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Lectures by Kathleen FitzpatrickSimon Fraser University

Copyright 2012 Pearson Education Inc.Mark F. Sanders John L. Bowman

G E N E T I C A N I N T E G R A T E D A P P R O A C H

A N A LY S I S Chapter 4Gene Interaction

Slides adapted from lectures byKathleen Fitzpatrick

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Copyright 2012 Pearson Education Inc.Genetics Analysis: An Integrated Approach

Genetic interactionsInteractions among alleles at a single locus- dominance

Dominance is one of the simplest types of genetic interaction.Dominance of one allele over another may not be complete,or heterozygous genotypes may give rise to phenotypes verydifferent from either homozygote.

Interactions among alleles at multiple loci- epistasisTwo or more genes may affect the same trait, eitheradditively or non-additively.

In addition, the expression of a trait may also depend on theinteraction of genes with non-genetic factors.

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4.1 Dominance relations describe interactionsbetween alleles

Mendel chose to examine traits with just two alternative formsin which one form was completely dominant over the other, i.e.heterozygous individuals were phenotypically indistinguishablefrom one of the homozygotes. This is known as simple (orcomplete) dominance.

There are other forms of dominance, including incompletedominance, co-dominance, and over-dominance.

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Incomplete Dominance

Often the dominance of one allele over the other isnot complete

This is why allele designations such as A1, A2 or B1,B2 are often preferred over A, a or B, b

Incomplete dominance , or partial dominance -heterozygous individuals display phenotypesintermediate to either homozygous type

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Molecular basis of ABO dominance relations

The A and B antigens represent distinct modifications (additionsof different sugars) to a core five sugar molecule present onerythrocytes called the H antigen; no extra sugar moleculeadded produces type O.

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Dominance Relationships of ABO Alleles

Because blood typingtests for the presence ofthe A and B antigens,I A and I B alleles arecompletely dominant over

the i allele but co-dominant to each other.

Note that if we used adifferent type of assay, wewould find differentdominance relations.

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Effects of Mutation

Mutant alleles can be classified as:Loss-of-function , in which there is a decrease in(hypomorphic or leaky) or complete loss of (null)gene activity/function

Gain-of-function, in which the mutant allele acquiresincreased (hypermorphic) activity or a completely novel

activity (neomorphic)

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Dominant Negative Mutations

Multimeric proteins, composed of two or morepolypeptides that join together to form a functionalprotein are particularly subject to dominant negativemutations

These mutations are dominant due to loss of functionof the multimeric protein due to an amino acid changein one subunit

These are negative mutations due to their spoilereffect on the protein as a whole

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Allelic Series

Some genes have many phenotypically distinctalleles

A locus with more than two alleles is said to havemultiple alleles

An order of dominance among the alleles may forma sequential series referred to as an allelic series

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The C locus for mammalian coat color

Many genes are required to produce and distributepigment to hair follicles or skin cells, where they influenceskin or coat color

The C locus is responsible for coat color variation inseveral mammals, including cats, rabbits, mice, andothers.

It produces an enzyme active in the production of melanin

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Allelic Series of the C Gene

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Dominance relationships in the allelic series

Crosses among different genotypes has revealedthe dominance relationship of the alleles

The C allele is dominant over all the others

The c ch allele is incompletely dominant to c h

The c allele is recessive to all other alleles

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Molecular basis of the C dominance relations

The C allele produces a Tyrosinase enzyme that is 100%active, whereas that of the c ch allele is less than 20% active

The c h allele enzyme is temperature-sensitive ; functional at

lower temperatures (like the paws, ears and tail) and non-functional at higher temperatures (the trunk)

The c allele produces no functional enzyme

Note that c ch and c h could be considered either incompletelydominant or co-dominant depending on how the traits aredefined

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Molecular basis of the A Y lethality

The AY mutation is caused by a deletion that connects the Raly

promoter to the Agouti gene, causing ectopic expression of Agouti (yellow, dominant) and the loss of Raly (lethal,recessive).

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Sex-Limited Traits

The sex of an organism can influence gene expressionSex-limited gene expression is a pattern of expressionlimited to one sex or the other

The traits involved are called sex-limited traits ; both sexes

carry the genes for such traits, but they are expressed in justone sex

Examples include antlers, prostate cancer, and ovarian cancer

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Sex-Influenced Traits

Sex-influenced traits are those in which the phenotypecorresponding to a genotype differs between sexes

Male pattern baldness is an example:

In males and females, BB individuals have full hair bb individuals of both sexes experience hair loss, but it ismuch more severe in males due to the effect of androgensBb males experience hair loss just like bb males, while Bb

females have full hair

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4.2 Some genes produce variable phenotypes

Interpretation of genotypic and phenotypic ratios is based onthe assumption that there is a strict correlation betweenphenotype and genotype

However in some cases different phenotypes can result fromthe same phenotype

Incomplete penetrance and variable expressivity can

complicate interpretation of genotypic and phenotypic ratios

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Incomplete Penetrance

Traits for which individuals routinely occur that have thegenotype corresponding to a trait, but do not express thetrait are said to display incomplete penetrance

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Variable Expressivity

In variable expressivity , individuals who carry the alleles for

a trait show a phenotype but to a varying degree of severityWaardenburg syndrome has four principle features

Each affected member of the below family shows a differentcombination of symptoms

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Gene-Environment Interactions

Genes alone are not responsible for all the variationbetween organisms

Gene-environment interaction is the result of theinfluence of the environment on the expression ofgenes and on the phenotype of the organism

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Environmental modification to preventhereditary disease

The human autosomal recessive condition, PKU(phenylketonuria) is caused by the absence of anenzyme involved in phenylalanine catabolism

Infants with PKU are normal at birth, but over time,the inability to break down phenylalanine is toxic todeveloping neurons

PKU is one of the hereditary disorders infants areroutinely screened for

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Preventing symptoms of PKU

The key to preventing the most severe symptoms of PKU is torestrict dietary phenylalanine

Thousands of people with PKU are living normal lives due to

the simple dietary modification that prevents the expression ofthe PKU phenotype

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Pleiotropy

Pleiotropy is the alteration of multiple distinct traits by a

mutation in a single gene (e.g. decapentaplegic inDrosophila)

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Pleiotropy in Sickle Cell Anemia

Sickle cell anemia is an autosomal recessive conditioncaused by a mutation in the -globin gene

Many red blood cells of people with sickle cell anemia take

on a sickle shape and cause numerous physical problemsand complications

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4.3 Genetic interactions alter Mendelian ratios

Single-gene trait describes an inherited variation of a genethat can produce a mutant phenotype. However, this is not acomplete depiction of the underlying processes. Many geneswork together to build the complex structures and organsystems of plants and animals.

A genetic interaction occurs when the phenotype causedby a particular genotype of one locus is affected by thegenotype of another locus

e.g. Numerous genes contribute to the normal red eye colorof Drosophila , including those responsible for production ofeye pigments or transport proteins

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Three Genes Involved in Drosoph i l a Eye Color

The brown gene produces an enzyme in a pathway thatsynthesizes a bright red pigment; mutant flies, bb , have browneyes

The vermillion genes produces an enzyme in a pathway thatsynthesizes a brown pigment; mutant flies, vv , have bright redeyes

The white gene encodes a transporter that carries pigment tothe eye; flies that do not produce this protein have white eyes

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The One-Gene-One Enzyme Hypothesis

George Beadle and Edward Tatum were among the first toinvestigate biosynthetic pathways, and laid the groundwork forlater examination of genetic pathways

They studied growth variants of the fungus, Neurospora crassa

Their proposal, the one-gene-one enzyme hypothesis cameout of their experiments

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The Hypothesis Made a Connection BetweenGenes, Proteins and Phenotypes

Each gene produces an enzyme and that each enzyme has aspecific role in a biosynthetic pathway that produces thephenotype

Each mutant phenotype was attributable to the loss ormalfunction of a specific enzyme

Each enzyme defect was inherited at a single-gene defect

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More Recent Adjustments to the Hypothesis

Some protein producing genes produce transport proteins,structural or regulatory proteins, rather than enzymes

Some genes produce RNAs rather than proteins

Some proteins (e.g. -globin) must join with other proteins toacquire a function

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Genetic Dissection to Investigate Gene Action

Biosynthetic pathways consist of sequential steps

Completion of one step generates the substrate for the nextstep in the pathway

Completion of every step is necessary to produce the endproduct

Genetic dissection is an experimental approach taken toinvestigate the steps of biosynthetic pathways

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Horowitzs Experiments on Met - Mutants ofNeurospora

Horowitzs analysis aimed to:

Determine the number of intermediate steps in themethionine synthesis pathway

Determine the order of the steps

Identify the step affected by each mutation

l f i i

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Results of Horowitzs Experiments

Whether or not a mutant strain grows on a medium containinga component of the pathway allows determination of the step atwhich the mutant is blocked

Mutants blocked at a step after the intermediate still cannotgrow

Mutants blocked at a step before the intermediate will grow

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E i i i i

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Epistatic interactions

A minimum of two genes are required for epistaticinteractions; by definition, these participate in the samegenetic pathway

Epistasis is readily detected among progeny of dihybrid crosses

There are six ways epistasis could alter the predicted 9:3:3:1dihybrid ratio

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Complementary Gene Interaction (9:7 Ratio)

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Complementary Gene Interaction (9:7 Ratio)

Bateson and Punnett crossed two pure-breedingstrains of white flowered sweet peas

They found all the F1 were purple flowered; the F1 xF1 cross yielded 9/16 purple and 7/16 white floweredprogeny

They recognized that the two genes interact toproduce the overall flower color; when genes work intandem to produce a single gene product, it is calledcomplementary gene interaction

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Duplicate Gene Action (15:1 Ratio)

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Duplicate Gene Action (15:1 Ratio)

Two genes that duplicate each others activityconstitute a redundant system in which a dominantallele at either locus gives rise to a wild typephenotype

The genes in a redundant system have duplicategene action ; they encode the same product, or theyencode products that have the same effect in apathway or compensatory pathways

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Dominant Epistasis (12:3:1 Ratio)

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Dominant Epistasis (12:3:1 Ratio)

In dominant epistasis , a dominant allele at one locuswill mask the phenotypic expression of the alleles at asecond locus, giving a 12:3:1 ratio

E.g. in foxglove flowers a dominant allele at one locusrestricts the deposition of pigment to a small area ofthe flower

This allele masks the affect of the genotype at asecond locus that is responsible for producing thepigment for flower color

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Dominant Suppression (13:3 Ratio)

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Dominant Suppression (13:3 Ratio)

In dominant suppression , a dominant allele at onelocus completely suppresses the phenotypicexpression of the alleles at a second locus, giving a13:3 ratio

In chickens, the C allele is responsible for pigmentedfeathers and the c allele for white feathers

The dominant allele of a second gene, I, can suppressthe color producing effect of the C allele, leading towhite feathers in both C/- and c/c individuals

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4.4 Complementation Analysis

When geneticists encounter organisms with thesame mutant phenotype, they ask two questions:

Do these organisms have mutations in the same or in

different genes?

How many genes are responsible for the phenotypesobserved?

Genetic Complementation

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Genetic Complementation

Genetic heterogeneity is when mutations indifferent genes can produce the same or verysimilar mutant phenotypes

Mating of two organisms with similar recessivemutant phenotypes can lead to wild-type offspring, aphenomenon called genetic complementation

Complementation occurs when the mutations in theparents affect different genes

Complementation Testing

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Complementation Testing

Complementation testing is performed to determineif two mutant strains result from mutations of thesame gene (allelic) or different genes (non-allelic).involves mating two individuals with similarrecessive mutant phenotypes

If wild-type offspring are obtained, the mutations areinferred to affect two different genes

If mutant offspring are obtained, the mutations areknown to affect the same gene

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Complementation Analysis

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Complementation Analysis

In complementation analysis multiple crosses areperformed among numerous pure breeding mutantsto try to determine how many different genescontribute to a phenotype

Mutations that mutually fail to complement oneanother are called a complementation group

A complementation group in this context refers to agene

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