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1. Genetic variation
Inherited disease II
Prof Isaac Quaye

2. What is the nature of genetic
variation?
• How different are we?
• How do these differences arise?
• Are these characteristics common in my community?
• At the population level
• At the molecular level
• How are these differences enabling me/us to survive?
• These differences form a basis for medical care and
counseling in the event of a disease state

3. Individual differences
• Physical attributes (height, eye color)
• Disease susceptibility (diabetes, cancer)
• Behavior (intelligence, personality)

4. Population genetics
• Deals with the nature and mechanism of
variation among groups of individuals
• Variation may be affected by :
• Migration (influx of migrants with different gene
frequencies
• Changes in allele frequencies due to mutations
• Adaptation to natural selection
• Genetic Drift (small reproducing population
effect)

5. Polymorphism
• In normal humans DNA sequence variation persists
without disease
• These variations are important for adaptation and
survival
• All genetic variation starts from mutations-changes in
DNA sequence
• May be at the gene level(alleles) or position of a gene
on a chromosome (locus) or whole chromosomes
• May be somatic or germline
• May be lethal, lead to infertility or neutral

7. What constitutes polymorphism?
Where a locus has two or more alleles
whose frequencies each exceeds 1%
in a population,
the locus is said to be polymorphic
or exhibit polymorphism

8. Conditions that determine gene
frequencies
• Founder Effects (affect frequencies of
recessive conditions)
• Heterozygote advantage

9. Types of mutations
• Deletion
• Insertion
• Addition
• Substitution
• Duplications
• Rearrangements

10. Traits and polymorphism
• Usually have no impact on form or function
• Important point: Traits abound in populations
• Mutation rates are defined as the number of mutations per locus
per generation
• Estimated mutation rate in humans is 10-6 per locus per
generation(beneficial for adaptation and evolution)
• Total gene pool = 25,000 therefore risk = 2.5%
• Mean heterozygosity is estimated to be 0.001-0.004 (i.e. 1:250 to
1:1000) bases are different between two allele sequences
• Mutation rates are generally low so most mutations are inherited!!!

11. Types of DNA polymorphism
Polymorphism Nature of polymorphism Number of alleles
Single Nucleotide
Polymorphisms (SNPs)
Substitution of one or the
other of two bases at a locus
2
Insertion/deletion(Indels) Insertion or deletion 2-100
Simple indel Presence or absence of a
short segment of DNA
2
Short Tandem Repeat
Polymorphism (STRP)
2,3, or 4 nucleotide repeat in
copies of about 5 in tandem
5 or more
Variable Number of Tandem
Repeats
Hundreds to thousands of
copies in tandem of 10-1000
bp repeat unit
5 or more
Copy Number Polymorphism
(CNP)
Presence or absence of 200-
1.5 Mb DNA segment (has
random duplication upto 4
times in some cases)
2 to a few

12. DNA polymorphism
• Indels with many alleles (STRP, VNTR<,CNP)
are described as :
• Microsatellites
• Minisatellites

13. Microsatellites
If DNA is repeated in short segments, they constitute microsatellites
Eg
TATATA……….GAAGAAGAA………..TAAATAAATAAA……TAAA
The different alleles are defined by the numbers of repeats present in different individuals in
A population
They constitute the STRP units
Microsatellites can be determined using PCR

14. microsatellite

16. Minisatellites
• VNTR results from the insertion in tandem of
variable repeats (commonly 100-1000
copies)of a sequence of DNA 10 – 100 bp long
• These sequences are minisatelites
• It has more allelic difference than in STRP
• There can be several dozens or more allele
differences such that individuals can be
distinguished using these sequences

17. Minisatellites

18. Population Frequencies of
Polymorphisms
• If a population has two alternative alleles Hp1
and Hp2 at a locus (diploid) with frequencies
of p and q the total allele frequencies within
the population is:
• = p + q=1
• The frequencies of the genotypes within the
population can be determined using the allele
frequencies or vice versa.

19. Hardy-Weinberg Equilibrium
Hardy-Weinberg Law:
Populations with allele frequencies of p and q
have corresponding
Genotypic frequencies of p2, 2pq, q2

20. Assumptions
• The population is large and matings are
random
• Allele frequencies do not change over a period
• Mutation rate is low to maintain allele
frequencies
• Individuals with all genotypes are fit to pass
their genes on
• Migration from one population to a different
population (with different alleles) is minimal

21. Example
Genotype Number of
people
Obsvd Rel.
Genotype
freq.
Allele Allele freq.
CCR5/CCR5 647 0.821
CCR5/∆CCR5 134 0.168 CCR5 0.906
∆CCR5/∆CCR5 7 0.011 ∆CCR5 0.094
Total 788 1.000

22. Disease gene identification
• Genes are linked if they do NOT assort
independently
• linkage analysis is used to determine disease
inheritance patterns in a family in association
with a region of the gene
• Or Correlation between the presence or absence
of a gene and a disease phenotype.
• Association studies- determines the frequency of
an allele or sets of alleles in a population with a
disease in relation to those without the disease

23. Recombination

24. Independent assortment

25. Cross over

26. Genetic variation