Introductory genetics for veterinary students · Benefits of sex ? Merging of beneficial mutations...

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Introductory genetics for veterinary students

Michel Georges

Introduction

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References

Genetics – Analysis of Genes and Genomes – 7th edition. Hartl & Jones

Molecular Biology of the Cell – 5th edition. Alberts et al.

Table of contents

Genes in cells

Genes in pedigrees

Genes in populations

Evolutionary genetics

Genome analysis

Veterinary genetics

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Genes in pedigrees

Haploid gametes are produced by meiosis

Sexual vs asexual reproduction

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Haploid and diploid cells in the life cycle

The immortal germ line

Meiosis: “1S + 2M”

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Meiosis: “1S + 2M”

Meiosis: “1S +2M”

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Prophase I

Prophase I: bivalent formation a role for telomeres?

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Prophase I: bivalent formation recombination

Prophase I: bivalent formation Holiday junction

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Prophase I: bivalent formation cross-over vs gene conversion

Prophase I: bivalent formation cross-over vs gene conversion

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Prophase I: Bivalent formation Synaptonemal complex

Prophase I: bivalent formation Chiasmata

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Metaphase, anaphase, telophase I

Oogenesis

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Oogenesis

Spermatogenesis

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Spermatogenesis

Functional diploidy of spermatides

Benefits of sex ?

Merging of beneficial mutations that appeared in distinct lineages

Purging deleterious mutations

Creation of genetic variation

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Creation of genetic variation

Mendel genetically inferred the key properties of meiosis

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Experimental design Pure lines

Experimental design Selfing vs outcrossing

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Observations Phenotypic ratio in F1’s & F2’s

Mendel’s model Segregation of gene particules

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Testing the model F3

Testing the model Testcross

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Testing the model Testcross

Observation: independent phenotypic assortment

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Mendel’s model independent segregation

Mendel’s model independent segregation

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Testing the model testcross

Genes in pedigrees

Haploid gametes are produced by meiosis

Chromosomal sex determination: the gonosomes

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Homogametic vs heterogametic sex: X-Y or Z-W

The sex chromosomes: sex specific regions, PARs & PABs

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Evolution of the sex chromosomes

Dosage compensation: X-inactivation + increased expr.

Barr body

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Influence of Sry on gonad determination

Genes in pedigrees

Haploid gametes are produced by meiosis

Chromosomal sex determination: the gonosomes

Single Nucleotide Polymorphisms (SNPs)

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SNPs: nucleotide diversity, MAF & haplotypes

Nucleotide diversity ( ) 1/1,000 (=> millions)

Minor Allele Frequency (MAF)

SNPs: nucleotide diversity, MAF & haplotypes

Haplotypes

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SNPs: types

Substitutions: Transitions: Py<->Py; Pu<->Pu

Transversions: Py<->Pu

1bp indels

SNPs: Molecular effects

The vast majority of SNPs have no effect => “neutral”

Protein variants (“cSNPs”)

Synonymous

Non-synonymous = missense

Nonsense

Frameshift

Splice site variants

Regulatory SNPs (rSNPs)

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Allelic series of cSNPs in MSTN gene causes double-muscling

SNPs: Molecular effects

The vast majority of SNPs have no effect => “neutral”

Protein variants (“cSNPs”)

Synonymous

Non-synonymous = missense

Nonsense

Frameshift

Splice site variants

Regulatory SNPs (rSNPs)

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Splice site variants

Splice site variant causes dwarfism in BBCB

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SNPs: Molecular effects

The vast majority of SNPs have no effect => “neutral”

Protein variants (“cSNPs”)

Synonymous

Non-synonymous = missense

Nonsense

Frameshift

Splice site variants

Regulatory SNPs (rSNPs)

An rSNPs in IGF2 contributes to the muscular hypertrophy of Piétrain pigs

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A rSNP in mSTN contributes to the muscular hypertrophy of Texel sheep

SNPs: phenotypic effects

Recessivity: Loss-of-function with haplosufficiency

Dominance:

Loss-of-function with haploinsufficiency

Dominant negative loss-of-function

Gain-of-function

Incomplete dominance & codominance

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Recessive: Loss-of-function, haplosufficiency

Dominant: Loss-of-function, haploinsufficiency

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Dominant: loss-of-function, dominant negative

Dominant: gain-of-function

1-antitrypsin deficiency, Pittsburgh allele (elastase -> thrombine)

Black coat color in cattle

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Incomplete dominance

(overdominance)

Codiminance

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Codominance

The Roan locus in BBCB: incomplete or co-dominance?

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Genes in pedigrees

Haploid gametes are produced by meiosis

Chromosomal sex determination: the gonosomes

Single Nucleotide Polymorphisms (SNPs) and their effects

Monogenic traits

Monogenic traits

Drawing pedigrees

Basic Mendelian inheritance patterns

Allelic heterogeneity

Multiple phenotypic classes Co/Incomplete dominance

Allelic series

Variable expressivity

Altered Mendelian proportions Incomplete penetrance

Lethal alleles

Pleiotropy

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Drawing pedigrees

Basic Mendelian inheritance patterns

Autosomal dominant

Autosomal recessive

X(Z)-linked dominant

X(Z)-linked recessive

Y-linked

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Autosomal dominant

Autosomal dominant

An affected individual usually has at least one affected parent Affects either sex Transmitted by either sex An offspring of an affected x unaffected mating has a 50% chance of being affected (this assumes that the affected individual is heterozygous, which is usually true for rare conditions)

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Autosomal dominant

Polled

Autosomal recessive

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Autosomal recessive

Affected individuals are usually born to unaffected parents Parents of affected individuals are usually asymptomatic carriers There is an increased incidence of parental consanguinity Affects either sex After the birth of an affected offspring, each subsequent full-sib has a 25% chance of being affected.

Autsomal recessive

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X(Z)linked dominant

X(Z)linked dominant

Affects either sex, but more females than males Females are often more mildly and more variably affected than males The offspring of an affected dam, regardless of its sex, has a 50% chance of being affected For an affected male, all his daughters but none of his sons are affected.

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X(Z)linked dominant Slow feathering

X(Z)linked recessive

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X(Z)linked recessive

Affects almost exclusively males Affected males are usually born to unaffected parents; the dam is normally an asymtomatic carrier and may have affected male relatives Females may be affected if the sire is affected and the dam is a carrier; or occasionally as a result of X inactivation There is no male-to-male transmission in the pedigree (but matings of an affected sire and carrier dam can give the appearance of male-to-male transmission)

Z-linked dwarfism in chicken

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Y(W)linked inheritance

Y(W)-linked inheritance

Affects only males Affected males always have an affected sire All sons of an affected sire are affected

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Y(W)-linked inheritance

Monogenic traits

Drawing pedigrees

Basic Mendelian inheritance patterns

Allelic heterogeneity

Multiple phenotypic classes Co/Incomplete dominance

Allelic series

Variable expressivity

Altered Mendelian proportions Incomplete penetrance

Lethal alleles

Pleiotropy

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Distinct mutations in the same gene may cause the same phenotype

Distinct mutations in the same gene may cause different phenotypes

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Monogenic traits

Drawing pedigrees

Basic Mendelian inheritance patterns

Allelic heterogeneity

Multiple phenotypic classes Co/Incomplete dominance

Allelic series

Variable expressivity

Altered Mendelian proportions Incomplete penetrance

Lethal alleles

Pleiotropy

Multiple phenotypic classes: Co- / incomplete dominance

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Multiple phenotypic classes: Allelic series

Multiple phenotypic classes: Variable expressivity

Piebald spotting

Mulefoot

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Monogenic traits

Drawing pedigrees

Basic Mendelian inheritance patterns

Allelic heterogeneity

Multiple phenotypic classes Co/Incomplete dominance

Allelic series

Variable expressivity

Altered Mendelian proportions Incomplete penetrance

Lethal alleles

Pleiotropy

Incomplete penetrance

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Lethal alleles

Monogenic traits

Drawing pedigrees

Basic Mendelian inheritance patterns

Allelic heterogeneity

Multiple phenotypic classes Co/Incomplete dominance

Allelic series

Variable expressivity

Altered Mendelian proportions Incomplete penetrance

Lethal alleles

Pleiotropy

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Pleiotropy

White Heifer Disease

Malignant hgyperthermia - PSS – PSE

Genes in pedigrees

Haploid gametes are produced by meiosis

Chromosomal sex determination: the gonosomes

Single Nucleotide Polymorphisms (SNPs) and their effects

Monogenic traits

Oligogenic traits

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Oligogenic traits

Two phenotypic classes Locus heterogeneity – complementation

Suppression

Duplicated genes

Three phenotypic classes: epistasis

Four phenotypic classes: modifier genes

Sex modified expression patterns

Rhesus haemolytic disease

Two phenotypes: locus heterogeneity – complementation

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Two phenotypes: locus heterogeneity – complementation

Two phenotypes Suppression

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Two phenotypes Duplicate genes

Three phenotypes: recessive epistasis

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Three phenotypes: recessive epistasis

Three phenotypes: dominant epistasis

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Three phenotypes: dominant epistasis

Three phenotypes:

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Four phenotypes: modifier genes.

Four phenotypes: modifier genes.

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Oligogenic traits

Two phenotypic classes Locus heterogeneity – complementation

Suppression

Duplicated genes

Three phenotypic classes: epistasis

Four phenotypic classes: modifier genes

Sex modified expression patterns

Rhesus haemolytic disease

Sex modified expression patterns – f.i. horns

The horned phenotype in sheep:

in Rambouillet and Merino breeds only the rams are horned, although the ewes can have small horn buds. When the Dorset Horns (ram and ewes horned) and the Suffolk (rams and ewes hornless) are crossed, the F1 ewes are hornless and the rams horned.

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Sex modified expression patterns – f.i. horns

Scurred (B. taurus)

African horns (B. indicus)

Oligogenic traits

Two phenotypic classes Locus heterogeneity – complementation

Suppression

Duplicated genes

Three phenotypic classes: epistasis

Four phenotypic classes: modifier genes

Sex modified expression patterns

Rhesus haemolytic disease

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Rhesus haemolytic disease

Genes in pedigrees

Haploid gametes are produced by meiosis

Chromosomal sex determination: the gonosomes

Single Nucleotide Polymorphisms (SNPs) and their effects

Monogenic traits

Oligogenic traits

Polygenic traits

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Polygenic traits

Quantitative traits

Discrete traits

Quantitative traits

… are characterized by a continuous often gaussian distribution

… are “complex”, i.e. influenced by genetics and environment

… are influenced by a large number of polygenes map at Quantitative Trait Loci (QTL)

… few QTL have large (sometimes major) effects, many have very small effects

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Gaussian distribution of height

Genes and environment

“Variance components”

Broad and narrow sense heritability

G2= A

2+ D

2+ I

2

H 2= G

2

P2 h2 = A

2

P2

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Estimating the heritability

Polygenes at QTL

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Many “minor”, few “major” polygenes

Discrete traits: Liability & threshold

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Discrete traits: Relative risk

Genes in pedigrees

Haploid gametes are produced by meiosis

Chromosomal sex determination: the gonosomes

Single Nucleotide Polymorphisms (SNPs) and their effects

Monogenic traits

Oligogenic traits

Polygenic traits

Genetic linkage

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Genetic linkage

Defining parental versus recombinant chromosomes within the context of Mendel’s 2nd law: interchromosomal recombination

Intrachromosomal recombination between syntenic loci crossing-over

Variation of %R with distance allows map construction

Using centimorgans rather than %R

Chromosome and chromatid interference

Linkage analysis plays a central role in genetics as a first step in genome characterization and for the positional cloning of “trait loci”

Mendel’s 2nd law

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Parental vs recombinant gametes: interchromosomal recombination

Genetic linkage

Defining parental versus recombinant chromosomes within the context of Mendel’s 2nd law: interchromosomal recombination

Intrachromosomal recombination between syntenic loci crossing-over

Variation of %R with distance allows map construction

Using centimorgans rather than %R

Chromosome and chromatid interference

Linkage analysis plays a central role in genetics as a first step in genome characterization and for the positional cloning of “trait loci”

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Syntenic loci: intrachromosomal recombination

Syntenic loci: intrachromosomal recombination

66.5% parentals

33.5% recombinants

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Intrachromosomal recombination results from crossing-over

Genetic linkage

Defining parental versus recombinant chromosomes within the context of Mendel’s 2nd law: interchromosomal recombination

Intrachromosomal recombination between syntenic loci crossing-over

Variation of %R with distance allows map construction

Using centimorgans rather than %R

Chromosome and chromatid interference

Linkage analysis plays a central role in genetics as a first step in genome characterization and for the positional cloning of “trait loci”

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Syntenic loci: intrachromosomal recombination

66.5% parentals

33.5% recombinants

Coupling versus repulsion of of syntenic alleles

Repulsion Coupling

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Coupling versus repulsion of of syntenic alleles

62.3% parentals

37.7% recombinants

Each pair of linked genes has a characteristic frequency of rec.

98.6% parentals

1.4% recombinants

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Building linkage maps Multiple two-point crosses

10.6%

14.7%

23.7 < 10.6 + 14.7%

Lz Su Gl

Building linkage maps Three-point crosses

Parental (most frequent) genotypes

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Building linkage maps Three-point crosses

Double recombinant (DR) (rarest) genotypes

Building linkage maps Three-point crosses

Identification of parental genotypes + double-recombinants unambiguously determines locus order => Lz-Su-Gl

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Building linkage maps Three-point crosses

Lz_Su_Gl

LzxSu_Gl

Lz_SuxGl

LzxSuxGl

LzxSuxGl

Lz_SuxGl

LzxSu_Gl

Lz_Su_Gl

Building linkage maps Three-point crosses

RFLzxSu = FLzxSu_Gl + FLzxSuxGl = 9.8+0.8 = 10.6

RFSuxGl = FLz_SuxGl + FLzxSuxGl = 13.9+0.8 = 14.7

RFLzxGl = FLz_SuxGl + FLzxSu_Gl = 9.8+13.9=23.7

RFLzxGl = RFLzxSu + RFSuxGl – 2xFLzxSuxGl

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Frequency of recombination versus map distance

Genetic linkage

Defining parental versus recombinant chromosomes within the context of Mendel’s 2nd law: interchromosomal recombination

Intrachromosomal recombination between syntenic loci crossing-over

Variation of %R with distance allows map construction

Using centimorgans rather than %R

Chromosome and chromatid interference

Linkage analysis plays a central role in genetics as a first step in genome characterization and for the positional cloning of “trait loci”

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Haldane’s mapping function

Haldane’s mapping function

0 crossing-over:

P0=e-m

Rec = 0%

1 crossing-over:

P1= m1e-m/1!

Rec = 50%

2 crossing-over:

P2 =

Rec = ?%

3 crossing-over:

…

…

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1 crossing-over => 50% recombinant gametes

Haldane’s mapping function

0 crossing-over:

P0=e-m

Rec = 0%

1 crossing-over:

P1= m1e-m/1!

Rec = 50%

2 crossing-over:

P2 = m2e-m/2!

Rec = ?%

3 crossing-over:

…

…

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2 crossing-over => 50% rec. gam. !!

Haldane’s mapping function

0 crossing-over:

P0=e-m

Rec = 0%

1 crossing-over:

P1= m1e-m/1!

Rec = 50%

2 crossing-over:

P2 = m2e-m/2!

Rec = 50%

3 crossing-over:

…

Rec = 50%

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Haldane’s mapping function

Haldane’s mapping function

=Haldane’s MF

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Haldane’s mapping function

Non-syntenic loci are characterized by a RF of 50%

Syntenic loci are characterized by a RF 50%

Genetic linkage

Defining parental versus recombinant chromosomes within the context of Mendel’s 2nd law: interchromosomal recombination

Intrachromosomal recombination between syntenic loci crossing-over

Variation of %R with distance allows map construction

Using centimorgans rather than %R

Chromosome and chromatid interference

Linkage analysis plays a central role in genetics as a first step in genome characterization and for the positional cloning of “trait loci”

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Chromosome interference

Lz_Su_Gl

LzxSu_Gl

Lz_SuxGl

LzxSuxGl

LzxSuxGl

Lz_SuxGl

LzxSu_Gl

Lz_Su_Gl

Chromosome interference

I(nterference) = 1 – coefficient of coincidence

Coefficient of coincidence = Observed DR / Expected DR

Observed DR = FLzxSuxGl

Expected DR = RFLzxSu x RFSuxGl

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Chromosome interference

Positive interference first crossing-over reduces probability to have a second one in the vicinity

=> fewer observed than expected DR

The rule in many genomes (at low resolution) => Kosambi’s mapping function

Negative interference First crossing-over increases probability to have second one in the vicinity

=> more observed than expected DR

Observed as a result of gene conversion at very high resolution

Kosambi’s mapping function

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Chromosome interference

Positive interference first crossing-over reduces probability to have a second one in the vicinity

=> fewer observed than expected DR

The rule in many genomes (at low resolution) => Kosambi’s mapping function

Negative interference First crossing-over increases probability to have second one in the vicinity

=> more observed than expected DR

Observed as a result of gene conversion at very high resolution

Chromatid interference

Positive: First crossing-over involving specific non-sister chromatids decreases probability for their involvement in second one

Would increase 4-strand DC

Would push FR > 50%

Never observed

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Genetic linkage

Defining parental versus recombinant chromosomes within the context of Mendel’s 2nd law: interchromosomal recombination

Intrachromosomal recombination between syntenic loci crossing-over

Variation of %R with distance allows map construction

Using centimorgans rather than %R

Chromosome and chromatid interference

Linkage analysis plays a central role in genetics as a first step in genome characterization and for the positional cloning of “trait loci”

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Genes in pedigrees

Haploid gametes are produced by meiosis

Chromosomal sex determination: the gonosomes

Single Nucleotide Polymorphisms (SNPs) and their effects

Monogenic traits

Oligogenic traits

Polygenic traits

Genetic linkage

Parent of origin effects

Parental imprinting

Ex.: IGF2 and IGF2R

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Prader-Willi syndrome (PWS) A

n im

po

rin

ted

QT

L w

ith

ma

jor

effe

ct

on

muscle

mass is d

ue t

o a

poin

t m

uta

tion

inactivating a

sile

ncer

ele

ment

of

IGF

2

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Polar overdominance at the ovine Callipyge locus

Mitochondrial inheritance

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Mitochondrial inheritance H

ete

ropla

sm

y

Genes in pedigrees

Haploid gametes are produced by meiosis

Chromosomal sex determination: the gonosomes

Single Nucleotide Polymorphisms (SNPs) and their effects

Monogenic traits

Oligogenic traits

Polygenic traits

Genetic linkage

Parent of origin effects

Chromosomal “polymorphism”

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Chromosomal “polymorphisms”

Structural variation

Deletions

CNVs

Tandem duplications

Duplicative transposition

Inversions

Reciprocal translocations

Aneuploidies

Monosomies

Trisomies

Aberrant euploidies

Parental origin changes

Mixoploidy

Deletions

Causes: Intrachromosomal recombination cause microdeletions

Repair of chromosome breaks cause macrodeletions

Chromosomal translocations

Consequences:

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Ectopic recombination between direct repeats

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Chromosomal “polymorphisms”

Structural variation

Deletions

CNVs

Tandem duplications

Duplicative transposition

Inversions

Reciprocal translocations

Aneuploidies

Monosomies

Trisomies

Aberrant euploidies

Parental origin changes

Mixoploidy

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Copy Number Variation

Tandem duplications & unequal crossing over

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Tandem duplications Red-green color blindness

Dominant white in the pig

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Duplicative transposition

Triplet repeat expansion

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Hannes Lohi

Chromosomal “polymorphisms”

Structural variation

Deletions

CNVs

Tandem duplications

Duplicative transposition

Inversions

Reciprocal translocations

Aneuploidies

Monosomies

Trisomies

Aberrant euploidies

Parental origin changes

Mixoploidy

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Inversions Causes

Chromosome breakage and inversion

Ectopic recombination between inverted repeats

Ectopic recombination between inverted repeats

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Inversion heterozygotes Inversion loops

Inversion heterozygotes No recombination

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Paracentric inversion heterozygotes: recombination

Cross-over suppressors

Pericentric inversion heterozygotes: recombination

Cross-over suppressors

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Chromosomal “polymorphisms”

Structural variation

Deletions

CNVs

Tandem duplications

Duplicative transposition

Inversions

Reciprocal translocations

Aneuploidies

Monosomies

Trisomies

Aberrant euploidies

Parental origin changes

Mixoploidy

Reciprocal translocations Definition

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Reciprocal translocations Causes

Chromosome breakage and translocation

Ectopic recombination

Reciprocal translocations Semisterility

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Reciprocal translocations Robertsonian translocations

Reciprocal translocations and trisomy 21

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Chromosomal “polymorphisms”

Structural variation

Deletions

CNVs

Tandem duplications

Duplicative transposition

Inversions

Reciprocal translocations

Aneuploidies

Monosomies

Trisomies

Aberrant euploidies

Parental origin changes

Mixoploidy

Down syndrome Symptoms

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Down syndrome Chromosomal non-disjunction

Non crossover bivalents

Down syndrome Effect of mother’s age

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Down syndrome Prenatal diagnosis

Down syndrome Trisomic segregation

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Sex chromosome abnormalities

Frequency

Trisomy X

Double Y

Klinefelter syndrome

Turner syndrome

Klinefelter syndrome

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Turner syndrome

Chromosomal “polymorphisms”

Structural variation

Deletions

CNVs

Tandem duplications

Duplicative transposition

Inversions

Reciprocal translocations

Aneuploidies

Monosomies

Trisomies

Aberrant euploidies

Parental origin changes

Mixoploidy

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Aberrant euploidies

Animals: Generally lethal

Somatic polyploidy

Evolution: Salmonids

Plants:

Autopolyploid

Allopolyploid

Autopolyploids and allopolyploids

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Autopolyploids and allopolyploids

Chromosomal “polymorphisms”

Structural variation

Deletions

CNVs

Tandem duplications

Duplicative transposition

Inversions

Reciprocal translocations

Aneuploidies

Monosomies

Trisomies

Aberrant euploidies

Parental origin changes

Mixoploidy

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Parental origin

Uniparental diploidy Hydatiform mole

Teratocarcinoma

Unparental disomy pUPD

mUPD

Chromosomal “polymorphisms”

Structural variation

Deletions

CNVs

Tandem duplications

Duplicative transposition

Inversions

Reciprocal translocations

Aneuploidies

Monosomies

Trisomies

Aberrant euploidies

Parental origin changes

Mixoploidy

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