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- Statistical test to compare expected ratios (based on assumptions about genotypes, dominance relationships, etc) with observed ratios
- Standard way to decide whether unexpected observations are due just to sampling effects, or are due to incorrect assumptions
Mutation is a heritable change in DNA sequence
- Not all mutations results in mutant phenotypes
- Not all mutations are deleterious (can be neutral, can give a selective advantage can be deleterious, disadvantage)
- Most mutations that affect a protein coding gene or its expression are loss-of-function mutations
All variation in DNA comes from mutation
Polymorphism (rather than mutation) describes variants that are common in a population (>1%), and for which no obvious "wild-type" allele can be distinguished
Origin of mutations
- Spontaneous or induced
DNA strand slippage: type of biological slippage
- Tandem repeats of simple sequences (di, tri, tetra nucleotides) are prone to mistakes (slippage) during replication
- This can cause increase or decrease in the number of repeats present at a given locu
- Sippage occurs frequently enough to produce polymorphisms that can distinguish individuals in a population, but is usually heritable between generations
- SSR = simple sequence repeat = microsatelitte loci
Transposable elements (TE): form to biological mutations
- Two main classes of TE
- Class 1: move by copy/paste of an RNA intermediate
- Class 2: move by cut and paste of the original DNA sequence
- TEs most common feature in large eukaryotic genomes
- TEs can cause mutation by: insertion into a gene or its regulatory sequences, breaking DNA strands leading to recombination, rearrangements, deletions, etc.
- Human genome is 45% TEs, most of this is class 1 elements called LINEs, SINEs
- TEs can be autonomous OR non-autonomous (non-autonomous TEs rely on TE protein produced by autonomous elements for movement through the genome)
- The short, Alu SINE is present in >1 million copies in human
- The number of Alu tandem repeats at a given locus is a useful polymorphic trait in forensics, paternity, population genetics, etc
Tautomerism: form of biological mutations
Probably not a significant source of mutation, but spontaneous mutations can occur for unexplained reasons
- Usually alter bases and affect base pairing (eg alkylating agent EMS)
- Some chemicals mutagens alter the shape of the DNA helix (eg. intercalating agents, eg benzopyrene from smoke)
- Some chemicals mutagens can break DNA strands, which can lead to deletion or recombination
- High energy particles (eg. fast neutron) can induce strand breakage
- Smaller particles (eg. gamma rays, x-rays) can alter bases and base pairing
- UV induces thymine dimers
- Point Mutations (substitute one base for another)
- Insertion or deletion (INDEL)
- Effect on gene function (muller morphs)
- Loss-of-function (amorph, hypomorph) vs. gain-of-function (hypermorph, neomorph, antimorph)
- Amorph, hypomorph tend to be recessive because w.t. alleles tend to be haplosufficient
- Hypermrph, neomorph, antimorph tend to be dominant
Null = no w.t. protein function
Partial loss of w.t. function
More of the w.t. function than in the w.t.
A new function that is different from w.t.
A new function that works in opposition to w.t.
- Learn about almost any biological process by identifying mutants that disrupt that process
- Mutagenize (chemical, physical, biological) thousands of individuals
- Gametes from a mutagenized individual will typically have different mutations from each other
- Mutations will almost always be heterozygous
- Most induced mutations are recessive
- Must make any induced mutation homozygous, so that we can detect any mutant phenotype that might be present
- This may require thousands of crosses
Limitations of mutant screening
- Must be able to detect a mutant phenotype, but may not be able to if:
- some mutations may not be detected if they affect very early stages of gametogenesis or embryo development (lethality)
- Pleiotropy: mutation affects more than one process; if defect in one process affcts ability to detect phenotype of another process, then mutant screen may not be successful
- Redundancy: a function is encoded by more than one gene
- Protect chromosome ends and their loss appears to be related to aging and some diseases
- DNA polymerases can't replicate the 3' end of a template at its very end (because of the need fro primers)
- Chromosomes would therefore grow shorter afte each round of replication, if not for telomerases
- Telomerases replicate telomeric DNA to prevent shortening of chromosome ends.
Transposable Elements (TEs)
- Two types of mobile genetic elements in chromosomes that move either as RNA (copy & paste) or DNA (cut & paste)
- Both mechanisms require proteins to recognize conserved DNA sequences in TE and start copying or cutting there.
- Autonomous TEs encode their own proteins. Non-autonomous TEs do not encode their own proteins; these have only the conserved recognition sequences in the TEs
Penetrance & expressivity
- These are descriptive terms for some situations in which the phenotype varies from what is expected based on the genotype.
- These terms do not explain or imply why phenotype and genotype don't match
- Penetrance: what % of individuals with the mutant genotype have the expected mutant phenotype?
- Expressivity: what is the difference in the intensity of the phenotype between individuals?
- Many human diseases eg. for example, show incomplete penetrance and/or variable expressivity
- The number of chromosomes in a gamete
- Number of chromosomes means that total number of chromosomes you count on under the microscope or on a karyotype.
- There is no such thing as 4n, 6n, 8n...
- Humans are 2n=46, because you count 46 chromosomes in a human cell.
- DNA content changes throughout the cell cycle; if gamete is 1 c, fertilization doubles this to c, then replication doubles this to 4c
The number of chromosomes in a zygote
Chromosome number, ploidy, and DNA count
- Note that replication and mitosis changes c-value, but not chromosome number. Fertilization and meiosis change both c-value and chromosome number
- "x" can be used to define ploidy, eg. tetraploids are 2n=4x so there would be 4 copies of each chromosome in a karyotype, rather than 2 as in a diploid
- Dosage compensation requires all cells to have the same number of copies of most genes expressed
- Without dosage compensation, XX cells would make twice as much protein as XY cells make for most X-linked genes
- Mammals handle dosage compensation for X-linked by inactivating almost all genes on one randomly selected X chromosome homolog in each cell, at an early stage of embryonic development
- Dominance relationships for redO and redo alleles not defined (some would call this co-dominance, but I wouldn't) because no examples of expression of these in the same cell
- Given 2 mutants with the same phenotype, hoe do we know whether these mutants have defects in the same gene, or in different genes?
- Many mutants affect biochemical pathways, or other types of pathways; defects in different genes in the same pathway can have similar effects (ie, no wildtype end product is produce)
Complementation test shows whether independent mutations affect the same gene or different genes
- Need to have fully dominant alleles eg. wild-type allele is haplosufficient
- Cross individuals with recessive phenotype
- -if F1 generation has the recessive (mutant) phenotype, then no complementation occurred and mutations in the same gene (aa x aa) - "same complementation groups = alleles of the same gene"
- -If F1 generation has the dominant (wt) phenotype, then complementation DID occur and mutations are in different genes (aaBB x AAbb) -- "different complementation groups groups = different genes"
- Multiple alleles need to be distinguished with distinct symbols, that still make it clear that they are two different versions of the same gene (e.g. a1a2)
- When you need a mutation in many genes to see phenotypic parts
- When one phenotype masks another and the desired mutation (evident via phenotype) is not seen (such as lethality, kills before you see the brain damage)
Depends on how you define the phenotype
Masks other expressions of other loci
Bands of dark and light in one hair shaft
Striping has many things happening, but Godi does have a lot to do with that AA or Aa is taby, aa is non-taby or solid colored
Same principles of genetics apply as already discussed, but experimental approach is different - cannot make controlled crosses; families are small
Symbols for pedigree analisys
- Filled - affected (trait of interest)
- Circle - female
- Square - male
- Half-filled - known carrier
Mode of inheritance
- AD autosomal dominant inheritance: Every affected individual must have an affected parent
- XD X-linked dominant: cannot be XD if affected father has affected son (assuming mother is not affected), but all daughters of an affected father must be affected
- AR autosomal recessive - unaffected individuals have affected offspring (true also of XR)
- XR X-linked recessive - can't be XR if unaffected father has affected daughter.
Deducing mode of inheritance
- Assume: complete penetrance
- New mutations are rare
- Unaffected individuals with no family history of the trait (ie in-laws) are unlikely to be carriers
- Test each possibility in turn (AD, XD, AR, XR) assigning genotypes based on phenotypes and assumptions; see which mode(s) of inheritance are consistent with data in the pedigree
- Infer mode of inheritance, infer genotypes, for genotypes that are not certain, calculate probabilities (usually calculate probability of being carrier and/or affected)
- Use Punnet square to calculate expected frequency of relevant genotypes
- Use product rule to combine individual probabilities to given overall probability of inheriting a given genotype