Lecture 6 Flashcards
Examples of local adaptation in other organisms
- Rock pocket mice (Mice in the southern USA that occupy different substrates on deserts. Their coat colours have adapted depending on what type of substrate they’re on)
- Spine stickle backs, after the ice age, some were left in glacial lakes with no predators so adapted less heavy armour
- Dawins Finches in the Galopogas islands adapted different shaped beaks depending on their food resource
Whats the challenge of trying to detect local adaptation in humans?
We often don’t know which traits are adaptive or not so we could look at the genetic diversity/ lack of genetic diversity within a population
What was used for the first attempts at finding selective sweep regions
They developed extended haplotype homozygosity (EHH) test which uses the concept of core haplotypes
The approach tested on two genes known to be associated with resistance to malaria; allele 202A at G6PD confers 50% reduced risk
What are core haplotypes
Region of the genome- series of SNPs that are close by to one another and particular alleles in linkage disequilibrium with one another
How does the EHH work
- Define the core haplotypes in a gene
- For each haplotype examine all the individuals that carry that haplotype and “walk to the next SNP in each direction one direction at a time”
- Ask whether all those individuals are the same at that new SNP. If yes, keep walking; if no stop (where the extended homozygozity comes in)
- Measure how far each haplotype extends. Long haplotypes provide evidence of selective sweeps (extended haplotype homozygozity)
- Why? because, over time recombination moves alleles between haplotypes and so ones that extend a long way much have reached a high frequency recently. Usually this happens because they are under positive selection
Recent positive selection should result in these extended homozygous haplotypes
Showing EHH results graphically
Filled in circle- core haplotype.
Different branches coming away from it. Every time a branch splits, some of those individuals have different alleles to others.
The thickness of the branch indicates what proportion of people have that particular haplotype
Haplotype 8 looks like it has the best evidence for selective sweeps
A look at G6PD, core haplotype 8
- Ran a bunch of simulations to try and predict when a gene is neutral
- They did this for lots of simulations and they plotted core haplotypes on the data for those simulations
- Simulations determine the typical EHH
- Each dot represents a different simulated gene/ haplotype.
Haplotype 8 is a massive outlier so something non neutral is happening
HapMap phase 2 data
This dataset had 3 million SNPs, 420 chromosomes, 3 continents and 210 people with two copies of the genome
What’s the cross population extended haplotype homozygosity test (XP- EHH)
Compared two populations and tried to identify which population selection has happened in by looking at an allele that has reached fixation in one population but is still polymorphic in the other
How was selection detected in cross population EHH test
Used pair wise comparisons e.g. European-African, Asian-African which showed greater difference than European-Asian comparisons
Bordered and filled symbols are SNPs of likely functional importance 233 SNPs were derived allele at high frequency
Of which 39 were highly different between populations
and of those 5 were at low frequency in non-selected populations. Only 1 is filled in and is functionally important aka CLC245A which results in an amino acid change from alanine to threonine
SLC245A (solute carrier family 24 member 5)- distribution and what does it do
This derived allele is at high frequency in Europeans and low frequency elsewhere
This gene is known to be involved in pigmentation; involved in melanosome synthesis which are found in skin cells
The derived allele is associated with lighter skin
Light skin possible required for adequate vitamin D synthesis at higher latitudes
Whats the vitamin D synthesis hypothesis
Lighter skin has fewer, smaller, paler melanosomes (vesicles with melanocyte cells)
Dark skin protects against effects of ultra violet radiation (UVR), without it leads to sunburn (short term), cancer, nutrient degradation, neural tube defects (NTDs)
But UVR is required for vitamin D synthesis
In low sunlight conditions, vitamin D synthesis may be inadequate unless skin is pale (i.e. derived SLC45A allele will be favoured)
Humans only evolved lighter skin in Europe and Asia relatively recently
How common was/is this selection? (of SLC45A)
- 300 candidate regions
-22 of them exceeded a threshold never seen in 10Gb of simulated data
-Included the pigmentation gene, as well as genes associated with lactase persistence*, resistance to Lassa fever and hair colour/ density
Tibetan adaptations compared to other humans
Tibetan people live at >3000m without suffering from the effects of Hypoxia (insufficient oxygen).
Most of would be at risk of altitude sickness at altitudes > 2500m
Tibetan plateau has been populated for more than 10,000 years
What was the rationale, predictions, approach done behind the tibeten studies
- Any regions involved in high altitude adaptations should be different between those two populations
- Prediction: greater differentiation at relevant genes than elsewhere in the genome
- Approach: compared 500k SNPs between Tibetans (n=35) and Han Chinese (n=84)
