Download Association Studies with Haplotype Information

Methods of Genome Mapping
linkage maps, physical maps,
QTL analysis
The focus of the course should be on
analytical (bioinformatic) tools for genome
mapping, i.e., relevant background from
(a) statistics,
(b) appl. math.
(c) software
A few elementary genetic and molecular-genetic notions
(subjects) you are supposed to know
General Genetics: meiosis, syngamy, gamete, zygote, DNA, genome,
nucleus, chromosome, centromere, bivalent, hybrid, homozygote, F1, F2,
heterozygote, inbred, haploid, diploid, mutant, gene, allele, locus, phenotype,
Mendelian segregation (single-, two-, multilocus), dominant, co-dominant,
recessive, additive, linkage, recombination, epistasis, quantitative variation,
heritability, test-cross, backcross, intercross, linkage phase (coupling,
repulsion), multiple crossovers, interference, polymorphism, linkage
disequilibrium, haplotype
Molecular Genetics: restriction fragment, DNA hybridization, Southern
blot analysis, PCR, tandem repeats, microsatellite, SNP, DNA cloning,
BAC-clone, genomic library, DNA fingerprinting, overlapping clones,
contig, radiation hybrid, candidate gene, microarray
Mendelian (qualitative) vs qualitative traits
Simple Mendelian traits - discrete (discontinuous) traits • One gene = one trait
• Finite number of genotypes
• One gene = 3 genotypes = 2 or 3 phenotypes
(folding hands, blood type, fruit color, wing shape)
Complex non-Mendelian traits – continuous distribution
• Quantitative or continuous traits - controlled by several loci
Each quantitative trait locus (QTL) contributes to phenotype
QTL(s) + Environment (e.g., climate) + Culture = Phenotype
A fundamental question: Do QTLs represent the same
Mendelian genes, or these are a specific class of elements ?
Complexity of segregation of quantitative traits
Distribution of “tolerance traits” of F4 means
in a cross of mesic  xeric ecotypes of wild barley
(the transgressive segregation is noteworthy)
45
10-30
35
35
30
30
25
20
15
10
25
20
15
10
5
0
33,0
5
35,8
38,6
41,4
44,2
47,0
49,8
52,6
0
0,36
55,4
0,40
0,44
0,48
R WC (%)
0,56
0,60
0,64
0,68
40
40
10-30
35
35
23-38
10-30
23-38
30
30
25
25
No of obs
No of obs
0,52
R TH (mm)
45
20
15
20
15
10
10
5
5
0
0,40
10-30
23-38
40
No of obs
No of obs
45
23-38
40
0,69
0,98
1,27
1,56
1,85
SEN (deg ree)
2,14
2,43
0
6,0
6,2
6,4
6,6
6,8
7,0
WT (day)
7,2
7,4
7,6
7,8
Phenotypic distribution of quantitative traits
(A) single genetic locus
+ non genetic factors
1:2:1
(B) two and more unlinked genetic loci
2 loci
4 loci
many loci
Genetic Architecture of Quantitative Traits
and properties of QTL
 Multiple loci & alleles, variable individual effects
 Variable intralocus relationships (additive, dominant, heterotic)
 Epistatic interactions
 Pleiotropy
 Environmental & developmental effects, canalization
An old discussion: What is the nature of QTLs ?
 Mendelian genes, but with smaller individual effects
 Specific modifiers, e.g., changes in the promoter regions
 Infinitesemal model (diffused effects of chromosomal
regions, rather than a set of Mendelian loci)
Mendelian vs Biometrical schools in Quantitative Genetics
Genetic dissection of complex traits
genotype
development
environment
phenotype + markers
observations (data)
“explaining”
the phenotype
QTL analysis
Applications
QTL of economic or medical importance
Fitness-related QTL
Gene expression as molecular phenotype
Genetics
Statistics
Comp. Sci.
Appl. Math.
Complex traits as applied to human/medical genetics
• Multi-factorial, due to genetic and environmental precursors
– migraine, cancer, hypertension
• Difficult to study  many influences
• Do not exhibit “classic” Mendelian segregation
• No distinct relationship between genotype and phenotype
• Difficult to find a marker co-segregating with a complex trait
• Low penetrance (of individuals exhibiting phenotypic
characteristics of a genotype for a trait) – missing heritability
• Phenocopy (environmentally induced phenotype that resembles
the phenotype produced by a mutation – epigenetics)
Quantitative Genetics:
Mendelian vs Biometrical
Marker analysis
Payne, 1918
Sax, 1923
Marker-trait
association
vs
Variance components
Fisher, 1918
Lush, 1949
Broad- & narrow-sense
heritabilities
Strategies for finding QTLs
1. Genome mapping (family-based linkage analysis)
2. Local analysis (population-based mapping association analysis, LD analysis)
3. Candidate gene approach (guess-based analysis)
QTL mapping
• QTL detection
– check if QTL is present
• QTL location
– determine the position of the QTL on the chromosome
• QTL effect
– estimate the allelic effect or trait variance due to QTL
• Diagnostics (risk factors in human genetics)
• Marker assisted breeding
• Positional cloning
Molecular Strategies for QTL detection
Identify QTL based on association of trait phenotype
with alleles at marker loci (anonymous or gene-based)
• Required components:
- Molecular genetics - identification and mapping
of genes and of genetic markers
- Suitable resource (mapping) populations, molecular markers
- Statistics – tools for detection and estimation of associations
of identified genes or markers with economic traits

 

markers
    

traits x,y,z, …

Analysis of the genetic composition of
segregating recombinant genotypes
AB
generations of selfing (RIL)
generations of intercross (IRL)
individual recombinant chromosomes
Segments
from
Parent A
:
Segments
from
Parent B
Examination of the effect of a genetic segments
(with different alleles) on a trait
genotypes:
1 2 3 4 5 6 7 8 ....
1 2 3 4 5 6 7 8 ......
Chromosome
Large values
?
Small values
Population structure at QTL
The population content
at a quantitative trait locus
(backcross, RIL, DH).
Can be deduced by observation
of marker groups. In the figure,
the observation using a marker
coinciding with QTL.
A B CD E Q F G H
a b
c d e q f g h
d