Population Genetics

Population genetics is the study of the occurrence of a genetic disorder in a specific population. For
example, population genetics addresses questions such as:

• What are the risks that a couple will have a child with a genetic disease?

A population is a group of individuals of the same species. Population genetics allows geneticists to
detect variant within the same population using different tools and approaches.

In population genetics, a locus is a location on the genome of a single nucleotide or a stretch of

nucleotides. The simplest form of variation can be a difference in a single nucleotide which is known as
single-nucleotide-polymorphism (SNPs).

There are some common genetic approaches in which we can detect variety within a population.

single-nucleotide-polymorphism
SNPs (pronounced snips) are genetic variation within a single nucleotide. For example, let’s consider the
following sequence.

Abdulrahman have the same seq but with a variation

AACTAGCAA

AACTTGCAA

Fatimah has the same seq but with another variation

AACTTGCAA

AAGTTGCAA

This nucleotide difference allows us to differentiate between Abdulrahman and fattom.

In the above figure, the locus in the circle is a SNP because it can either be G:C or A:T. Both SNPs are
possible and individuals with both SNPs are completely okay.

SNPs have two alleles from each parent, the blue allele and the green allele.

SNPs are classified based the frequency of occurrence

• Common SNPs
o Frequency of about 5 percent or greater. (‫)احتمالية الحدوث‬
• Rare SNPs
o Frequency below 5 percent.

SNPs occur within genes, including within exons, introns, and regulatory regions.

SNPs within protein-coding regions can be classified into three groups:

• Synonymous if the different alleles encode the same amino acid.

• Nonsynonymous if the two alleles encode different amino acids.
• Nonsense if one allele encodes a stop codon and the other an amino acid.

SNPs located outside of coding sequences are called noncoding SNPs. If non-coding SNPs have no effect
on gene function and phenotype, they are called silent.

In order to study SNPs in a population, we must first detect which region in the genome is subject to
variation. This is usually done by sequencing partial segments of the genome, aligning these sequences
together and comparing them to see where they differ.

For example, SNP discovery in humans began by partially sequencing the genomes of 48 individuals from
around the world. Variable nucleotide sites were discovered by comparing the partial genome
sequences of these 48 individuals with one another.

For this purpose, we use Microarrays for SNPs detection.

 • In the microarray there are many wells, in each well there is a known DNA sequence (probe).
• The sample is applied onto the chip and hybridization take place (binding of the probe with the
studied sequence).
• If the person is homozygous for one allele, then the color will be red.
• If the person is homozygous for the other allele, the color will be green.
• If the person is heterozygous, the color will be yellow.

Microsatellites
• Microsatellites are region in the genome that has many repetitive sequences. For example, you
can find region on the genome about 200 base pairs that are made of GC repeats
(GCGCGCGCGCGCGCGCGC….. n =200).
• These repetitive sequences vary from person to person, making it possible to use them as
genetic screening tools.
• These microsatellites have high rate of mutation.
• Example
o The Huntington disease gene (HD) contains a repeat of CAG, which encodes a string of
glutamines. Individuals carrying alleles with more than 30 glutamines are prone to
develop the disease.
Haplotypes
• A haplotype is a group of genes within an organism that was inherited together from a single
parent.
• In addition, the term "haplotype" can also refer to the inheritance of a cluster of single
nucleotide polymorphisms (SNPs).

• Sometimes useful to group haplotypes into classes.

• The haplotype network shows the relationships among the haplotypes.

What insights can we gain from haplotype analysis?

• Population geneticists studying the human Y chromosome among Asian men discovered one
highly prevalent haplotype, termed the “star-cluster” haplotype.
• Typically, most men have a rare Y chromosome haplotype, but the “star-cluster” haplotype is
present in 8 percent of Asian men.
• This haplotype is most common in Mongolia, suggesting that it arose there. The researchers
inferred that the “star-cluster” haplotype traces back to one man in Mongolia about 1000 years
ago.
• It appears that contemporary men with this haplotype are all descendants of Genghis Khan (or
his male-lineage relatives).

Other sources and forms of variation

• Interesting genetic variation can also be found in the mitochondrial (mtDNA) and chloroplast
(cpDNA) genomes of eukaryotes.
• Since mtDNA is usually maternally inherited, their analysis can be used to follow the history of
female lineages.
• A study of the human mitochondrial lineage traced the history of the human mtDNA haplotypes
and determined that the mitochondrial genomes of all modern humans trace back to a single
woman who lived in Africa about 150,000 years ago.
THE GENE-POOL CONCEPT AND THE HARDY–WEINBERG LAW
• Gene pool: is the sum total of all alleles in the breeding members of a population at a given
time.

For example, the figure shows a population of frogs.

• The size of the population is 16 (number of frogs).

• Each frog has two alleles and by counting we can see the different combinations
o AA: 5
o Aa: 8
o Aa: 3
• Each frog has two alleles-> number of all alleles is 16x2=32.
• The numbers above describe the gene pool for the population of frogs.
• We should be interested in the frequency of having AA, Aa or aa. -> Genotype Frequency.
• Frequency of AA = #of AA/total population= 5/16=0.3
• Frequency of Aa= #of Aa/total population= 8/16=0.5
• frequency of a/a is 0.19.
• Sum of all frequencies is 1.

Instead of calculating the Gene frequency, we can calculate the allelic frequency.

• In total we have 32 alleles

o 18 A
o 14 a
• Frequency of A (p) = 18/32= 0.56
 • Frequency of a (q) = 14/32= 0.44

• Under the Hardy–Weinberg law, neither gene nor genotype frequencies change from one
generation to the next when an infinitely large population is randomly sampled for the
formation of eggs and sperm.
• Thus, an important lesson from the Hardy–Weinberg law is that, in large populations, genetic
variation is neither created nor destroyed by the process of transmitting genes from one
generation to the next.
• Populations that adhere to this principle are said to be at Hardy– Weinberg equilibrium.

If three alleles A1, A2 and A3 have the following frequencies 0.5,0.2 and 0.3 respectively. What are all
the possible gene frequencies according to this law.

Hint: if the same letter is repeated such as in A1A1, then the gene frequency = 0.5*0.5.

If different letters like A1A2-> the gene frequency is =2A1*A2.

Where p1=A1, p2=A2 and p3=A3

All possible genotypes are presented in the table below

Mating systems
One critical assumption of the Hardy-Weinberg law is that the mating must be random, however, there
are three ways in which this randomness can be violated.

• Assortative mating
o Individuals choose to mate based on resemblance (similarity) or non-resemblance.
▪ Positive assortative mating:
• Occurs when similar types mate; for example, if tall individuals
preferentially mate with other tall individuals and short individuals mate
with other short individuals.
▪ Negative assortative or disassortative mating
• occurs when unlike individuals’ mate—that is, when opposites attract.
• One example of negative assortative mating is provided by the self-
incompatibility, or S, locus in plants
• The S locus has 4 alleles s1, s2, s3 and s4.
• The stigma of the plants having S1/S2 will accept pollination from plants
carrying S1/S2 but will accept from S3/S4. In this way self-pollination is
prevented.
• Isolation by distance
o Individuals are more apt to mate with a neighbor than another member of their species
on the opposite side of the continent.
• Inbreeding
o Mating between relatives.
o The offspring of marriages between relatives are at higher risk of having an inherited
disorder.
o Progeny of inbreeding are more likely to be homozygous at any locus than progeny of
non-inbred matings.
o Thus, they are more likely to be homozygous for deleterious (allele that can cause a
disease) recessive alleles
o Inbreeding leads to condition called inbreeding-depression in which the health and
reproductive success decreases among generations.
The inbreeding coefficient
• Inbreeding increases the risk that an individual will be homozygous for a recessive deleterious
allele and exhibit a genetic disease.
• The amount that risk increases depends on two factors:
o (1) the frequency of the deleterious allele in the population
o (2) the degree of inbreeding
• To measure the degree of inbreeding, geneticists use the inbreeding coefficient (F).
• Inbreeding Factor = probability that two alleles in an individual trace back to the same copy in a
common ancestor.

• B and C have the same mother but different fathers.

• The mother has two copies of the allele blue and pink.

• It happens that both child B and C inherited the pink

copy from their mother.

• Child I inherited both pink copies from B and C.

• Alleles in I are called Identical by decent because they

came from the ancestor A.

The effect of inbreeding is shown in the figure

red columns are children with a recessive disease whose parents are related.

Blue = parents are not related.

Population size and inbreeding
• Population size is a major factor contributing to the level of inbreeding in populations
• In small populations, individuals are more likely to mate with a relative than in large ones.

GENETIC VARIATION AND ITS MEASUREMENT

The data used are for the glucose-6- phosphate dehydrogenase (G6PD) gene from humans.

G6PD is gene that encodes an enzyme that catalyzes a step in glycolysis.

The wild-type allele (B) of G6PD has full enzyme activity.

A second allele called A leads to strongly reduced enzyme activity, and individuals who carry this allele
develop hemolytic anemia.

Another version of the allele A+ causes a slight reduced activity with no phenotypic effect.

The likelihood of having the A- allele among African sociality is higher.

The following figure shows 47 men tested for the

presence of A- allele. The question is how can we
quantify the genetic variety among these men? There
are four measures

1. Segregating sites (S): in this case, it is 18. 14

African sample and 7 for the non-African.
2. Number of haplotypes (NH):
a. There are 12 haplotypes in the total
sample.
b. 9 for the African and 6 for the non-
African.

These two depends on sample size

The third measure does not depend on the sample size:

3. Gene diversity
a. which is the probability that two alleles
drawn at random from the gene pool
will be different.
4. Nucleotide Diversity
a. Which is the diversity calculated for
each nucleotide.
These results are summarized in the table

The following figure shows the nucleotide diversity among different species

• Unicellular eukaryotes are the most diverse, followed by plants and then invertebrates.
• Vertebrates are the least diverse group; however, most vertebrates still possess a lot of
nucleotide diversity.

New alleles enter the population: mutation and migration

Mutation is the source of all variation. In population genetics, we are interested In the mutation rate.

Mutation rate: is the probability that a copy of an allele changes to some other allelic form in one
generation.

Luckily, the vast majority of mutations are not detrimental since they occur in regions of the genome
that are not critical.
The following table shows the mutation rate of SNPs and microsatellites in different species.

The other source of variations is

• Gene flow or migration: movement of individuals (or gametes) between populations

Recombination and linkage disequilibrium

• Recombination creates new forms of variation -> new haplotypes.

For example, we have two haplotypes here: AB and ab

If recombination occurs, then the new haplotypes will be Ab and aB. Thus, recombination can create
variation that takes the form of new haplotypes.

Genetic drift and population size

• In finite populations, allele frequencies may change from one generation.
• Change in allele frequencies between generations due to sampling error is called genetic drift.
• As the population size increases, the genetic drifts decreases.
Selection
• So far, we have considered how new alleles enter a population through mutation and migration
and how these alleles can become fixed in (or lost from) a population by gene drift.
• They cannot explain adaptations, features of an organism’s form or physiology that allow it to
cope with the environmental conditions under which it lives.
• Adaptations arise through the action of another process, which he called “natural selection’’.
• Let’s define natural selection as the process by which individuals with certain heritable features
are more likely to survive and reproduce than are other individuals that lack these features.
• Nature has a mechanism (mutation) to select new heritable forms or variants.
• Thus, populations will change over time (evolve) as the environment (nature) favors (selects)
features that enhance the ability to survive and reproduce.
• This is Darwin’s theory of evolution by means of natural selection.
• Darwinian evolution is often described using the phrase ‘’survival of the fittest’’
• An individual who is physically strong, resistant to disease, and lives a long life but has no
offspring is not fit in the Darwinian sense.
• Darwinian fitness refers to the ability to survive and reproduce. It considers both viability and
fecundity (‫)خصوبة‬.
• One measure of Darwinian fitness is simply the number of offspring that an individual has. This
measure is called absolute fitness (W).
• W. For an individual with no offspring, W equals 0, for an individual with one offspring, W equals
1, for an individual with two offspring, W equals 2, and so forth.

Another measure is the relative fitness (w)

• which is the fitness of an individual relative to some other individual, usually the most fit
individual in the population.
• If individual X has 2 offspring and the most fit individual, Y, has 10 offspring, then the relative
fitness of X is w = 2/10 = 0.2

The concept of fitness applies to genotypes as well as to individuals.

• The absolute fitness for the A/A genotype (W ) is the average number of offspring left by
individuals with AA genotype.
Let’s consider the table

• In this case, A is a favored dominant allele since the finesses of the A/A and A/a individuals are
the same and superior to the fitness of the a/a individuals
• The relative contribution of each genotype to the gene pool is determined by the product of its
fitness and its frequency

Expected Genotype frequency is calculated by dividing each relative contribution by the sum (0.595)

To calculate the frequency of these alleles in the next generation we use the following rule.
To calculate the increase of allele in the population, we take the difference between the probability of
the first and the second generation.

Delta P = P’ – P(A)

P(A)= 0.01+0.5(0.18)

= 0.17-0.1= 0.07

%increase = 0.07x100= 7 percent.