BG24 Flashcards

1
Q

what is GWAS

A
  • large populations
  • identify cases with phenotype and controls without
  • genotype all subjects with a high density panel of SNPs
  • determine association
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2
Q

What is the odds ratio

- underlying probabilities

A

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
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3
Q

what are the odds of SNPa occuring in the phenotypic cases and in the control cases

A
Ocase =  Pcont/1-Pcont
Ocont = Pcont/1-Pcont
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4
Q

what is the odds ratio

A

OR = Pcase/1-Pcase/Pcont/1-Pcont

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5
Q

if
OR = 1
OR > 1
OR <1

A

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

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6
Q

GIANT consortium

A
17k individuals
500 markerss
OR = 1.2-1.5
found 24 new genes for diseases 
such as crohns and hypertension
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7
Q

Human height, the history of genetic association

A

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.

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8
Q

pathways or genes associated with humans height

A
  1. hypothalamus piturity growth axis = systemic growth reg in mammals
    - dwarfs and giants due to abnormal signalling here
  2. endochondral bone: many genes picked up giants are expessed in chondrocytes or MSCs, QTLS associated with signalling pathways that regualte chondrocyte proliferation
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9
Q

endochondral bones, growth and regulation

A
  • 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
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10
Q

Diseases cinvolved in height mutations

A
  1. achondroplasia - dom gain of function FGFR3 - regs chondrocyte proliferation = heterozygous
  2. Thantophoric dysplasia = homozygous - severe skeletal disorder
  3. Bloomstrand chondroplasia - short limbs, enlarged skull = recessive loss of function in parathyroid related peptide.
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11
Q

cline in height

A

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

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12
Q

Drosophila selection for fly size experiment

A
  1. start with outbred population of 1800 flies
  2. use sieves select for body size for 100 generations
  3. make 2 large, 2 small, 2 control pops
  4. pool 75 females from each population and resequence
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13
Q

candidate genes in drosophila

A

several IGF like ILS pathways are candidate for drosophila size

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14
Q

potential ILS involved in drosophila size

A
  1. IGF ligand
  2. IGF-R RTK
  3. chico-vertebrate IRS-4 homolog - insulin receptor suubstrate.
  4. TOR: target of rapomycin, ser/thr kinase - regs cell growth, proliferation, survival, protein synthesis and transcription.
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15
Q

results of drosophila fly experiment

A

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

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16
Q

Stickleback shape in marine and freshwater

A

G. aculetus freshwater and marine sticklebacks differ in pelvic morphollogy and body shape as well as other traits

17
Q

Classifiying stickleback genes method

A

sequenced and made a self-organising map (multivariate classification method) used to classify 2.5kb sliding window genomic regions.

18
Q

results of classifying stickleback genes

A
  • 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
19
Q

Genomic regions associated with freshwater vs marine

A

regions pull out and examined

  1. ectyodysplasin - Eda locus previously identified in being important for scale armour (strong marine, weak in freshwater)
  2. inversions identified
  3. 41% of the seqyence split between marine and freshwater are cis acting reg ** function unknown
20
Q

Identifying numerous adaptation genes in a single population

A
  1. start with variation in a single population (e.g europeans for heigh).
  2. QTL/GWAS
  3. Estimate % hertibaility
  4. Bioinformatics, expression databases, candidate pathways and gene ontology
21
Q

identifying numerous adaptation genes in divergent populations

A
  1. start with divergent populations
  2. resequence
  3. pull out regions with divergent allelic frequencies
  4. bioinformatics, expression databases, candidate pathways and gene ontology.
22
Q

what are the problems with the methods for identifying numerous and adaptation genes in divergent and single populations

A

although this is a search for unbiased loci

rescue of trait cant be applied which is gold standard.