Comprehensive lecture notes for the Evolutionary genetics module covered in MCB3023S. These notes cover all content taught in lectures as well as additional materials (powerpoints, textbooks) required to succeed. These notes were created by a student who achieved a distinction in this course.
Topic 1: Selection and Lactose persistence
What is evolutionary genetics
- Definition: it is the broad field of studies that examines evolution in terms of changes in gene & genotype frequencies
within populations, and the processes that convert the variation within populations into permanent variation observed
between species
- migration is a massive way to homogenise genes and genetic drift is when alleles or genes change in a population
randomly (small population)
- example: lipid metabolism in the Afrikaans population and in the Armish population an example is very high gene
association with mental illness, jewish population married other jews for cultural reasons and have a high frequency of
cystic fibrosis
- many different selections (purifying selection, positive selection)
- positive selection is when something is valuable and so spreads through the population fast and frequency becomes very
high
What is lactase persistence
- lactose is a simple disaccharide
- evolutionary milk came from a mothers breast, now milk comes from cows
- milk is broken down by the enzyme lactase to 2 monosaccharides called glucose
and galactose
- in the gut, the molecules get transported to where needed, if enzyme is absent, the
disaccharide does not get broken down
- gut bacteria are in a perfect balance, when given the food source, it gets fermented
into other molecules such as methane, carbon dioxide, hydrogen (gases) so lactose
intolerance makes gas that causes paid in the gut, dizziness, changes gut peristalses,
constipation and diarrhea
- after weaning, humans lose ability to make the enzyme (natural process), it is
ancestral so lost the ability to digest lactose
Lactose persistence is not ancestral
- most modern humans’ adults are lactose-intolerant
- lactose persistence is a result of plant/animal domestication (dairy as a new food source)
- lactase biosynthesis regulation after weaning determines lactase intolerance versus lactose persistent
- some populations have lactose persistence mutations, these mutations keep the lactase genes switched on and are able to
digest dairy
- initially, someone had a natural mutation in the population which provided this selective advantage and the people with the
mutation could ingest the alternative energy source from cow (dairy)
- lactose persistence mutations are adaptive (selective force) and subject to positive selection (generally something that is
selected that gives an individual or population a benefit or increase fitness)
How common is lactose persistence?
- many European and some African populations can digest lactose
- lactose free milk is milk that adds the enzyme allowing the individual to digest diary
Domestication of cattle led to lactose persistence
- alleles conferring lactose persistence became prevalent in societies after cattle domestication and constant supply milk
- constant milk selected for lactose persistence in adults and rapid spread of the lactose persistence allele
- the 2 populations with the highest frequency was Europe and central Africa
- lactase persistence is p resent in 80% of European populations
- domestication is linked to climate, domestication (meditation is warm and many populations could not digest milk)
- lactase persistence is linked to 2 SNPs in the lactase gene in European populations: C/T-13910 and G/A-22018
- SNP 13910 affects transcription factor (Oct1) binding and results in more lactase mRNA
- found 2 SNPs in the lactase gene, specifically affects the upstream regulatory area of the gene
- paper concluded that the lactose persistence is result of selective sweep spanning roughly 1 million bp of DNA
The lactase gene
- like all genes, has introns and exons and upstream promoter area
- 55 000 base pairs and the lactase gene is on chromosome 2 and is translated into a
protein of 1927 amino acids and found that the mutations associated with lactose
persistence was found upstream of the gene
,- ultimately, while gene is small, the area selected spans 1 million base pairs
- mutations associated effect binding ability of transcription factors of the promoter region, found that promoter factor could
not bind, make less RNA and protein and enzyme
Selective sweep
- that a particular piece of DNA becomes prevalent in a whole population that happens quickly
- example: before selection, is a whole bunch of people (grey) and 1 person (red) and shows the
whole genome, imagine blue red region is where the lactase gene is and the default is to have it
switched off (cannot digest dairy)
- the one person has a chance mutation and can digest dairy and has a greater fitness and more likely
to survive
- if there is selection, gene is selective so very quickly the piece of DNA will spread through the
population, spread would be very slow
- moves through the population and becomes a dominant version and selective sweep also implies it
is a big region of DNA
- red stays next to the blue due to linkage disequilibrium
- Linkage disequilibrium
- 2 things always associated more that is expected by random
- the lactose gene has accumulated mutations mostly in the upstream promoter region and for
thousands of base pairs and is associated with the genes due to linkage disequilibrium
Origin of modern humans
- early modern humans were African
- the origin of modern humans is relatively recent
- early human populations were small and subject to
genetic drift and under many other selective pressures
- tree suggests some genes carried by the African
population was spread to other populations
- south America are the most recently split modern
humans
- overlaying lactose persistence to domestication of cattle, evidence suggests domestication happened around the 40 KYA
- lactose tolerance is an ancestral trait and persistence is convergent evolution due to a convergent selection pressure
Linkage disequilibrium and SNPs
- Linkage disequilibrium: non-random association of alleles at different loci
- two genes are in linkage disequilibrium means that certain alleles of each gene are inherited together more often than
would be expected by chance
- this is generally indicative of combinations of alleles at the two loci affect the viability of potential offspring (i.e.
selection)
- SNPs are DNA variants present within a population
- alternate allele should be present in at least 1% of the population
- most SNPs are selectively silent and SNP haplotypes can be created
Lactase persistence (LP)
- 80% of European populations LP linked to 2 SNPs
- lactase mRNA is regulated by cis acting elements on the LCT promoter
- LP is a result of a selective sweep
- lactase intolerance is ancestral in modern human adults
- persistence is driven by RNA expression and a result of a selective sweep and evidence shows intolerance is ancestral
- need Darwins’ thesis of how life and populations are connected to answer the questions
- work based on taking blood, extracting DNA, using PCR to target gene of interest, get sequencers to show selection or
genetic drift and to try look for when it happened combining statistical and evolutionary thought
- take home idea: selection sweep is linked to linkage disequilibrium and involves a large piece of DNA (genetic
hitchhiking)
Lactose persistence and selection in African populations
Convergent adaptation of human lactase persistence in Africa and Europe
- convergent implies selection that arises from a mutation and becomes more prevalent and fixed in that population by
genetic drift
- authors knew two SNPs are in linkage disequilibrium in Finnish populations in the promoter region of the lactase gene
, - these SNPs had SNPs have 97 to 100% association with LP in Finnish populations
- these SNPs had high (80%) association with other LP European populations
- these SNPs were absent in most African LP populations
- same phenotype and same selective force (dairy) that drove
- Finland is in the artic circle is a small population with little inbreeding and migration so genetic drift played a role
Objectives of the study
- how common was lactose persistence in African populations
- which SNPs for LP are present in African populations
- were these SNPs same as European populations
- were these SNPs associations with LP
- did these change lactose metabolism
- when did these African SNPs arise
- what selective forces were responsible
How common was LP in East African populations?
- study included 470 people from 3 countries: Sudan, Kenya and Tanzania (speak many
different languages and different cultural practices, complex populations)
- participants were divided by language family or geographical region
- this avoided false associations because of expected genetic substructure given large
geographical area
- note: different sample sizes in each region or language group
- LIP: lactose intermediate phenotype
- LP: lactose persistent
- LNP: lactose non-persistent
- phenotype of lactose persistence is measured by giving participants a dose of lactose and
they measured glucose, if enzyme is present, glucose will be produced and should increase
as the lactose is being broken down (patient needs to fast). If glucose stays flat, are lactose
non-persistent
- intermediate phenotype may result from co-dominance or partial repression
- tested lactose metabolism of all the participants
- LP was highest in Northern Sudan in Afro-Asiatic speaking Beja pastoralist (88%)
- LP frequency was lowest in the South in Khoisian speaking Sandawa in Tanzania (26%)
Molecular methods used to find SNPs in African populations
- sequenced 3314 bp region which included the LCT gene and
regulatory regions on chromosome 2
- done for a subset of samples from 3 countries
- PCR region of interest, sequencing part of the lactase gene and
the upstream regulatory region, sequence alignments to identify
SNPs
- identified 146 SNPs that were used for genotyping all other participants (some SNPs may be neutral, not necessarily
associated with lactose persistence)
- designed genotyping assays to look at the variable positions in the other participants
- only sequences some people due to cost, wanted geographical coverage and sequenced SNPs from LP and non-LP
SNP genotyping
- genotypes all the African samples at 146 SNPs identified and also included the 2 European SNPs
- used multiplex assay that could amplify 10 SNP loci in one experiment
- multiplex PCR used more than 1 primer set in 1 tube to allow 1 analysis
- is always natural variance so need QC and of all the SNPs, 123 SNPs passed QC and were used for final analysis
- genotyping done in multiplex PCRs was done in duplicate, samples that failed QC were removed and SNPS with call rates
below 70% were removed or if departed from Hardy-Weinberg equilibrium (for example if a SNP was only associated with
the Y chromosome)
SNPs associated with LP in African populations
- found certain SNPs with certain populations
- hints that it arose completely separately and also shows the rich diversity in Africa compared to Finland (population SNP
association due to population structure)
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