Chapter 3:

Transmission genetics:The principle of segregation

Overview

Mendel’s lawsSegregation of a single geneSegregation of a single geneSegregation of two or multiple genes

H di l iHuman pedigree analysisProbability in genetic analysisy g yMonogenic and oligogenic inheritance

Overview

Mendel’s lawsSegregation of a single geneSegregation of a single geneSegregation of two or multiple genes

H di l iHuman pedigree analysisProbability in genetic analysisy g yMonogenic and oligogenic inheritance

Mendel’s lawsSegregation of a single gene

Experimental designObservation: phenotypic ratios in F2’sObservation: phenotypic ratios in F2 sMendel’s “gene” modelTesting the model: F3 & testcrossEquivalence of reciprocal crossesEquivalence of reciprocal crossesMorphological versus molecular h tphenotypes

Experimental designp gPea cultivation

Experimental designp gPure lines

Experimental designp gSelfing vs outcrossing

Mendel’s lawsSegregation of a single gene

Experimental designObservation: phenotypic ratios in F2’sObservation: phenotypic ratios in F2 sMendel’s “gene” modelTesting the model: F3 & testcrossEquivalence of reciprocal crossesEquivalence of reciprocal crossesMorphological versus molecular h tphenotypes

ObservationsPhenotypic ratio in F2’s

Mendel’s lawsSegregation of a single gene

Experimental designObservation: phenotypic ratios in F2’sObservation: phenotypic ratios in F2 sMendel’s “gene” modelTesting the model: F3 & testcrossEquivalence of reciprocal crossesEquivalence of reciprocal crossesMorphological versus molecular h tphenotypes

Mendel’s modelSegregation of gene particules

Mendel’s lawsSegregation of a single gene

Experimental designObservation: phenotypic ratios in F2’sObservation: phenotypic ratios in F2 sMendel’s “gene” modelTesting the model: F3 & testcrossEquivalence of reciprocal crossesEquivalence of reciprocal crossesMorphological versus molecular h tphenotypes

Testing the modelgF3

Testing the modelgTestcross

Testing the modelgTestcross

Mendel’s lawsSegregation of a single gene

Experimental designObservation: phenotypic ratios in F2’sObservation: phenotypic ratios in F2 sMendel’s “gene” modelTesting the model: F3 & testcrossEquivalence of reciprocal crossesEquivalence of reciprocal crossesMorphological versus molecular h tphenotypes

Equivalence of reciprocal q pcrosses

Mendel’s lawsSegregation of a single gene

Experimental designObservation: phenotypic ratios in F2’sObservation: phenotypic ratios in F2 sMendel’s “gene” modelTesting the model: F3 & testcrossEquivalence of reciprocal crossesEquivalence of reciprocal crossesMorphological versus molecular h tphenotypes

Molecular versus morphological p ggenotypes

Molecular versus morphological p ggenotypes

Overview

Mendel’s lawsSegregation of a single geneSegregation of a single geneSegregation of two or multiple genes

H di l iHuman pedigree analysisProbability in genetic analysisy g yMonogenic and oligogenic inheritance

Mendel’s lawsSegregation of 2 or more genes

Observation: independent phenotypic assortmentassortmentMendel’s model: independent seg egationsegregationTesting the modelThree or more genes

Observation: independent pphenotypic assortment

Mendel’s modelindependent segregation

Mendel’s modelindependent segregation

Testing the modelgtestcross

Three or more genes Overview

Mendel’s lawsSegregation of a single geneSegregation of a single geneSegregation of two or multiple genes

H di l iHuman pedigree analysisProbability in genetic analysisy g yMonogenic and oligogenic inheritance

Human & animal pedigree analysis

Drawing pedigreesCharacteristics of dominant and Characteristics of dominant and recessive inheritanceMost human genetic variation is not “bad”

Drawing pedigrees

Dominant in heritance Dominant inheritance

Males and females are equally affectedaffectedAffected have one affected parent, eq all likel to be fathe o mothe equally likely to be father or mother (! neomutations) On average, half the offspring of an affected parent are affectedp

Recessive inheritance Recessive inheritanceMales and females are equally likely to be affectedAffected individuals, if fertile, usually have no affected offspringMost affected individuals have unaffected parentsh f ff d d d l fThe parents of affected individuals are often

related (consanguinous matings or inbreeding)A t ibli f ff t d i di id l th Amongst siblings of affected individuals, the proportion of affected is ∼ ¼.

Most human genetic variation is gnot “bad”

DNA sequence polymorphisms segregate according to Mendel’s lawsMost polymorphisms are “neutral” …… but, phenotypes that segregate according to Mendel’s laws are primarily:

Humans: inherited defectsD ti i lDomestic animals:

Inherited defectsSelected “attributes”: e.g. coat color, horns …g ,

Mendelian segregation of a g gVNTR

Most human genetic variation is gnot “bad”

DNA sequence polymorphisms segregate according to Mendel’s lawsMost polymorphisms are “neutral” …… but, phenotypes that segregate according to Mendel’s laws are primarily:

Humans: inherited defectsD ti i lDomestic animals:

Inherited defectsSelected “attributes”: e.g. coat color, horns …g ,

Overview

Mendel’s lawsSegregation of a single geneSegregation of a single geneSegregation of two or multiple genes

H di l iHuman pedigree analysisProbability in genetic analysisy g yMonogenic and oligogenic inheritance

Probability in genetic analysis

DefinitionsProbability of the union of eventsProbability of the union of eventsProbability of the intersection of eventsConditional probability and Bayes p y ytheorem

Probability in genetic analysisy g yDefinitions

Elementary outcomeProbability of elementary outcomesProbability of elementary outcomesSample space

E tEventProbability of an event

Elementary outcomes and ysample space Event

EventProbability in genetic analysisy g yUnion of events

Probability in genetic analysisy g yUnion of events

{ } { } { } { }ABPBPAPBAP +=+{ } { } { } { }ABPBPAPBAP −+=+

Probability in genetic analysisy g yIntersection of events

Probability in genetic analysisy g yIntersection of events

{ } { } { }BPAPABP ={ } { } { }BPAPABP =

Conditional probability and p yBayes theorem

{ } { }{ }ABPBAP =|{ } { }BP

|

{ } { }{ } { }'|

AAABPBAP ={ } { } { }'|

BAPBAP +

{ } { } { }{ } { } { } { }

|| ABPAPBAP ={ } { } { } { } { }'|'||

ABPAPABPAP +

Overview

Mendel’s lawsSegregation of a single geneSegregation of a single geneSegregation of two or multiple genes

H di l iHuman pedigree analysisProbability in genetic analysisy g yMonogenic and oligogenic inheritance: complications to Mendel’s inheritance: complications to Mendel s rules

Complications to Mendel’s rules

Monogenic inheritanceBinary traits: altered Mendelian Binary traits: altered Mendelian proportions

Incomplete penetranceIncomplete penetranceLethal alleles

Multiple phenotypic classesMultiple phenotypic classesCodominance and incomplete dominanceAllelic seriesAllelic seriesVariable expressivity

Alterered Mendelian proport.:p pIncomplete penetrance

Alterered Mendelian proport.: p pLethal alleles

Complications to Mendel’s rules

Monogenic inheritanceBinary traits: altered Mendelian Binary traits: altered Mendelian proportions

Incomplete penetranceIncomplete penetranceLethal alleles

Multiple phenotypic classesMultiple phenotypic classesCodominance and incomplete dominanceAllelic seriesAllelic seriesVariable expressivity

Multiple phenotypic classesp p ypCo- and incomplete dominance

Multiple phenotypic classesp p ypAllelic series: blood groups

Multiple phenotypic classesp p ypAllelic series: blood groups

Multiple phenotypic classesp p ypAllelic series: C gene

Multiple phenotypic classesp p ypVariable expressivity

Syndactyly

Complications to Mendel’s rules

Oligogenic inheritanceTwo phenotypesTwo phenotypes

Locus heterogeneity – complementationSuppressionSuppressionDuplicate genes

Three phenotypesThree phenotypesEpistasis

Four phenotypesFour phenotypesModifier genes

Two phenotypes: locus p ypheterogeneity – complementation

Two phenotypes: locus p ypheterogeneity – complementation

Two phenotypesp ypSuppression

Two phenotypesp ypDuplicate genes

Three phenotypes: p yprecessive epistasis

Three phenotypes: p yprecessive epistasis

Three phenotypes: p ypdominant epistasis

Three phenotypes:Four phenotypes: p ypmodifier genes.

Four phenotypes: p ypmodifier genes.