Genetic variation refers to differences in genes between individuals of a population. It arises due to mutations, recombination during meiosis, gene flow between populations, and environmental factors. Genetic variation is important for evolution and survival of species as it provides raw materials for natural selection. While some genetic variations are harmful, others can provide benefits like disease resistance. Variations in genes involved in drug metabolism can impact individual responses to medications. Understanding genetic diversity is important for personalized medicine and drug development.

1. Genetic Variation and its Role in
Health/Pharmacology
BP 104 T – CMP
Unit - IV 10-05-2021
Department of Pharmacology

3. Genetic variation
• In a very simple language, genetic variation is a measure of the
variation that exists in the genetic makeup of individuals within
population.
• Variation in alleles of genes that occurs both within and among
populations
Genetic Diversity
• The level of biodiversity, refers to the total number of genetic
characteristics in the genetic makeup of a species
Crossing Over
• The exchange of genetic material between homologous
chromosomes that results in recombinant chromosomes

4. Phenotypic Variation
• Variation (due to underlying heritable genetic variation); a
fundamental prerequisite for evolution by natural selection
Alleles
• Each of two or more alternative forms of a gene that arise by
mutation and are found at the same place on a chromosome.
Natural Selection
• The process whereby organisms better adapted to their
environment tend to survive and produce more offspring.
• The theory of its action was first fully expounded by Charles
Darwin, and it is now regarded as be the main process that brings
about evolution.

5. What is genetic variation?
Polymorphisms
• Variation between individuals in a population (within species)
Substitutions
• Fixed variation between individuals of species (between species)
Species A Species B Species C

6.  Genetic variation generally refers to the differences in genes between
individual members of a population, or the frequency in which the
various gene types are expressed.
 Genetic variation is incredibly important for the survival and adaptation
of a species, as it helps in terms of natural selection and evolution.
 Individuals of a species have similar characteristics but they are rarely
identical, the difference between them is called variation.
 In genetic variation, the genes of organisms within a population
change.
 Gene alleles determine distinct traits that can be passed on from parents
to offspring.
 Gene variation is important to the process of natural selection.
 The genetic variations that arise in a population happen by chance, but
the process of natural selection does not.

7. Gene alleles determines the distinct traits of an
individual
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8. Sources of Genetic Variation
• Gene duplication, mutation, or other processes can produce new genes and
alleles and increase genetic variation.
• New genetic variation can be created within generations in a population, so
a population with rapid reproduction rates will probably have high genetic
variation.
• However, existing genes can be arranged in new ways from chromosomal
crossing over and recombination in sexual reproduction.
• Overall, the main sources of genetic variation are the formation of new
alleles, the altering of gene number or position, rapid reproduction, and
sexual reproduction.

11. DNA Mutation
• Mutations are changes to an organism’s DNA and are an important
driver of diversity in populations.
• Species evolve because of the accumulation of mutations that occur over
time.
• The appearance of new mutations is the most common way to introduce
novel genotypic and phenotypic variance.
• Some mutations are unfavorable or harmful and are quickly eliminated
from the population by natural selection.
• Others are beneficial and will spread through the population.
• Whether or not a mutation is beneficial or harmful is determined by
whether it helps an organism survive to sexual maturity and reproduce.
• Some mutations have no effect on an organism and can linger,
unaffected by natural selection, in the genome while others can have a
dramatic effect on a gene and the resulting phenotype.

12. Mutation in a garden rose: A mutation has caused this garden moss rose to produce
flowers of different colors. This mutation has introduce a new allele into the population
that increases genetic variation and may be passed on the next genera9
tion.

13. Gene Flow
 An important evolutionary force is gene flow: the flow of alleles in
and out of a population due to the migration of individuals or
gametes.
 While some populations are fairly stable, others experience more
movement and fluctuation.
 Many plants, for example, send their pollen by wind, insects, or birds
to pollinate other populations of the same species some distance
away.
 Even a population that may initially appear to be stable, such as a
pride of lions, can receive new genetic variation as developing males
leave their mothers to form new prides with genetically-unrelated
females.

14.  This variable flow of individuals in and out of the group not only
changes the gene structure of the population, but can also introduce
new genetic variation to populations in different geological locations
and habitats.
 Maintained gene flow between two populations can also lead to a
combination of the two gene pools, reducing the genetic variation
between the two groups.
 Gene flow strongly acts against speciation, by recombining the gene
pools of the groups, and thus, repairing the developing differences
in genetic variation that would have led to full speciation and
creation of daughter species.

15.  For example, if a species of grass grows on both sides of a highway,
pollen is likely to be transported from one side to the other and vice
versa.
 If this pollen is able to fertilize the plant where it ends up and
produce viable offspring, then the alleles in the pollen have
effectively linked the population on one side of the highway with the
other.

16. Gene flow: Gene flow can occur when an individual travels from one
geographic location to another.

17. Crossing over and sexual reproduction
• Chromosomal crossover (or crossing over) is the exchange of
genetic material between 2 homologous chromosomes non-sister
chromatids that results in recombinant chromosomes during sexual
reproduction.
• Crossing over accounts for genetic variation, because due to the
swapping of genetic material during crossing over, the chromatids
held together by the centromere are no longer identical.
• Sexual reproduction promotes genetic variation by producing
different gene combinations.
• Meiosis is the process by which sex cells or gametes are created.
• Genetic variation occurs as alleles in gametes are separated and
randomly united upon fertilization.

18. Crossing over and recombination during meiosis
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19. Nonrandom Mating and Environmental Variance
 Population structure can be altered by nonrandom mating (the preference
of certain individuals for mates) as well as the environment.
 Nonrandom mating can occur when individuals prefer mates with
particular superior physical characteristics or by the preference of
individuals to mate with individuals similar to themselves.
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Assortative mating in the
American Robin
• The American Robin may practice
assortative mating on plumage
color, a melanin based trait, and
mate with other robins who have
the most similar shade of color.
• However, there may also be some
sexual selection for more vibrant
plumage which indicates health
and reproductive performance.

20. Environmental Variance
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• Genes are not the only players involved in determining population
variation.
• Phenotypes are also influenced by other factors, such as the
environment.
Temperature-dependent sex
determination:
• The sex of the American
alligator (mississippiensis) is
determined by the temperature
at which the eggs are
incubated.
• Eggs incubated at 30 degrees
C produce females, and eggs
incubated at 33 degrees C
produce males.

21. Genetic variation in the shells of Donax variabilis: An enormous amount of
phenotypic variation exists in the shells of Donax varabilis

22. Human genetic variation
• Human genetic variation is the genetic differences in and among
populations.
• There may be multiple variants of any given gene in the human
population (alleles), a situation called polymorphism.
• No two humans are genetically identical.
• Even monozygotic twins (who develop from one zygote) have infrequent
genetic differences due to mutations occurring during development.
• The study of human genetic variation has evolutionary significance and
medical applications.
• It can help scientists understand ancient human population migrations
as well as how human groups are biologically related to one another.

23. • For medicine, study of human genetic variation may be important
because some disease-causing alleles occur more often in people from
specific geographic regions.
• New findings show that each human has on average 60 new mutations
compared to their parents.

24. HIV Attachment

25. Role of genetic variation in health and pharmacology
• Differences in allele frequencies contribute to group differences in the
incidence of some monogenic diseases and they may contribute to
differences in the incidence of some common diseases.
• For the monogenic diseases, the frequency of causative alleles usually
correlates best with ancestry, whether familial (for hemoglobinopathies
among people with ancestors who lived in malarial regions).
• To the extent that ancestry corresponds with racial or ethnic groups or
subgroups, the incidence of monogenic diseases can differ between
groups categorized by race or ethnicity, and health-care professionals
typically take these patterns into account in making diagnoses.

26. • Some other variations on the other hand are beneficial to human, as they
prevent certain diseases and increase the chance to adapt to the
environment.
• For example, mutation in CCR5 gene that protects against AIDS.
• CCR5 gene is absent on the surface of cell due to mutation.
• Without CCR5 gene on the surface, there is nothing for HIV viruses to
grab on and bind into.
• Therefore the mutation on CCR5 gene decreases the chance of an
individual’s risk with AIDS.
• The mutation in CCR5 is also quite popular in certain areas, with more
than 14% of the population carry the mutation in Europe and about 6-
10% in Asia and North Africa.

27. • Apart from mutations, many genes that may have aided humans in
ancient times plague humans today.
• For example, it is suspected that genes that allow humans to more
efficiently process food are those that make people susceptible to
obesity and diabetes today.
• As far as pharmacological role of genetic variation is concerned,
Variability in drug efficacy and adverse effects are observed in clinical
practice
• Drug-related genes show high extent of genetic variability across millions
of individuals

28. Cancer drug target genes have many germ line functional-variants
• Especially in cancer therapy, genetic variation in drug targets has been
recognized to play a crucial role for treatment success.
• While some cancer drugs do not act in the tumor tissue, the cancer
drug’s primary site of action usually is in the tumor, whose genome
contains tumor specific somatic variants as well as a subset of patient-
specific germ line variants30.
• Information on somatic variants from tumor samples is thus
increasingly used to enable research on drug design and to implement
stratified or personalized cancer therapy.
• South Asian and European ancestry compared to the cohort of African
ancestry (DRPSAS/NFE = 85% vs DRPAFR = 45%) due to functional
variants in the four taxane targets, TUBB1, MAP2, MAP4, and MAPT.

30. • Dopamine D2 (encoded by the DRD2 gene) receptors are primarily
expressed in the terminal regions of dopaminergic neurons.
• Studies in DRD2-null mice suggest that the D2 receptor functions as an
auto receptor on dopamine neurons.
• The most well-established polymorphism in the DRD2 gene is Taq1A, a
C>T substitution located 10kb (kilobases)3’ of the DRD2 gene.
• This Taq1A polymorphism is associated with an increased risk for
multiple types of substance abuse, including heroin use, cocaine
dependency , psychostimulant polysubstance abuse and smoking.
• In addition to the dopaminergic system, nicotinic acetylcholine receptors
have been implicated in nicotine reward and dependency.
• Two non synonymous SNPs on exon5 (rs1044396/1629G>T
andrs1044397/1659G>A)of the gene encoding for the α4 subunit of the
nicotinic acetylcholine receptor (CHRNA4) were associated

31. Is Genetic Diversity Good or Bad?
 Genetic diversity is, in general, a good thing for a population, for a
simple reason: adaptation via natural selection depends on the
existence of variation
 Other things being equal, a population possessing a greater amount of
genetic diversity has a greater probability of already possessing
adaptive alleles that might be necessary to meet new environmental
challenges (e.g., pathogens).
 Even the boundaries between the useful/neutral/deleterious
categories are blurred.
 Deleterious anaemia-causing mutations are known to have benefits of
malaria- resistance.

32.  Neutral variants may be “useful” ones in waiting: for example, lactase
persistent mutants may have existed in the human species for
hundreds of thousands of years, appearing and re-appearing by
mutation, but it is when they encountered cow’s milk and the need to
drink it that they shifted from “neutral” to “useful”.
 And, even useful alleles can cease to be so, e.g., the eradication of
swamps and malaria in Greece has removed the benefit of malaria-
resistence, and left only the harm of anaemia.