L29 Human Population Genetics 2

Question 1

Population Genetics

Answer 1

see onenote

• extension of Mendelian genetics to evolving populations
• understanding human pop gen is essential to understanding humans today
• there are many ways of describing the genetic relationships within and between populations

Question 2

Humans are surprisingly not diverse

Answer 2

see onenote

• vast majority of existing diversity in human pop is segregating at really low freq (<5%)
• singletons: SNPs seen in a single individual

Question 3

Understanding migratory patterns

Answer 3

see onenote

Migratory patterns
- Different migratory patterns leave different traces on genomes of populations

Island model
○ All populations exchange migrations with one another
○ Low Fst, constant migrants going back and forth

Stepping-stone model
○ Populations exchange migrants only with their geographic neighbour
○ Higher Fst, restricted migration only to neighbours

Geographic distance does not matter in island model
Geographic distance does matter in stepping-stone model

Question 4

A relationship between genetic and geographic distance

Answer 4

see onenote

• can answer this by calculating Fst between all pairs of HGDP-CEPH populations

Question 5

Pairwise Fst in the HGDP-CEPH populations

Answer 5

see onenote

data from HGDP-CEPH supports stepping stone model for human dispersals
- strong isolation by distance, suggests populations tend to exchange alleles with populations in geographic proximity

Question 6

Geographic distance is a good predictor of genetic distance

Answer 6

see onenote

High geographic distance, usually higher Fst

all 8 grandparents from the same place? Pretty similar

Question 7

How do we know it was OOA into elsewhere?

Answer 7

see onenote

• what does Hs look like within-population measures
• heterozygosity decreases as a function of distance from Africa
• humans outside Africa contain only a subset of all african genetic variation
• really strong evidence of a genetic bottleneck and founder effect in OOA event
• Populations outside of Africa only carry a subset of genetic diversity seen in Africa

Question 8

How many bottlenecks?

Answer 8

continuous decrease in diversity as distance increase suggests not one but many bottlenecks as humans spread throughout the world: serial founder effect model

• Steady loss of diversity indicates that there were many founders effects, serial founder effect
• You lose a bit of diversity each founders effect

Question 9

Post OOA expansions also shape us

Answer 9

see onenote

• individuals and populations did no stop acquiring mutations once they exited Africa
• distribution of worldwide derived allele frequencies suggests one more dramatic demographic process following the OOA exit; recent large scale human population expansion worldwide
• Despite having a subset of genetic diversity from Africa, humans out of Africa have their own local diversity not seen in Africa
• Frequency of alleles increase in frequency as population expansion increases
• Humans expanded recently, indicated by dramatic increase in worldwide derived allele frequencies

Question 10

Genetically restricted variation is common

Answer 10

see onenote

• when a mutation was seen only twice in the entire panel, both copies were in a single population or in a geographically close group

Question 11

Admixture

Answer 11

see onenote slides

• populations that split do not always remain separate
• coming together after a long period of isolation to form a hybrid population is known as admixture
• admixture can be a sex biased process and contributions of two parent populations do not have to be 50/50
• admixture can be identified on the basis of LD pattern, especially if the two parent populations can be sampled
• colonialism and Atlantic slave trade are recent examples
• can be genetically beneficial or harmful i.e. potentially exposing allele combinations to genetic background they are not adapted to

Question 12

Pharmacogenetics of warfarin

Answer 12

see onenote slides

• Warfarin is a blood thinning drug used to prevent strokes
• highly variable response to the same dose between individuals, severe side effects if dosed wrong
• highly variable response that is stratified by self-reported ethnicity
• caused in part by population differences in presence of multiple SNPs in the genes that metabolise the drug

Question 13

What is a population?

Answer 13

see onenote

• genetic background is not synonymous with race
• racial categories are social constructs that often fail to correlate with genetically distinct populations
• traditional markers of race do not correlate with genetic differentiation
• two individuals from the same population can be more different from one another than two from different populations

Question 14

Humans are still evolving

Answer 14

see onenote slides

• natural selection continues to shape human population but ongoing selection is much harder to spot than past selection
• Selection’s impact on genome changes over time
• no single method can detect both recent and ancient selection
• Different tests for different time periods e.g. haplotype decay for 50,000 - 100,000 years ago

Question 15

Recent hard sweeps

Answer 15

see onenote

• easiest to detect using haplotype length test
• Recent hard sweeps from de novo variants
• advantageous mutation arises once through mutation and rises quickly in freq in a population, as does its associated haplotype
• Entire haplotype rises to high frequency
• Hard sweeps are not common at all

Question 16

Soft sweeps

Answer 16

see onenote

• occur more frequently than hard sweeps
• similar to hardsweep but selected variant was already present in the population and often associated with more than one haplotype
• depending on starting freq, this can make them much more difficult to detect

Question 17

Polygenic adaptation

Answer 17

see onenote

• probably the most common of all
• Most complex traits e.g. height, are polygenic
• Selection has to shift allele frequencies across multiple loci in order to shift polygenic traits
• can be very hard to differentiate from random drift acting on population structure

Question 18

Immune pressures

Answer 18

see onenote slides

• Hbs in Africa, sickle cell anaemia, protects against malaria
• balancing selection
• adaptation to pathogen is pervasive and stratified by geography
• diversity at HLA-MHC shows clear signs of adaptation, including adaptive admixture with Neanderthals

Question 19

Gene-culture co-evolution

Answer 19

see onenote

• culturally driven changes in behaviour can be powerful drives of adaptive changes
• lactase persistence: ability to digest milk in adulthood
• this trait has evolved multiple times worldwide, always in association with dairying

Question 20

FADS2 in Inuits

Answer 20

allows them to consume high amounts of very fatty whale meat with limited cardiovascular impact

copy number variation in AMY1, a gene involved in starch digestion is associated with historical access to high or low starch diets across different populations

Question 21

Mildly polygenic adaptations to high altitude

Answer 21

see onenote slides

• human have successfully colonised multiple high altitude environments e.g. Himalayan plateau, Ethiopian highlands, Andean altiplano

Populations from these regions show strong evidence of convergent adaptation to challenges of life at high altitude

• decreased o2 availability causes chronic mountain sickness
• blood viscosity increases, impacting cardiovascular health
• very dangerous during pregnancy/child birth - so a very strong selective pressure

Question 22

Hypoxia inducible factors (HIF)

Answer 22

• HIF pathway becomes activated during hypoxic exposure
• multiple genes in pathway show evidence of selection in Tibetan and Ethiopian groups

Tibetan

• see evidence of adaptive admixture with Denisovans
• these groups have blunted psychological response to hypoxia, enabling them to live successfully at high altitude
• this mechanism suggests possible avenue of treatment for some blood thickening disorders

Question 23

Ongoing selection: polygenic adaptation and height

Answer 23

see onenote slides

• 3290 SNPs, individually have a tiny effect contributing to height but together add up to a big difference, heigh has a complex genetic architecture
• Selection has to act polygenically, selection acting on a single SNP would not get far

If height is under selection, we should see a concerted shift in “tall” frequencies across individuals with greater heights

• In taller populations, increase in frequency for tall alleles
• Northern Europeans tend to be taller than Southern Europeans, - Northern Europeans have more tall alleles than short alleles and vice versa for Southern Europeans

Question 24

Why does any of this matter?

Answer 24

Humanity’s past conditions our present

• Much more variation within populations than between populations
• understanding how and why will help us make better decisions, whether as a clinician, researcher or just in everyday life
• there are fewer genetic differences between any pair of humans worldwide than between a pair of chimpanzees from the same population