Lecture 16- Mutation and Genetic Variation Flashcards
The Importance of Genetic Variation
Genetic Variation
genetic differences that exist
among individuals in a population at a particular
point in time
Mutations
mutations result in _____ ________? Mutations that occur in the germ line can be passed on
some mutations are? other have? and some are?
over time thru evolution these mutations increase or decrease in frequency in the population
Mutations result in genetic variation!
Mutations that occur in the germ line can be passed on
* Some mutations are harmful; others have no effect; some are beneficial
* Over time, through evolution, these mutations
increase or decrease in frequency in the
population
Gene Pool
– All alleles present in all individuals in a species
- Genotype
– the genetic makeup of a cell or organism
Alleles
- the different forms of any gene
Alleles correspond to different DNA sequences in the genes
– Homozygous vs. heterozygous
- Polymorphism
Any genetic difference that is present in multiple individuals in a population
Phenotype
an individual’s observable characteristics (i.e., height, eye color,
lactose intolerance, weight, color blindness, etc.)
Alleles
Different forms of any genes are called
Homozygous
An individual with two copes of the same allele of a gene
Heterozygous
Individuals with two different alleles of a gene
Genotype vs. Phenotype
Genotype
– the genetic makeup of a cell or organism
Phenotype
– an individual’s observable characteristics (i.e., height, eye color,
lactose intolerance, weight, color blindness, etc.)
Harmful Genetic Differences
E.g. Emphysema risk:
Normal
a1AT gene encodes
enzyme that inhibits
elastase function
Normal lung elasticity
maintained (balanced
elastin production and
destruction)
Smoking
Smoking reduces
a1AT activity;
increased elastin
breakdown, enzyme that inhibits elastase function is not inhibited Emphysema results
Mutant
Individuals
homozygous for PiZ
allele produce a1AT
with reduced activity
Individuals who never smoke can also develop emphysema
* mutation in the gene encoding alpha-1-antitrypsin (a1AT)
* Mutant allele = PiZ.
* Homozygous individuals produce a1AT with reduced activity and
therefore have reduced elastase inhibition
* Individuals with the mutant gene and that smoke are far more
susceptible to developing emphysema and also lung cancer
Harmful Genetic Differences
smoking and PiZ mutation
Smoking
- reduces a1AT activity–>emphysema results
* 80% of all emphysema cases are associated with smoking PiZ mutation
– PiZ/PiZ non smokers –>reduced a1AT activity–> emphysema results (life
expectancy 65 yrs)
– PiZ/PiZ smokers-> increases severity and progression of disease (life expectancy 40 yrs)
* This is an example of a genetic risk factor i.e. a mutation that increases the risk of a disease
– A risk factor does not cause the disease, but makes the disease more likely to occur
Harmful Genetic Differences
Example 2: Huntington’s Disease and HTT (called huntington) gene on pp. 270-271
– You must know this example – testable content!
Harmful mutations are exemplified by alleles of a gene HTT, which encode the protein HTT or huntingtin, although the function or functions of huntingtin remain unknown, the protein is important in maintaining nerve cells, mutant forms of HTT result in huntingtins disease, the disease is associated with characteristic changes in brain morphology including enlarges ventricles and atrophy of cerebral nerve tissue, and basal ganglia, the result is incurable and relentless degeneration of the nervous system usually beginning sometime in middle age and progressing rapidly
The HTT gene encodes a protein of more than 3000 amino acids, and the gene is expressed in various cell types, especially in the brain, near its amino end, the protein contains a sequence of consecutive glutamines, the run of glutamine results from repeats of codon CAG, in the messenger RNA. . Nonmutant forms of the gene contain 6-35 CAG repeats and therefore 6-35 glutamines in the protein. The CAG repeats are genetically unstable, however and can undergo a process called trinucleotide expansion that increases the number of CAG repeats, resulting in 36-250 glutamines in the protein, the excessive number of glutamines in turn results in huntingtins disease
Huntingtins Disease
Nonmutant vs Mutant
Nonmutant: The HTT gene encodes a large protein that is expressed in many cell types but is highly expressed in brain –>HTT gene (expression of nonmutant HTT protein)–>Different nonmutant alleles code for a protein containing 6-35 consecutive glutamine (Q) amino acids (KSFQQ…QQQPPP)–>Ventricle, Basal ganglia
Mutant: Mutant HTT genes produce an mRNA that contains excessive repeats of the codon CAG, which increases the number of successive Q’s in the protein–> Mutant HTT gene (expression of mutant HTT protein)–>Different mutant alleles code for a protein containing 36-250 consecutive glutamine (Q) amino acids (KSFQQQQQQ…QQQQQQPPP) –>enlarged ventricles, atrophy of cerebral tissue and basal ganglia
Huntingtins Disease
Harmful Mutations
(a) Nonmutant forms: of the HTT gene encode a protein that includes a consecutive run of the amino acid glutamine (Q).
(b) Mutant forms: of HTT encode proteins with longer runs of Q’s, which result in Huntington’s disease and characteristic brain abnormalities.
Neutral Genetic Differences
* Neutral Mutations
No effect on organism or have effects not associated with reproduction and survival
– Often found in noncoding DNA
– Sometimes occur in coding sequences but still harmless
* E.g. PTC tasting (phenylthiocarbamide, gene=TAS2R38=Taste receptor, PAV/PAV=Tasters of PTC, AVI/AVI or AVi/PAV=nontasters of PTC)
Beneficial Genetic Differences
Example: Mutation that protects against aids by means a glycoprotein
Some mutations are beneficial
1) An example of such a mutation is one that protects against AIDS.
2) By means of a glycoprotein, a product of the env region in the HIV genome,
3)HIV combines with a cell-surface receptor CD4 to gain entry into T cells.
* Interaction with CD4 alone does not enable the virus to infect the T cell.
4) The surface glycoprotein must also interact with another receptor (CCR5) co receptor, in the early stages of infection
* Cells that lack it (CCR5) are more difficult to invade.
*For HIV to invade a T cell, it must interact with a CD4 receptor and a CCR5 co-receptor
Beneficial Genetic Differences
of a mutation called 🔼32 in CCR5
how was it discovered
The mutation has a 32 nucleotide deletion that shifts ?
The beneficial effect of a mutation (called Δ32) in CCR5 was
discovered in studies focusing on patients who did not develop AIDS for 10+ years
* The mutation has a 32 nucleotide deletion that shifts the reading
frame and results in a defective CCR5 protein
- Patients with HIV that are homozygous(Δ32CCR5/Δ32CCR5) for this allele rarely progress to AIDS, and even those heterozygous (Δ32CCR5/CCR5) for Δ32 have a delay in the progression of AIDS by about 2 years
Types of Mutations
Broad categories of mutations:
A. Small-scale Mutations
-Nucleotide substitution or point mutation
- Synonymous (silent) mutations
-Nonsynonymous (missense) mutations
- Nonsense mutations
-Insertion/Deletion of small number of nucleotides
-Frameshift
B. Chromosomal Mutations (large scale)
- Duplications/Deletions
- Inversion
- Translocation
Small-scale Mutations
* Nucleotide Substitution or
Point Mutation
Error incorporated during replication can become?
Effect of point mutation depends partly on? (non-coding region or coding region)
functions of non-coding DNA known or not known?
functions of coding DNA known or not known?
Mutations in DNA coding regions have?
Most frequent type of mutation
* Error incorporated during
replication can become
permanent change to
genome
* Effect of point mutation
depends partly on where in
genome it occurs
* i.e. in coding or non-coding region
In most multicellular eukaryotes, most of the DNA in
genome doesn’t code for proteins or RNA
* Function of noncoding DNA regions not known
* May explain why many mutations in noncoding DNA
have no detectable effect on organism
* Not the case for mutations in the coding regions
* Mutations in DNA coding regions have predictable
effects…
Small-scale Mutations
* Nucleotide Substitution and Point Mutation
Synonymous (silent) and Nonsynonymous (missense)
mutations:
DNA to RNA to AA
A. Nonmutant- the nonmutant gene expresses normal B-globin
B. Synonymous Mutation- A nucleotide substitution that does not change the amino acid is a synonymous (silent) mutation
C. Nonsynonymous mutation- A nucleotide substitution that changes the amino acid is nonsynonymous (missense) mutation
*: DNA sequence that codes for b-globin (a subunit in hemoglobin)
Small-scale Mutations is
Nucleotide Substitution and Point Mutation
Nonsense Mutations
A point mutation can change an amino acid into a stop codon that terminates translation this is called nonsense mutation
What is the result?
A point mutation can change an amino acid to a stop codon that terminates translation
* Result: truncated
polypeptide – most
are nonfunctional
and unstable
*a nucleotide substitution that creates a stop codon is called a nonsense mutation
Sickle-cell anemia is caused by a point mutation
Sickle-cell anemia is caused by a
change in only a single amino
acid:
– Glu is replaced by Val or Lys.
* Result: misfolding of the
hemoglobin subunit β-globin.
* Individuals who inherit two
copies of the mutant β-globin
gene (either S or C) have sickle- cell anemia.
* In this condition:
-hemoglobin crystallizes in low levels of oxygen, causing the cell to collapse.
-oxygen is not carried through the body effectively, causing anemia.
-Sickled cells block capillary vessels, causing pain and low oxygen levels.
