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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
  1. Score a population for (i) a trait, and (ii) distribution of genome markers
  2. 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)