Download Lecture on Population Genetics

Lecture on Population Genetics
March 10, 2000
1). Introduction
In the past few weeks we have covered some of the fundamental concepts of biology,
genetics and molecular biology. This has all been in preparation for the remainder of the
course which will focus on the science that Discovery Manager supports—the discovery
of disease genes.
To this point we have focused on the fate of genes in a single cell and the biochemical
processes involved in replicating it, expressing it, and transferring it from one generation
to the next.
Today we will focus on the fate of genes in populations. The principles of this field,
known as population genetics, underpin the analysis of the genetics of normal biological
variation. As an extension, these same priniciples underpin the analysis of the genetic
epidemiology of human diseases.
In the next two weeks, we will focus on genetic epidemiology of human disease which is
the first step in the disease gene discovery process supported by Discovery Manager.
2). Definitions
Locus: The specific place on a chromosome where a gene is located. A locus may have
one or more genes in it. It is a physical location.
Gene: The fundamental physical and functional unit of heredity that carries information
from one generation to the next.
Allele: One of the different forms (variants) of a gene that can exist at a locus.
Homozygous gene pair: A gene pair having identical alleles in the two chromosome sets
of the diploid individual.
Heterozygous gene pair: A gene pair having different alleles in the two chromosome
sets of the diploid individual.
Genotype: The specific allelic composition of a gene or set of genes
Phenotype: The detectable outward manifestation of some genotype (measurable traits,
ex. blood glucose level)
Population: The quote is from Introduction to Quantitative Genetics by D. S. Falconer,
1960, Ronald Press.)
"A population in the genetic sense, is not just a group of individuals, but a breeding
group; and the genetics of a population is concerned not only with the genetic
constitution of the individuals but also with the transmission of the genes from one
generation to the next. In the transmission the genotypes of the parents are broken
down and a new set of genotypes is constituted in the progeny, from the genes
transmitted in the gametes. The genes carried by the population thus have
continuity from generation to generation, but the genotypes in which they appear do
not. The genetic constitution of a population, referring to the genes it carries, is
described by the array of gene frequencies, that is by specification of the alleles
present at every locus and the numbers or proportions of the different alleles at each
locus."
3). Key Concepts in Population Genetics
The following are five key concepts in the filed of population genetics that we will focus
on today.
 The goal of population genetics is to understand the genetic composition of a
population and the forces that determine and change that composition.
 In any species, a great deal of genetic variation within and between
populations arises from the existence of various alleles at different loci.
 A fundamental measurement in population genetics is the frequency at which
alleles occur at any gene locus of interest.
 The frequency of a given allele can be changed by recurrent mutation,
selection, or migration or by random sampling effects.
 In an idealized population, in which no forces of change are acting (such as
mutation), a randomly interbreeding population would show constant
genotypic frequencies for a given locus from one generation to the next.
4). Population Genetics and Classical Evolutionary Genetics
Population genetics is the translation of Charles Darwin’s theory of evolution into precise
genetic terms.
Darwin’s theory of evolution through natural selection can be summarized in the
following three principles
 Principle of variation. Among individuals in any population there is
variation in morphology, physiology, and behavior. This combination of
characteristics is termed the phenotype of an individual.
 Principle of heredity. Offspring resemble their parents more than they
resemble unrelated individuals. This principle describes the genetic basis of
heredity or the genotype of an individual.
 Principle of selection. Some forms are more successful at surviving and
reproducing than other forms in a given environment. The selective process
acts on variations in the genetic makeup of an organism (survival of the
fittest).
Population genetics deals with the description and measurment of genetic variation
in populations and with the experimental and theoretical determination of how that
variation changes in time.
5). General Principles of Population Genetics
5.1). Variation
Population genetics is the study of inherited variation and its modulation over time. The
study of variation consists of two stages.
Stage 1:
Describe the phenotypic variation
Stage 2:
Translate these phenotypes into genetic terms and redescribe the
variant genetically.
5.1.1). Observation of Variation
 Population genetics deals with genotypic variation but by definition only
phenotypic variation can be observed.
 The relationship between phenotype and genotype can vary from the very
simple to highly complex.
 The simplest relationship between genotype and phenotype exists for
traits that are qualitative. These traits include the various genetically
determined blood groups which give qualitatively distinct phenotypes.
 Highly complex relationships are found between genotype and
quantitative traits. These are traits that vary over a range, like height.
These relationships must be analyzed with statistical tools like
distributions and association and are termed quantitative traits.
 Phenotype can be affected by other factors beside genetics, including the
environment.
 Most phenotypes (traits) are quantitative.
5.1.2) Description of Variation
We will focus today on the simplest case of a qualitative trait.
 The simplest description of genetic variation is the frequency distribution of
genotypes (alleles) in a population. The frequencies of all alleles of a gene always
adds up to 1.
Example
Blood Group Locus MN has two alleles M and N
These alleles can exist in three possible combinations:
MM, MN, NN
Let’s look at the frequency distribution of these three alleles in different populations.
Population
Eskimo
Australian aborigine
Egyptian
German
Chinese
Nigerian
MM
0.835
0.024
0.278
0.297
0.332
0.301
Genotype
MN
NN
0.156 0.009
0.304 0.672
0.489 0.233
0.507 0.196
0.486 0.182
0.495 0.204
Allele frequencies
p(M)
p(N)
0.913
0.087
0.176
0.824
0.523
0.477
0.550
0.450
0.575
0.425
0.548
0.452
Note that there is variation amongst individuals within a population and between
populations.
5.1.3). Measurement of variation
 The simplest measure of genetic variation (as opposed to description) is the
amount of heterozygosity at a locus in a population. This number is the
frequency of heterozygotes at a locus.
In this example, heterozygosity is simply equal to the frequency of the MN genotype in
the population.
Population
Eskimo
Australian aborigine
Egyptian
German
Chinese
Nigerian
MM
0.835
0.024
0.278
0.297
0.332
0.301
Genotype
MN
NN
0.156 0.009
0.304 0.672
0.489 0.233
0.507 0.196
0.486 0.182
0.495 0.204
Allele frequencies
p(M)
p(N)
0.913
0.087
0.176
0.824
0.523
0.477
0.550
0.450
0.575
0.425
0.548
0.452
If one allele is present at very high frequency and the remainder at low frequencies, there
will be very little heterozygosity because by necessity most of the individuals will be
homozygous for the common allele. Heterozygosity will be greatest when there are many
alleles at a locus all at equal frequency.
5.1.4). Kinds of Variation
 Variation between and within populations is widely observed at various levels of
phenotype. This variation can be seen from external morphology (ex. height) down to
the DNA sequence level.
 Every species of organism examined has revealed considerable genetic variation, also
know as polymorphism.
 A gene or a phenotypic trait is said to be polymorphic if more than one form of the
gene or trait is observed in a population.
 This genetic variation is the raw material for evolution and the emergence of disease
genes.
The following is a partial list of the types of variation measured by scientists. Ultimately,
all phenotypic variation can be correlated with genotypic variation and alterations in
nucleotide sequence.
5.1.4.1). Morphological variation
The form of an organism can vary dramatically. Just look around the room.
5.1.4.2). Immunological polymorphism
A number of loci in humans code for antigenic specificities such as the ABO blood types.
Over 40 different specificities on human red cells are known. These form the basis of
blood typing and blood incompatibilities.
5.1.4.3). Protein polymorphisms
Changes in the nucleotide sequence that result in the incorporation of alternate amino
acids in a polypeptide chain can sometimes be detected electrophoretically. If the new
amino acid results in a change in overall charge the proteins will migrate differently in
gel electrophoresis.
5.1.4.4). DNA sequence polymorphisms
These polymorphisms reside within the coding sequence of genes, in regulatory regions
and in sequences between genes. They can be multi-nucleotide in nature or involve only a
single base pair. The following is a partial list of DNA polymorphism types.



RFLP-restriction fragment length polymorphism. A restriction enzyme that
recognizes six-base sequences will recognize an appropriate sequence approximately
every 4096 base pairs. If there is a polymorphism in the population in one of the six
bases at the enzyme recognition site, then there will be a restriction fragment length
polymorphism in the population. The enzyme will cut one variant and not another.
VNTR-variable number tandem repeats. In the human genome there are a variety of
short DNA sequences dispersed throughout the genome, each one of which is
repeated in a tandem row. The number of repeats may vary from a dozen to more than
100.
SNP-single nucleotide polymorphisms. These are single-base variations in the genetic
code that occur about every 1000 bases along the three billion bases of the human
genome.
5.1.5). Mutation- A source of genetic variation
The possibility of continued evolution of a population is dependent on a constant supply
of variation. There are three sources of variation for a given population.
 Recombination
 Immigration
 Mutation
The major source of genetic variation is mutation.
5.1.5.1). Mutation
 Mutation is the change of genetic material that may alter the length or arrangement of
DNA.
 Mutations can occur anywhere in the genome but there appear to be hot spots where
chromosomal breaks and point mutations are more likely to occur.
 There are several causes of mutation.
 Mutation occurs if a chemical mutagen or ionizing or ultraviolet radiation
damage the DNA.
 The DNA polymerase that replicates the DNA does not operate with perfect
fidelity.
 If DNA repair enzymes do not repair the damage, a mutation results.
5.1.5.1.1). Macromutation
 Occasionally, chromosomes break into pieces that do not rejoin normally but may
form a rearrangement on the same chromosome or may be translocated to join
another chromosome. Many leukemias are caused by rearrangements or
translocations.
 Many repeat sequences such as VNTRs change their copy number through various
mechanisms. Changes in the number of repeat sequences are at the core of certain
types of muscular dystrophy.
 Macromutations, which occur in the germ line (egg or sperm), can be inherited. This
is rare but accounts for the karyotypic differences between species.
5.1.5.1.2). Micromutations
These mutations that are not visible by light microscopy. The following is a list of the
types of micromutations identified. They occur about once every one million to ten
million meioses.


Point mutations- these lead to a change from one nucleotide to another. An example
of a point mutation which alters the phenotype of an individual, is the point mutation
in hemoglobin responsible for sickle cell anemia.
Single nucleotide deletions or insertions- if these occur in the coding sequence of a
gene they lead to “frameshifts” because they change the amino acid triplet reading
frame changing all amino acids down stream of the mutation
5.2). The Hardy Weinberg Law
The unifying concept of population genetics is termed the Hardy Weinberg law
 Named after the two scientists who simultaneously discovered the law
 The law predicts how gene frequencies will be transmitted from generation to
generation given a specific set of assumptions
 The assumptions are as follows
 Infinitely large population—no such population actually exists
 Random mating must occur in the population—within a population,
random mating can be occurring at some loci but not at others
 No evolutionary forces affecting the population—these evolutionary
forces include:
Mutation
Migration
Selection
 There is no selective advantage for any genotype; that is, all
genotypes produced by random mating are viable and fertile.
The Hardy-Weinberg Law predicts three important conditions within a population:
 Allele frequencies predict genotype frequencies
 At equilibrium, allele and genotype frequencies do not change from
generation to generation
 Equilibrium is reached in one genertion
The Hardy-Weinberg equation can be used to determine whether or not a population is in
equilibrium with respect to a particular gene. If there is no equilibrium, then one of the
conditions is not being met, and factors such as mutation, migration, natural selection,
genetic drift, and inbreeding may be playing a role in the population.