3/1/10 1 Introductory genetics for veterinary students Michel Georges Introduction
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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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