1a) Alleles and Allelic Variation

Allele

• A form of a gene

• A DNA sequence variant

Sequence alignment

• Can be used to compare two or more alleles

  • You just line them up and compare

Variants arise through…

• Mutations or,

• Changes in the nucleotide sequence

Mutation does NOT imply…

• That the mutation changed the function of the DNA

  • It implies that the DNA is different but the function is the same

• It also doesn’t imply that any function is worse, better, or neutral

• You only know the effect after looking at function or phenotype NOT from the word “mutation” ALONE

What is a gene product?

• The functional molecule encoded (output of expression)

• Protein Products !!!

• Sometimes RNA (deepening on the type of gene)

When is a gene expressed

• When its functional product is produced

• Usually we transcribed, translated, and regulation

• A gene can be expressed and not produce a functional product due to mutations

• Expressions DOES NOT = functional product

Mutations are described by…

• How they change DNA

• How they change an encoded gene product

• The amount of gene product

• How they affect the products activity

Mutations that change DNA Structure

• Substitution

• Indel

• Larger rearrangements

Mutations that change an encoded gene product

• They are called “Protein Coding sequence mutations”

• Ex)

  • Missense

  • Nonsence

  • Framshift

Mutations that change the amount of gene product

• Regulatory product

Mutations that affect the products activity

• Loss of function

• Gain of function

Substitution

• A single nucleotide change

Indel

• A short insertion and/or deletion of an indel (nulceotide base)

• Shortest possible indel = 1 nucleotide

Larger rearrangements

• Duplications: DNA is copied twice → 1 base (frameshift) → (3 bases) add an amino acid

• Deletions: DNA is lost → 1 base (frameshift) → (3 bases) lose of amino acid

• Inversion: DNA is broken off and flipped

Coding sequence mutations

• Missense

• Nonsense

• Frameshift

Missense

• Mutation leading to a single amino acid change in the resulting protein

Nonsense

• Mutation of an amino-acid encoding codon to a stop codon

  • Produces shortened proetin

Frameshift

• Mutation (insertion or deletion) that alters reading frame

• The amino acids encoded downstream of the mutation

Regulatory mutations

• Do not affect the sequence of the encode product

• Affect gene expression and this the AMOUNT of encoded product produced

Where are regulatory mutations

• In NON-CODING regions of DNA

• Found within DNA sequences that govern gene expression

• They can change mRNA

  • Stability

  • Localization

  • Splicing

• Mutations are found in DNA regulatory regions like

  • Promoters

  • Enhancers

  • Silencers

  • mRNA splicing signals (iN DNA sequence)

Loss of function mutations

• Alleles that decrease or eliminate functional activity of a gene product

• Most Loss of function alleles are recessive to functional alleles

Haplosufficient

• A single copy of a functional allele produces sufficient functional activity

Haploinsufficient

• Two copies of a function alallele are necessary to produce enough gene product activity for a wild-type phenotype

• Loss of function alleles are dominant to functional alleles

Three molecular classes that show dominant inhertance

• Haploinsufficient

• Dominant negative

• Gain-of-function

Exceptions to complete dominant/recessive allele relationships

• Incomplete dominance

• Co-dominance

Haplosufficent

• A single copy of a functional allele produces sufficient functional activity

Null or Amorphic alleles

• Example of a loss of function mutations

• Allele whose product has no functional activity

Homozygous vs Heterozygous Null/Amorphic mutations

• A loss of function mutation defines what the mutates allele does not by what the other allele does

• One allele can be null/amorphic and thus has a loss of function, but the other allele can be unaffected

  • Only non mutated allele will produce a product and the null or amophic one wont

  • The organism will have less total product than a homozygous wild-type

Hypomorphic Alleles

• Partial loss of function alleles

• Alleles with reduced functional activity

  • Reduced activity of protein product

    • Proteins works poorly

  • and/or

  • Reduced production (expression) of product

    • Less mRNA or less protein

Conditional Allele

• Loss of function allele

• Allele with loss of function only under SOME conditions

  • Temperature sensitive are a common type of naturally occurring conditional allele

Dominant negative allele

• Encodes product with functional activity that INTERFERES w/ the activity of functional allele product from the SAME gene

  • (The protein helps lift the coach but drops it)

• Produces a loss of function phenotype

  • Most commonly occur for genes encoding multimeric products (ex hemoglobin)

Gain of function

• Product has a new or higher activity

• or

• Product acts at a new time or place

Hypermorphic allele

• A gain of function allele

• Allele whose produce has increased activity

  • Ex) Hypermorphic agouti gene produces yellow coat collor (Extra phaomelanin)

Neomorphic Alleles

• A gain of function allele

• Neo-morphic → New Form

• Alleles whose product has a new function activity

  • Same product encoded but the product is express in a new PLACE or TIME

Neomorphic Allele Eyless example

• Eyeless gene controls eye development only in the head

• Neomorphic mutation = eyes form in a NEW location

• This is not a loss of eyes but of gain of a new function

Incomplete Dominance

• Blended phenotype

• When the phenotype of heterozygotes is intermediate b/w the phenotypes of the two homozygotes

  • WW (red)

  • Ww (pink)

  • ww (white)

Codominance

• Both phenotypes FULLY visible

• When the phenotypes associated with both alleles show in the heterozygote

Dose-Dependece

• How many functional alleles are needed to produce a wild-type phenotype

• Ex

  • Haplosufficiency

  • Incomplete dominance

  • Haploinsufficiency

Haplosufficiency

• You need a bit of expression to get W-T phenotype

Haploinsufficiency

• You need a lot more expression to get to W-T phenotype

Incomplete Dominance

• Above, Below 1, and Below 2

• Below threshold 1 = some product is produced leading to an intermediate phenotype

• Bellow threshold 2 = loss of function (mutant) phenotype

Multiple Alleles

• Any diploid individual has 2 copies of each gene (MAX two alleles)

• Any number of alleles can exist in a population or species

• Dom?Rec relationships are specific to a particular pair of alleles

Pleiotrophy

• When an allele or gene produces multiple different phenotype

• Can indicate that

  • A gene or allele acts in MULTIPLE biological process (A^Y)

  • A gene or allele acts in a SINGLE biological process that produces outcomes we categorize as different phenotypes

• EX)

  • A^y in mice = yellow fur AND predisposition to obesity

Lethal alleles

• Lead to modified Mendelian rations in crosses

• A^YA^Y is lethal

Other determinant of phenotype (NON Genotype)

• Gene - environment interactions

• Incomplete penetrance

• Variable expressivity

• Incomplete penetrance and variable expressivity can be CAUSE by gene - environment interactions but they can be cause by other things too

Phenotypic plasticity

• Reproducible

• Genetically controlled phenotypic variation in response to variation in environmental condition

Polyphenism

• A type of plasticity

• When 2 or more distinct body forms are produced by different developmental programs under different environmental conditions

  • Temperature - induced

  • Nutrient-induced

• Described by norm of reaction

Norm of reaction

• Describes polyphenism

• Describes the range of pheotypes produced by one genotype depending on an environmental condition

Penetrance

• Proportion of individuals that show a phenotype associated with a particular genotype

Incomplete penetrance

• When not all individuals show a phenotype associated with a particular genotype

• You can see this in pedigree

Expressivity

• The degree that a particular genotype is expressed in the phenotype of an individual

Variable ecpressivity

• All these beagles are S^PS^P but they vary drastically phenotypically while sharing the same genotype

Variable penetrance vs Variable expressivity

• Penetrance: You have it or you don’t

• Expressivity: You can have it in varying degrees

• You can have both variable penetrance and variable expressivity