Download Phenotype to genotype (Top down)

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Plant of the day!
Pebble plants,
Lithops, dwarf
South African
Plants consist of one
or more pairs of
bulbous leaves –
almost no stem
Leaf markings
appear to help plant
match its background
and be less
vulnerable to
Lithops lesliei
• Understand some top down and bottom up
approaches used to identify genes
responsible for adaptations
• Explain patterns of sequence variation
expected with positive and balancing
• Understand the principles of population
genetic tests of selection
The genetic basis of adaptation
• Phenotype to genotype (Top down)
– Candidate loci for traits responsible for
phenotypic differences
– QTL, association mapping
• Genotype to phenotype (Bottom up)
– Population genetics
Which locus is likely involved in the change in floral phenotype?
Selective sweep
Which locus is likely involved in the divergence in floral phenotype?
Quantitative trait loci (QTL) are regions of the genome associated
with the trait in question
-May not be the loci in other
-Statistical issues (sample size,
genes of small effect, epistasis)
-Can be large regions of a
chromosome (further mapping in
region needed)
-Can't perform in all species
Rodney Mauricio 2001
Association mapping
Associations between markers (SNPs) and phenotypes
in natural populations
allele1 allele2
SNP1 100% 0%
SNP2 50% 50%
allele1 allele2
SNP1 0%
SNP2 50% 50%
Can find precise mutation responsible
No crossing required
False associations due to population structure
Large sample size, many markers needed (if no
candidate loci)
The genetic basis of adaptation
• Phenotype to genotype (Top down)
– Candidate loci for traits responsible for
phenotypic differences
– QTL, association mapping
• Genotype to phenotype (Bottom up)
– Population genetics
Neutral Theory
Kimura (1968, 1983)
Motoo Kimura (1924-1994)
Ph.D. University of Wisconsin in 1956
Under James Crow
Kimura argued that the great majority of evolutionary
changes at the molecular level are not caused by
selection but by random genetic drift.
Neutral Theory: Evidence
Molecular evolution
takes place at a
relatively constant rate,
simply through random
genetic drift, enough to
provide a “molecular
clock” of evolution.
Selection-Neutral Debate
• Kimura’s work spawned a heated debate
on the relative importance of neutral
evolution (genetic drift) versus genetic
variation that is a result of natural
Neutral Theory
• Now considered the “null model” against
which evidence for selection should be
Detecting Natural Selection
There are many statistical tests for detecting
Natural selection
The approach is to test for deviations from a null
neutral model (where genetic variation arises only
from genetic drift)
Null hypothesis: Neutral, no selection
Deviation from Neutral: selection
Inferences regarding selection provide a powerful
tool for the prediction of genes underlying traits of
ecological or economic value
The effects of selection on the
Directional selection
– Best allele(s) sweep to fixation
– Loss of variation
– Change in frequency distribution of
– Increase in linkage disequilibrium around the site
The effects of selection on the
Balancing selection
– Maintains variation that otherwise would be lost to
– Heterozygote advantage, frequency dependent
selection, fluctuating selection, (divergent selection)
•A beneficial allele arises
•Variants with this allele rapidly spread through the species
•Genetic diversity is reduced around this adaptive locus
After selection
Chance of detecting positive selection depends on:
Strength of selection
Recombination, mutation
Initial frequency
Methods for Detecting Selection:
A. MacDonald-Kreitman Type Tests
B. Site Frequency Spectrum Approaches
C. Linkage Disequilibrium (LD) and Haplotype
D. Population Differentiation: Lewontin-Krakauer
These tests could be applied to single
genes, or across the whole genome.
Codon Bias in Amino Acid Substitutions
• Synonymous
Mutations that do not cause
amino acid change (usually
3rd position)
“silent substitutions”
• Nonsynonymous
Mutations that cause amino
acid change (1st, 2nd position)
“replacement substitutions”
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
A. MacDonald-Kreitman Type Tests
(1) Ka/Ks Test
Nonsynonymous substitutions
Synonymous substitutions
Need coding sequence (sequence that codes proteins)
Ks is used here as the “control”, proxy for neutral evolution
so Ka/Ks = 1
neutral evolution
A larger nonsynonymous substitution rate (Ka) than
synonymous (Ks) is used as an indication of selection
(Ka/Ks >1)
Ka/Ks < 1 ?
dN vs. dS for pairwise sequence comparisons in Physalis (nightshade)
Richman A D , Kohn J R PNAS 1999;96:168-172
B. Site Frequency Spectrum
• Selection affects the distribution of alleles within populations
• Method examines site frequency spectrum and compares to neutral
• Could be applied to a single locus. Now used often for genomic scans for
selective sweeps
•Domestication alleles (corn, rice)
Nucleotide diversity (π)
in maize and teosinte for
teosinte glume
architecture (tga1).
Tajima's D-statistic and
HKA tests for non-neutral
evolution are shown
(Nature 436, 714-719 (4
August 2005)
C. Linkage Disequilibrium (LD)
• The nonrandom association of alleles from
different loci, where they are found more or
less frequently together than expected
• Selection increases levels of linkage
disequilibrium during the process of selection
D. Population Differentiation:
Lewontin-Krakauer Methods
• Selection would often increase the degree of
genetic distance between populations
• Compute pairwise genetic distances (FST) for
many loci between populations
• When a locus shows extraordinary levels of
genetic distance relative to other loci, this locus is
a candidate for positive selection
Example of Fst scan in sunflower