequence. It may be induced by radiations
and chemical mutagens in the environment or
insult from endogenous reactive oxygen species
(ROS) or occur spontaneously due to endogenous
factors (errors in chromosomal segregation,
recombination, DNA replication and repair, and
also spontaneous chemical damage to DNA).
Mutations are inexorable. They may have adverse
effects on organism’s health and survival. Some-
times, they may have no obvious effects, or rarely,
they may be beneficial for the bearer.
Gene Flow
Gene flow is the transfer of genes from one pop-
ulation to another and thus affects the allele fre-
quency. The rate of gene flow is directly
proportional to the mobility of an individual and
is limited by geographical barriers which may be
natural or man-made. Cross-species hybridization
in plants to generate new and improved varieties
and gene transfer from bacteria or virus to new
hosts lead to genomic variations.
Sexual Reproduction
Somatic cells divide and multiply by mitosis that
produces daughter cells, identical to the parent
cell, whereas during gamete formation, a special
type of cell division, i.e., meiosis, results in newer
combinations of parental genotypes by crossing
over and independent assortment of homologous
chromosomes thus generating unique genotypes,
followed by random fertilization. Sexually
reproducing organisms are more diverse than the
asexually reproducing ones.
Types of Genetic Variants
Genetic variations are basically of three types,
viz., single-nucleotide variations, insertion/dele-
tions (indels), and structural variartions. These
variations may be rare or common depending
upon their frequency in population and patho-
genic or nonpathogenic.
Single-Nucleotide Variations (SNV)
SNVs are the most common type of all variations
where a nucleotide is replaced by another. It may
be either transition (purine to purine or pyrimidine
to pyrimidine) or transversion (purine to pyrimi-
dine or vice versa). When a SNV is common in a
population or we can say its frequency is 1%,
then it is known as single-nucleotide polymor-
phism (SNP). SNPs may fall within the coding
or noncoding region of genes or in the intergenic
regions. Coding region SNPs may be either syn-
onymous (no change in amino acid) or non-
synonymous (change in amino acid). SNPs are
usually selectively neutral, but they often make
an individual predispose to certain disease, e.g.,
SNPs in MTHFR (methylene tetra hydro folate
reductase) predispose an individual to cardiovas-
cular disease (Kluijtmans et al. 1996), cancer
(Izmirli 2013), and neural tube defects (Botto
and Yang 2000). SNPs also confer a selective
advantage to individuals harboring them, e.g.,
Duffy blood group allele, FY(a-b-) (Duffy null
phenotype), protects against malaria (Carvalho
and Carvalho 2011). SNPs are cataloged in a
public database, dbSNP (http://www.ncbi.nlm.
nih.gov/projects/SNP). Coding region SNVs
may affect the structural and functional aspect of
a protein. They are usually deleterious and present
less frequently in population (1%). They are
known as rare variants. Rare variants which are
clinically significant are cataloged in clinical var-
iation database, ClinVar (https://www.ncbi.nlm.
nih.gov/clinvar). SNPs present in noncoding
regions are also reported to influence gene splic-
ing and transcription factor binding. The func-
tional effect of variants on the protein’s structure
and function can be predicted using in silico tools
like SIFT, PolyPhen2, MutationTaster,
etc. (Table 1).
Insertions and Deletions (Indels)
Indels refer to DNA mutations involving insertion
and deletion of one or more base pairs. These can
have devastating effects on the gene because either
Genetic Variation 3

Genetic Variation, Table 1 List of bioinformatic tools and softwares to predict the pathogenicity of a missense genetic
variant
Tool Web address
AUTO-MUTE http://proteins.gmu.edu/automute/
Align-GVGD http://agvgd.hci.utah.edu/agvgd_input.php
CanPredict http://www.cgl.ucsf.edu/Research/genentech/canpredict
CADD http://cadd.gs.washington.edu/score
CONDEL http://bbglab.irbbarcelona.org/fannsdb/help/condel.html
FATHMM http://fathmm.biocompute.org.uk/
FunSAV http://sunflower.kuicr.kyoto-u.ac.jp/sjn/FunSAV/index.html
FuzzySnps http://rna.gmu.edu/FuzzySnps/
HANSA http://www.cdfd.org.in/HANSA/
I-Mutant2.0 http://folding.biofold.org/i-mutant/i-mutant2.0.html
LS-SNP http://ls-snp.icm.jhu.edu/ls-snp-pdb/
MAPP http://www.ngrl.org.uk/Manchester/page/mapp-multivariate-analysis-protein-polymorphism
Mutation assessor http://mutationassessor.org/r3/
MutationTaster http://www.mutationtaster.org/
MutPred2 http://mutpred.mutdb.org/
nsSNPAnalyzer http://snpanalyzer.uthsc.edu/
PhD-SNP http://snps.biofold.org/phd-snp/phd-snp.html
PMut http://mmb.irbbarcelona.org/PMut/
PolyPhen2 http://genetics.bwh.harvard.edu/pph2/
PROVEAN http://provean.jcvi.org/index.php
SAPRED https://omictools.com/sap-disease-association-predictor-tool
SIFT http://sift.jcvi.org/
SNAP http://www.bio-sof.com/snap
SNPs3D http://www.snps3d.org/
SNPs & GO https://snps-and-go.biocomp.unibo.it/snps-and-go/
SuSPect http://www.sbg.bio.ic.ac.uk/servers/suspect/about.html

translation of the gene is frame shifted or amino
acids are deleted. For example, 3 bp deletion
(DF508) in coding region of CFTR (cystic fibrosis
transmembrane conductance regulator) gene is the
most common cause of cystic fibrosis (Cutting
2015). However, nonpathogenic indel are often use-
ful in mapping common ancestry in kinship and
human origin studies because chances of two muta-
tions of the same length occurring in the same
genomic position are negligible.
Structural Variations
Structural variation refers to large-scale structural
differences in the DNA, originated mainly due to
chromosomal rearrangements – deletion, duplica-
tion, novel sequence insertion, or inversion. They
include copy number variations, variable number of
tandem repeats, and chromosomal rearrangement.
Copy Number Variations (CNV)
A CNV can be simple in structure, such as tandem
duplication, or may involve complex gain and loss
of homologous sequences at multiple sites in the
genome. CNVs are genomic structural variants in
which the number of copies of a particular seg-
ment is different in two or more different genomes
as compared to a reference genome.
Variable Number of Tandem Repeats (VNTRs)
These variations involve changes in the number of
repeated DNA sequences arranged in tandem
arrays.These are highly heterogeneous groups of
loci. These are multiallelic markers while SNPs
are generally biallelic. They are classified
according to the size and number of their repeat
units. They are sometimes considered as neutral
markers. But there are many instances among
4 Genetic Variation
various classes of VNTRs which shows pheno-
typic effects. VNTRs can be microsatellite, mini-
satellite, satellite, or telomere-repeat arrays.
Microsatellites
They are also known as “short tandem repeats”
(STRs) or “simple sequence repeats” (SSRs) hav-
ing 1–6 bp long repeat units. Their copy number
varies from 10 to 30. Microsatellites with some
specific repeat units show clustering, but most are
distributed throughout the genome which is useful
in linkage analysis. The most common microsat-
ellite is (CA)n repeat. Mutation at these regions
may involve either increase or decrease in repeat
units. Microsatellites are reported to be associated
with many human diseases like fragile
X syndrome (FMR1/FMR2;(CA)n repeat) and
Huntington’s disease (HD; (CAG)n repeat).
Minisatellites
Minisatellites are tandem arrays of repeat unit
around 8–100 bp with a copy number of
5– >1000. They are generally GC rich. They are
among most dynamic loci in our genome. Like
most of the microsatellites, these are considered to
be neutral markers, but there are examples that
they play essential roles. A few lie in the coding
regions, encoding repetitive, and highly variable
proteins.
Satellite
They are also called macrosatellite. They are large
tandem arrays spanning hundreds of kilobases to
megabases, composed of repeat units of wide
range of sizes that can display a higher-order
structure. Alpha satellite or alphoid DNA is a
good example. It is 170 bp in length. Their
detailed structure is difficult to study due to their
size and repetitive nature.
Telomere-Repeat Arrays
Telomeres are the structure present at the end of
chromosomes having tandem arrays of hexa-
nucleotide repeat TTAGGG, typically 10–15 kb
in length. One end of this array is contiguous with
subtelomeric DNA, while other is the true end of
the chromosome.
Chromosomal Rearrangements
Chromosomal rearrangement involves deletions,
duplications, inversion and translocations which
are caused by either breakage of DNA double
helices at two different points, followed by the
rejoining of the broken ends or through crossing
over between repetitive DNA sequences to pro-
duce a new chromosomal arrangement of genes.
Chromosomal rearrangement may lead to disrup-
tion of genes and implicated in many human dis-
orders particularly cancer like chronic
myelogenous leukemia where balanced transloca-
tion results in fusion of the breakpoint cluster
region (BCR) with the c-abl (ABL1) proto-
oncogene tyrosine kinase leading to the formation
of BCR-ABL fusion transcript which constitu-
tively activates tyrosine kinase that can transform
cells and inhibit apoptosis (Ren 2005). Chromo-
somal rearrangement is also a common mode of
speciation mainly through post-mating reproduc-
tive isolation, e.g., inversion resulted in species
diversity between two closely related drosophila
species, Drosophila pseudoobscura and
Drosohila persimilis. Gene duplication (16A)
also causes bar eye phehenotype in drosophila.
Techniques for Detecting Genomic
Variations
Genotyping provides a measurement of the
genetic variation between members of a species.
Genomic variations are often found to be the
etiology of many human diseases and are of par-
ticular interest in pharmacogenomics. The
increase in interest in GV has been reflected by
the rapid development of a diverse range of SNP
genotyping methods (summarized in Fig. 1).
Applications of Genomic Variations
Screening for Genetic Diseases
GV can cause many diseases in humans. These
diseases are usually rare but fatal, and an example
is cystic fibrosis, caused by mutations in the CFTR
gene. Many common diseases such as heart dis-
ease and cancer are genetically complex, with
Genetic Variation 5

Genetic Variation,
Fig. 1 List of techniques Hybridization based methods
used for detecting genetic • Dynamic allele specific hybridisation
variations
• Molecular beacons

Enzyme based methods

• Restriction fragment length polymorphism
• PCR based methods
• Flap endonuclease
• Primer extension

Methods based on physical properties of DNA

• Single strand conformation polymorphism

• Temperature gradient gel electrophoresis
• Denaturating high performance liquid chromatography

High throughput techniques

• Sanger sequencing
• Next generation sequencing

alleles from several genes contributing to the dis-
ease. Linkage and association studies are used to
conduct genetic tests for screening of diseases
which involves profiling of disease causing vari-
ants (Taylor et al. 2001).
Pharmacogenomics
GV in patients make them respond differently to a
medication. In the future, the most appropriate
drug for an individual could be determined in
advance of treatment by analyzing a patient’s
SNP profile and such kinds of treatment which
are specific for an individual are called “personal-
ized medicines.”
Biological Markers
Often GV tend to be relatively stable genetically;
they serve as excellent biological markers.
Constructing a chromosome map that shows the
positions of known genes with genetc markers
allows researchers to study and pinpoint disease
traits.
Forensic Technologies
Genetic profiling of biological material has
become one of the most powerful tools for solving
parental disputes and in criminal investigations.
Traditional methods in DNA “fingerprinting” is
now replaced by polymerase chain reaction
(PCR)-based technology which detects very
short polymorphic stretches of DNA.
Conclusion
Subtle differences in DNA are the ultimate cause
of genetic variation. They may include single-
nucleotide polymorphisms, variable numbers of
tandem repeats, and large-scale copy number var-
iants. Both inherited and denovo variations could
be either advantageous or deleterious for an
organism. Beneficial variations are selectively
favorable and allow an organism to adapt in
changing environmental conditions and hence
drive evolution. Studies of these variations are
directly relevant in understanding many features
of human populations. The structure of
populations in terms of inbreeding and reproduc-
tive isolation, the relationship of different
populations to each other, and the geographical
and historical origins of populations – all these
aspects are illuminated by studies of genetic var-
iation. Now with the advancement of next-
generation sequencing technologies, vast amount
of data is available which is being utilized for
screening of genetic diseases and for designing
personalized medicines. Despite of numerous
technical advances, many variations still may
6 Genetic Variation

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