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What is the genetic basis of complex traits?
One of the most enduring problems
in evolution and molecular biology
CH927 Quantitative Genomics
What is the genetic basis of complex traits?
- Lecture 1 (Mon 9:30-10:30): markers, maps
- Lecture 2 (Mon 11:00-12:00): QTL methods
- Wet-bench practical (Mon 13:15-16:15): data for QTL mapping
** bus leaves to go to Warwick HRI at 12pm **
- Lecture 3 (Tues 9:30-10:30): Alternative methods: association mapping
- Lecture 4 (Tues 10:45-11:45): eQTL mapping
- Workshop (Tues 14:00-17:00): eQTL analysis using R-QTL
- Many sequenced genomes
- Huge cost!
- But still not easy to identify the right genes
Genetics: the study of inheritance and its variations
Gene: the segment of DNA involved in producing a protein
Locus: a region of the genome, commonly a gene
Some definitions in molecular genetics
DNA promoter exon intron exon intron exon DNA
Chromosome: A linear end-to-end arrangement of genes and other DNA,
sometimes with associated protein and RNA
Genome: the entire complement of genetic material in an organism
Diploid : pair of chromosomes from cross- pollination Duplication of the chromosomes We can use this property to localise the parts of chromosomes involved in a trait
Also during meiosis: crossing over occurs
Crossing-over Separation of chromosomes at end of meiosis
Quantitative vs. Qualitative traits
- Qualitative traits follow ‘Mendelian’ inheritance
- Can predict the phenotype from the alleles carried
- Recessive allele: phenotypic effect is expressed in homozyous state but masked in heterozygous (Blue eyes in bb only)
- Dominant allele: same phenotypic character when heterozygous or homozygous (Brown eyes: Bb bB BB) e.g. A locus for eye colour with 2 alleles, B and b
- four possible combinations: BB Bb bB bb
Quantitative trait characteristics
- ‘Infinitesimal model’: genetic variation in a trait due to a large number
of loci, each of small effect
- Many genotypes can produce the same phenotype
- Quantitative traits often vary along a continuous gradient
e.g. height, skin colour
diseases such as cancer
disorders such as epilepsy
non-Mendelian inheritance
What is the genetic basis of complex traits?
- Complexity of these traits, esp. those involved in adaptation
probably arises from segregation of alleles at many interacting loci
= Quantitative Trait Loci (QTL)
- Combination of molecular genetics and statistical techniques
are needed to identify where these QTLs are located
- QTL effects are sensitive to the environment
By the end of this lecture you should be able to explain:
- Quantitative genetics: homozygotes, heterozygotes and inheritance
- The basis and features of quantitative vs. qualitative traits
- Why genetic markers are needed for QTL mapping
- How genetic maps are created Lecture objectives
Objectives of QTL analysis
- The statistical study of the alleles that occur in a locus and the phenotypes (traits) that they produce
- Methods developed in the 1980s, perform on inbred strains of any species
- Score a population for (i) a trait, and (ii) distribution of genome markers
- Associate occurence of a marker with the phenotype
F1 = Heterozygous at all loci
(i) A large population of mapping Recombinant Inbred Lines
A x B
F2 = Heterozygous at some loci Parents = Homozygous crossing-over (recombination) x F7 RILs = Homozygous at all loci & heterogeneous x Many different individuals are obtained & separately selfed to develop RILs
- Visible phenotypes or molecular markers (DNA sequence differences) (ii) Markers to enable identification of which parental genome each part of the chromosomes of the progeny have come from parent A parent B parent A parent B
Markers differ between parents (natural variants)
Parent A Chr 1 Parent B Chr 1
Different species variants
single nucleotide polymorphisms
GAATTC GA T TTC
(iv) You can distinguish these sequence differences using molecular techniques = molecular markers
- Restriction enzymes e.g. EcoRI cut DNA
only at a specific recognition sequence
- Compare restriction patterns: Parent A (^) Parent B ........GAATTC.......GAATTC.......GAATTC....... ........GAATTC.......GATTTC.......GAATTC....... ........GAATTC.......GAATTC.......GAATTC....... ........GAATTC.......GATTTC.......GAATTC....... Second generation (F2) from selfing F1: First generation (F1)