what is GWAS
- large populations
- identify cases with phenotype and controls without
- genotype all subjects with a high density panel of SNPs
- determine association
What is the odds ratio
- underlying probabilities
the association between an SNP and the phenotype = odds ratio.
- get odds for each SNP that it will appear in each group (O)
- P case = probability of SNPa occuring in these phenotype cases
- Pcont = probability of SNPa occuring in the controls
what are the odds of SNPa occuring in the phenotypic cases and in the control cases
Ocase = Pcont/1-Pcont Ocont = Pcont/1-Pcont
what is the odds ratio
OR = Pcase/1-Pcase/Pcont/1-Pcont
if
OR = 1
OR > 1
OR <1
OR = 1 SNP is equally likely to occur in case as controls
OR > 1 SNP is more likely to occur in cases than in controls
OR <1 SNP is less likely to occur in cases than controls
GIANT consortium
17k individuals 500 markerss OR = 1.2-1.5 found 24 new genes for diseases such as crohns and hypertension
Human height, the history of genetic association
2008: major studies identified 44 associated QTLs (found most chromosomes contain height associated QTLs)
2010: meta-analysis GWAS of european height by GIANT consortium accounting for 12% of the heritability of human height (180 subjects, 180 height QTLS)
2014: meta-analysis GWAS european height = 250k people, 700 SNPs, 400 height QTLs, 60% of heritbiality in height accounted for.
pathways or genes associated with humans height
- hypothalamus piturity growth axis = systemic growth reg in mammals
- dwarfs and giants due to abnormal signalling here - endochondral bone: many genes picked up giants are expessed in chondrocytes or MSCs, QTLS associated with signalling pathways that regualte chondrocyte proliferation
endochondral bones, growth and regulation
- formed by condensations of chondrocytes
- BMPs reg. chondrogenesis
(ectopic expression of BMP causes extra bone = FOP occurs due to gain of function bmp. - endochondral bone growth occurs around the growth plate - region of cell proliferation and hypertrophy
Diseases cinvolved in height mutations
- achondroplasia - dom gain of function FGFR3 - regs chondrocyte proliferation = heterozygous
- Thantophoric dysplasia = homozygous - severe skeletal disorder
- Bloomstrand chondroplasia - short limbs, enlarged skull = recessive loss of function in parathyroid related peptide.
cline in height
north south cline in height
height alleles differ in freq between northern and southern europe.
- too large drift to be due to drigt alone - weak selection rather than drift
Drosophila selection for fly size experiment
- start with outbred population of 1800 flies
- use sieves select for body size for 100 generations
- make 2 large, 2 small, 2 control pops
- pool 75 females from each population and resequence
candidate genes in drosophila
several IGF like ILS pathways are candidate for drosophila size
potential ILS involved in drosophila size
- IGF ligand
- IGF-R RTK
- chico-vertebrate IRS-4 homolog - insulin receptor suubstrate.
- TOR: target of rapomycin, ser/thr kinase - regs cell growth, proliferation, survival, protein synthesis and transcription.
results of drosophila fly experiment
41k SNPs differ between each pair of large and small lines
5.6k that differ are >95% in freq
1.2k distinct regions that differ in freq.
Only TOR ILS is thought to be important
Stickleback shape in marine and freshwater
G. aculetus freshwater and marine sticklebacks differ in pelvic morphollogy and body shape as well as other traits
Classifiying stickleback genes method
sequenced and made a self-organising map (multivariate classification method) used to classify 2.5kb sliding window genomic regions.
results of classifying stickleback genes
- most genomic regions group together by geography
- seperate e.g. scottish from british columbian sticklebacs
- some group fw vs marine.
- – these genomic regions are presumably invovled in adaptation to freshwater in particular shape changes that occured in evolution to fresh water
Genomic regions associated with freshwater vs marine
regions pull out and examined
- ectyodysplasin - Eda locus previously identified in being important for scale armour (strong marine, weak in freshwater)
- inversions identified
- 41% of the seqyence split between marine and freshwater are cis acting reg ** function unknown
Identifying numerous adaptation genes in a single population
- start with variation in a single population (e.g europeans for heigh).
- QTL/GWAS
- Estimate % hertibaility
- Bioinformatics, expression databases, candidate pathways and gene ontology
identifying numerous adaptation genes in divergent populations
- start with divergent populations
- resequence
- pull out regions with divergent allelic frequencies
- bioinformatics, expression databases, candidate pathways and gene ontology.
what are the problems with the methods for identifying numerous and adaptation genes in divergent and single populations
although this is a search for unbiased loci
rescue of trait cant be applied which is gold standard.
