a genetic variant (mutation) which is “common” (greater than or = 1%) in the population
Give 3 classes of Genetic mutations, describe each and give their mechanisms
- Genome Mutation - Affects the # of intact chroms in the cell, Chromosome missegregation
- Chromosome Mutation - Alters the structure of individual chromosomes, Chromosome rearrangement
- Gene Mutation - alters individual genes, Base pair mutation
Define Founder effect
a high frequency of a mutant allele in a population founded by a small ancestral group when one or more of the original founders was a carrier of the mutant allele
Define Genetic Drift
random fluctuation of allele frequencies, usually in small populations
active selection of favorable alleles over non-favorable alleles
Define genetic Fitness
a measure of the chance that an allele will be transmitted to the next generation
scale is 0 to 1
measures reproductive success
How does migration and gene flow work?
when two populations with different allele frequencies for a disorder mix (as in immigration) then allele frequencies can change.
alters the HW equilibrium estimates
How do doctors affect the frequency of a mutant allele (in theory)?
If a medical care improves the reproductive fitness of a person with a disease, then the frequency of the mutation in the population may rise.
Increase in allele frequencies for _________ diseases is usually slow while increases in allele frequencies for ____________ and ___________ diseases are usually higher (faster).
dominant and X-linked
Of the three (genome, chromosome, gene) mutation types, which is the most common and what is its frequency in humans?
Genome mutations (chromosomal aneuploidy)
rate of 1 missegregation per 25-50 meiotic cell divisions
What is the rate of chromosome mutations in the human population?
1 rearrangement per 1700 cell divisions
seems high, but usually not compatible with life
Why would the rate of increase of recessive alleles be slower than dominant alleles and/or X-linked alleles?
Dominant alleles are always expressed when present (as are hemizygous X-linked alleles in males) and so are subject to selective forces.
Recessive alleles (in heterozygotes) are silent and not necessarily subject to selective forces. Exception is the heterozygote advantage.
Describe the two main ways a DNA gene mutation can occur.
- errors during replication
2. failure to repair DNA after introduction of a mutation (damage)
It is estimated that between ________ and _______ nucleotides are damaged per human cell per day via spontaneous processes such as ____(list 5 causes)_____.
10,000 to 1,000,000
deamination, depuriation, demethylation
rxn with mutagens (natural or environmental)
ultraviolet or ionizing radiation
What is a dynamic mutation?
Give two examples (from the text) that are a result of this type of mutation.
Expansion (amplification) of a repeat region of a gene during gametogenesis. Resulting expansion interferes with normal function (transcription or translation)
ex: 10 CAG repeats in exon 1 of HD gene expanded to 12 CAG repeats in the next generation.
ex: fragile X syndrome - CGG repeats in the 5’UTR of the FMR1 gene
How does a dynamic mutation in the coding region of a gene interfere with gene expression?
Abnormal protein product.
How does a dynamic mutation in the 5’UTR or 3’UTR region of a gene interfere with gene expression?
Interferes with transcription, mRNA production or translation
Define mutation rate of a gene
number of new mutations per locus per generation
Achondroplasya, has a relatively high mutation rate (1.4x10^-5 mutations per locus per generation). Why is this high mutation rate surprising / interesting?
The high mutation rate results almost exclusively from mutation at one particular nucleotide: Gly380Arg in a fibroblast growth factor receptor
In general, we expect high mutation rates in larger genes and at many different nucleotide positions
methylated CpG repeats (islands) are often mutational ________.
Given a mutation rate of 10^-6 per locus per generation and 25,000 genes in the human genome we can calculate that 1 in _________ people will have a new mutation from either maternal or paternal germline.
1 in 40
Why is it more likely that trisomies of chromosomes 13, 18, 21 and X are more likely to come from the maternal germline?
The primary oocyte is paused in meiosis I for many years. Nondisjunction (lack of ability to handle nondisj. or breakage of homologue linkages) is more likely the older the oocyte is.
Paternal gametogeneis occurs throughout the lifetime of the individual so all sperm are “new”.
Give 4 diseases where mutations in the paternal germline is more common.
Cainosynostoses (Apert, Pfeiffer, Crouzon syndromes) Achondroplasia Apert syndrome X-linked hemophilia B Huntington disease (CAG expansions)
As a male or female ages, contrast their increased risk of passing a mutation through the germline.
As females age, there is increased risk of nondisjunction in the mieosis I suspended oocytes.
As a male ages, there is increased risk of replication errors as spermatogonia undergo 20-25 mitotic divisions per year before entering their final meiosis to become spermatozoa.
Take two individuals and grab a random 1000 bp sequence from homologous chromosomes. What is the expected number of bp differences?
Take two individuals and grab a random bp sequence from two homologous protein coding regions. What is the expected variation rate?
1 bp per 2500
Why might the protein coding regions of different individuals be more similar than a random (likely non-coding) region of the DNA?
It is likely that protein coding regions are under more tight scrutiny. Mutations with band phenotypic effects are more likely to be selected agains. Mutations that are silent (in the non-coding regions, for example) are less likely to be “corrected.”
Differentiate between a polymorphism and a rare variant.
polymorphism: present in 1% or more of the population
rare variant: present in less than 1% of the population
The assumptions of the Hardy-Weinberg Equlibrium
- Large population with random matings (wrt locus in question)
- Allele frequency remains constant
a. no mutations,
b. no selections, all individuals are equally capable of mating
c. no immigration of new allele frequencies into the population
What is positive selection for heterozygotes (the heterozygote advantage)?
pretty self explanatory…
Increased fitness of heterozygotes under certain environmental conditions.
Classic Example: resistance to malaria due to heterozygous for sickle cell mutation (as well as some other hemoglobinopathies)
Give three examples (as presented in the text p. 201) of the Founder Effect.
- Type I Tyrosinemia - Lac Saint Jean region of Quebec
- Ellis-van Creveld syndrome - Old Order Amish populations
- Choroideremia (X-linked degenerative eye disorder) - Finland
What is a balanced polymorphism?
Selective forces operate to both maintain a deleterious allele and to remove it from the gene pool so that the end result is that the disease sticks around in a large number of heterozygotes.
NextGen sequencing as (to date) sequenced ___________ exomes representing ___% of the entire genome.
NextGen sequencing found _____________ single nucleotide variants.