Download lecture7

Session VII
Basic Biological Principles
Previous sessions covered fundamental
concepts of biology, genetics and molecular
biology of genes in individual cells
Session VII
This was in preparation for the remainder of the course which
will focus on the science that Discovery Manager supports
The Discovery of Disease Genes
Session VII
What are disease genes?
A large portion of human ill health has a genetic
component
Genetic causes of human disease fall into three
categories
•Inherited genetic disease
•Somatic genetic disease
•Chromosomal aberration
What are disease genes?
Inherited genetic diseases
•Discovery Manager supports the investigation of
inherited genetic diseases
•Abnormal variants of genes passed from one
generation to the next
•Many inherited genetic diseases are caused by a
defect in a single gene
cystic fibrosis
muscular dystrophy
phenylketonuria
Inherited genetic disease
•Genetic determination of most human
hereditary diseases is complex
•Involves interaction of variants of more
than one gene and the environment
heart disease
diabetes
hypertension
How is Disease Gene Discovery Done?
•Characterize the disease traits--phenotype
•Examine the structure of the genome--genotype
•Correlate “variant” genotype with phenotype
•Identify chromosomal region associated with the
variant genotype
The Process of Gene Discovery
The first steps in this process, correlation
of phenotype and genotype, use the
principles of population genetics
Population Genetics
• Population genetics focuses on the fate of genes in
populations
• The principles of population genetics underpin the analysis
of genetics of normal biological variation
• As an extension, these same principles underpin the
analysis of the genetic variation associated with human
genetic disease
• In the next two weeks, focus on analysis of the genetic
variation responsible for human disease
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.
Definitions
• 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
Unit of Study In Population Genetics
” 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.”
The quote is from Introduction to Quantitative Genetics by D. S. Falconer,
1960, Ronald Press.)
Key Concepts in Population Genetics
Goals of population genetics
 understand the genetic composition of a population
 understand the forces that change that composition.
Key Concepts in Population Genetics
Genetic variation within and between populations
arises from the existence of various alleles at
different loci.
Key Concepts in Population Genetics
Fundamental measurement in population genetics is the
frequency at which alleles occur at any gene locus
Key Concepts in Population Genetics
 Frequency of a given allele can be changed by mutation,
selection, or migration
 Mutation may result in the creation of a disease gene
Key Concepts in Population Genetics
The Ideal Situation
In idealized population, where no forces of change are acting
(such as mutation), a randomly interbreeding population
shows constant genotypic frequencies for a given locus
from generation to generation
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
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
Darwin’s theory of evolution
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.
Darwin’s theory of evolution
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
•The description and measurement of genetic variation
in populations (both functionally normal and abnormal
variants)
•Determines how that variation changes in time.
Variation
The study of variation consists of two stages (correlation of
phenotype and genotype)
Stage 1: Describe the phenotypic variation----DM Study Variable Manager
Stage 2: Translate these phenotypes into genetic terms and redescribe the
variant genetically----DM Genotype Manager
Observation of Variation
Population genetics deals with genotypic
variation but by definition only phenotypic
variation can be observed.
Observation of Variation
The relationship between phenotype and genotype
can vary from the very simple to highly complex.
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.
Observation of Variation
The relationship between phenotype and genotype
can vary from the very simple to highly complex.
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, covariance, and association.
Most phenotypic traits are quantitative
Description of Variation
•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
Blood Group Locus MN
The Blood Group Locus MN has two alleles M and N
These alleles can exist in three possible combinations:
MM, MN, NN
Genotype
Allele frequencies
Population
MM
MN
NN
p(M)
p(N)
Eskimo
0.835
0.156
0.009
0.913
0.087
Australian
0.024
0.304
0.672
0.176
0.824
Egyptian
0.278
0.489
0.233
0.523
0.477
German
0.297
0.507
0.196
0.550
0.450
Chinese
0.332
0.486
0.182
0.575
0.425
Nigerian
0.301
0.495
0.204
0.548
0.452
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.
Blood Group Locus MN
Population
Eskimo
Australian
Egyptian
German
Chinese
Genotype
MM
0.835
0.024
0.278
0.297
0.332
MN
0.156
0.304
0.489
0.507
0.486
NN
0.009
0.672
0.233
0.196
0.182
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
Heterozygosity is simply equal to the frequency of the MN genotype in
the population
Kinds of Variation
Every species of organism examined has revealed considerable
genetic variation, also know as polymorphism.
A gene or a phenotypic trait is 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.
Kinds of Variation
DNA sequence polymorphisms
These polymorphisms reside in coding sequence, in regulatory
regions and in sequences between genes
RFLP-restriction fragment length polymorphism
VNTR-variable number tandem repeats
SNP-single nucleotide polymorphisms.
Sources of Genetic Variation
Recombination
Mutation
Immigration
Mutation
Change in DNA that may alter the length or
arrangement
Causes of mutation
Chemical mutagen or ionizing or ultraviolet radiation
damage the DNA
DNA polymerase does not operate with perfect fidelity
DNA repair enzymes do not repair the damage
Macromutation
•Chromosomes break into pieces resulting in rearrangement or
translocations
ex. leukemias
•Repeat sequences such as VNTRs change their copy number
ex. myotonic dystrophy
•Macromutations in the germ line (egg or sperm) accounts for
the karyotypic differences between species
Micromutations
Point mutations- 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- result in
“frameshifts”
Amino acid triplet reading frame is altered changing all amino
acids down stream of the mutation
The Hardy Weinberg Law
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
The Hardy Weinberg Law
No evolutionary forces affecting the population—these
evolutionary forces include:
Mutation
Migration
Selection
No selective advantage for any genotype; that is, all
genotypes produced by random mating are viable and fertile.
The Hardy Weinberg Law
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 generation
The Hardy Weinberg Law
• If there is no equilibrium, then one of the
conditions is not being met
• Factors such as mutation may be playing a role in
the population
Summary
•Heritable variation in the genome is the raw
material for evolution
•Selective pressure acts on this variation
•Variants that confer reproductive or survival
advantage are maintained
•What about disease genes????