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3s1: Evolution of health and disease > Week 4 > Flashcards

Week 4 Flashcards

1
Q

What is a population?

A

Group of individuals of one species that interbreed and live in the same place at the same time

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2
Q

How do populations exist?

A

Very few species exist as single, panmictic populations – there is nearly always population structure

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3
Q

What causes population subdivision?

A

Natural aggregations
Fragmented habitats

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4
Q

How does population subdivisions impact genetics?

A

Population subdivision leads to genetic differences among subpopulations because evolutionary processes affect each population differently

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5
Q

What is genetic drift?

A

Random fluctuations in allele frequencies in a population between generations

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6
Q

What does genetic drift lead to?

A

Can lead to the replacement of old alleles by new alleles (and the trait they confer) non-adaptive evolution

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7
Q

What is the founder effect?

A

The reduced genetic diversity which results when a population is descended from a small number of colonizing ancestors
Strong genetic drift as has a huge non adaptive impact on what alleles can be inherited

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8
Q

What is selection?

A

SELECTION - not random – favours mutations that give an adaptive advantage – adaptive evolution, local adaptation

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9
Q

What is the difference between drift and selection?

A

Therefore drift and selection mean that different populations evolve differently (their allele frequencies diverge) leading to: GENETIC POPULATION STRUCTURE

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10
Q

What counters genetic population structure?

A

Gene flow between the subpopulations

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11
Q

When did humans and chimps diverge?

A

Ancestors of humans and chimps diverged 5.4 million years ago

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12
Q

What is an overview of the evolutionary history of humans?

A

Homo Sapiens – a very young species (derived from ancestral hominin species)
Evolved in Eritrea – ca 200,000 years ago

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13
Q

What happened to human 100,000 years ago?

A

The population spread around and out-of-Africa ca 100,000 years ago
Serial sequential migration

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14
Q

What is serial sequential migration?

A

A series of populations founded by a small number of individuals from the last population each time

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15
Q

What is the main impact of sequential migration?

A

Less genetic diversity with each migration
This is non-adaptive evolution caused by founder effects

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16
Q

What is the main cause of genetic diversity among human populations?

A

Shortest route (via land) between 61 populations (Red Dots) and east African origin
Neutral genetic diversity – strongly correlated to geographical distance from east Africa (85%)

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17
Q

What is phylogeny?

A

Mapping of related of populaitons/species using DNA sequence variation
- branch length reflects relative genetic divergence

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18
Q

What is the population structure of humans?

A

African variants are basal, with high sequence diversity
Variants from the rest of the world form a single clade

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19
Q

What does the population structure of humans show?

A

Indicates - a longer period of evolution in Africa
With variation diminishing as humans recently spread out
Most variation was left in Africa !
A very significant event in the evolutionary history of modern Homo sapiens

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20
Q

What was dispersal like for other homins?

A

Archaic hominin forms had previously spread across the globe – but are now extinct
Homo sapiens only spread out from Africa recently

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21
Q

What evidence is there for introgression between humans and archaics?

A

2% Neanderthal DNA in non-African Humans
4-6% Denisovan DNA in Melanesian humans

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22
Q

What is an overview of the genetic differences between humans?

A

Human genetic variation is limited – and only 20% of it differs among populations
Humans cannot be subdivided into sharply defined, discrete races
But differences in the frequencies of alleles at specific loci exist
When accumulated - statistical genetic differences between populations

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23
Q

How could you divide humans genetically?

A

A division of the world’s human populations into eight classes of genetic similarity

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24
Q

What is the mitochondrial DNA comparison of human and great ape species?

A

Mitochondrial DNA comparison between pairs of individuals from different species
Humans average - 3%
Gorillas - 14%
Western Chimps - 8%

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25
Q

What is the functional genetic variation among humans?

A

Human genome - only 0.1% of nucleotide bases are variable between humans on average
Humans are 99.9% genetically identical
>3 billion bases in genome – 0.1% different = over 3 million bases are commonly variable
Some will be in genes – and have a profound effects on function - e.g. Sickle cell anaemia

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26
Q

What has happened with selection of specific loci in human populations?

A

Low levels of gene flow since expansion out-of-africa
So gene flow will not have negated local adaptation due to selection
Geographical differences in genes under selection – with health implication

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27
Q

What is an exmaple of certain genes being selected for in different populations?

A

A Manhattan plot of the genome-wide natural selection signatures obtained from the whole genome sequencing of 2234 Japanese individuals
Strong selection for a few genes for example around the MHC

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28
Q

What can genetics variation be important for medicine?

A

Genomic medicine – based on genetic differences within and among human populations

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29
Q

What is often the link between genes that can cause disease?

A

Many alleles linked to medical conditions are not inherently ‘bad’

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30
Q

What is an overview of myotonic dystrophy?

A

Caused by mutation in DMPK gene
Autosomal dominant
At very low frequency in African populations

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31
Q

How has the founder effect impacted myotonic dystrophy frequency?

A

Founder effect – the mutation was, by chance, in the small group that migrated out of Africa.
Now at much higher frequencies around the world

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32
Q

What is the ancestral human skin colour trait?

A

Ancestral trait in hominins - pale skin covered by dense dark hair

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33
Q

Why did hominins evolve hairlessness?

A

Hominins evolved hairlessness
– efficient whole body cooling system – required for the
temperature sensitive brain?

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34
Q

What is an overview of dark skin?

A

The evolution of dark skin (melanocortin 1 receptor - MC1R - and 7+ other genes)
No variation in MC1R in African humans
Strong selective sweep in hominins 1.2 mya

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35
Q

What is UV radiation impacts biological organisms?

A

UV radiation breaks down biologically important molecules
Dark skin (melanin) protects circulating folate from UVR photolysis

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36
Q

What is an overview of folate?

A

Water-soluble B vitamin - occurs naturally in food
Important in nucleic acid synthesis - Cell proliferation, formation of myelin, Neurotransmitters

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37
Q

How do humans get folate?

A

Cannot be made by humans – must be sequestered
Green leafy vegetables, fruits, peas and beans
Difficult to obtain and store in the body

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38
Q

How does UV impact folate?

A

UVR induced folate deficiency – reduced fitness
Failure of normal embryogenesis and spermatogenesis
Lower fertility and more birth defects (neural tube defects etc)

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39
Q

Why is UV important?

A

Some UV is needed for the synthesis of Vitamin D within the body

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40
Q

Why is vitamin D synthesis important?

A

Important in building and maintenance of bony skeleton
Without vitamin D normal life and reproduction impossible
Bone disease (Rickets), associations with various cancers, cardiovascular disease

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41
Q

How did light skin colour evolve?

A

Dark skin = ancestral in humans - who then spread into areas with low UV radiation

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42
Q

Why did light skin evolve?

A

Pale skin evolved – multiple times - to avoid Vitamin D deficiencies at higher latitudes
Alleles at various pigmentation loci – closely associated with light skin
Skin colour very closely related to levels of incident UV

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43
Q

How efficient is light skin at producing vitamin D?

A

Light skin can synthesis Vitamin D 5-10x faster than dark

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44
Q

What is the trade off skin colour?

A

Skin colour is a finely optimised trade-off
Between synthesising Vit D and losing Vit B (Folate)

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45
Q

What is the relation between skin colour and sex?

A

Women are the fairer sex
Study of spanish and indian men and women
Prepuperty roughly same reflectance
Post puberty women have paler skin as they need more vitamin D then men

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46
Q

Why is genetics important for medicine?

A

Genetic basis of variation in drug metabolism and response
- Pharmogenetics

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47
Q

What is codeine?

A

Codeine (an opioid) – widely used painkiller

48
Q

What converts codeine to morphine?

A

Has to be converted to morphine in the body to work –
requires CYP2D6 enzyme

49
Q

What is the prevalence of CYP2D6 gene?

A

Nearly all people from Arabian Peninsula have the enzyme
But 1 in 10 Northern Europeans lack it (we dont know why or is it adaptive)

50
Q

Why is understanding genetics important amogst population and people for medicine?

A

Need for population/individual specific treatments

51
Q

Is human population structure linked to pathogen exposure?

A

Humans moved away from areas of high pathogen species diversity
Loss of pathogens with sequential founder effects
Increase in crowd diseases with increased population size
Isolation and reconnection of populations

52
Q

How has human migration impact pathogen exposure?

A

Temperate regions have less pathogens affecting humans than tropics.
Most zoonotic/vector borne disease are restricted to tropics because of the restricted distribution of hosts

53
Q

How has the founder effect impact exposure to pathogens?

A

Each new human population founded by a small group of (healthy?) individuals
Viral pathogen diversity - lowest in SE Asia, S America furtherest migration distance

54
Q

What is an overview of measles infection?

A

Survivors have life-long immunity
Measles requires constant supply of uninfected individuals
250,000 individuals required in a population to be maintained
Human populations only reached this size ca. 5000 ya

55
Q

What is an overview of measles in humans?

A

Acquired disease from other species
Circulating ever since - previously would die out due to small population sizes
Can be lethal!

56
Q

What is an overview of human colonisation of the americas?

A

Humans colonised Americas 20,000 ya
Then isolated from the global population

57
Q

How did the timing of human colonisation of the Americas impact diseases and resisitance?

A

These populations not exposed to many of the diseases humans subsequently acquired which meant no selection for resistance
Until 1492 – Discovery of Americas
16th century - 90% of native Americans died of introduced disease, i.e. measles and small pox

58
Q

What is an overview of malaria?

A

Protozoan parasite
In humans, main species = Plasmodium falciparum -
Transmitted by the female Anopheles mosquito

59
Q

What is an overview of the evolution of malaria?

A

Host switch from Gorillas since Hominins evolved
With humans for 1000’s of years

60
Q

What is the impact of malaria in humans?

A

250 million cases – 1-3 million deaths - annually
Strong selective force on humans

61
Q

What is an overview of the sickle cell trait?

A

Hb-A allele = normal
Hb-S allele - Mutation - Glutamic acid (GAC) -> Valine (GCC) causes abnormal β-globin chain

62
Q

When does the sickle shape occur?

A

With SCT - sickling of cells occurs when stressed i.e deoxygenated or infected

63
Q

How does sickle cell trait overlap with distrubution of malaria?

A

Areas where malaria is present can be seen with greater levels of sickle cell trait overlapping

64
Q

What is the genetics of the sickle cell trait?

A

Co-dominant allele trait - has three phenotypes, one for each genotype

65
Q

What is an overview of normal rbc with malaria?

A

Malaria spreads unchecked

66
Q

What is an overview of heterozygote rbc with malaria?

A

Some sickling - breakdown of infected cells – stops spread of malaria but little anaemia
Heterozygote advantage

67
Q

What is an overview of 2 sickle cell alleles?

A

Lots of sickled RBCs - fragile, and block blood vessels causing anemia, tissue / organ damage

68
Q

What is an example of another red cell gene polymorphism in response to malaria?

A

Thalassemia (α and β)
Effects haemoglobin
From gene HBA and HBB
Protects from severe malaria
Found in Africa, middle east, India, Med, melanesia

69
Q

What is the MHC in humans?

A

Human Leukocyte Antigen (HLA)

70
Q

What is the MHC?

A

Suite of duplicated genes in all vertebrates (HLA in humans)
Encode molecules on cell surface that bind and present antigens to effector cells
Allow identification of non-self antigens
Major role in determining acquired immune response

71
Q

What is an overview of HLA classes?

A

Class 1 - On all nucleated cells, intracellular pathogens
Class 2 - On antigen presenting cell eg macrophages, extracellular parasite
Class 3 - Secrete proteins, involved in inflammation

72
Q

What is an overview of genetic variation in HLA?

A

The most polymorphic genes in humans, class 1 have 5 thousands and class 2 have over 1000
Most variation in the region of the gene which codes for the pathogen-binding site
Heterozygote excesses observed
Heterozygosity and multiple replicated loci means each individual has many different alleles

73
Q

What drives high HLA variation?

A

Pathogen-mediated balancing selection - maintains higher levels of genetic polymorphisms at a locus within a population than expected

74
Q

What is heterozygote advantage?

A

Being Heterozygous (especially at many loci) means an individual can detect and combat pathogens better or a wider range of pathogens

75
Q

What is rare allele advantage?

A

Cyclic coevolution between HLA and pathogens
Pathogens evolve to get around common resistant alleles in the host population - then new/rare alleles that confer host resistance are selected for and so on in repeating cycles

76
Q

What is fluctuating selection?

A

Changes in which pathogens are present in a population over time and space (e.g. because of climatic variation) – leading to selection for different alleles at different times/places within the greater population

77
Q

What does high HLA diversity mean for response to pathogens?

A

Overall greater HLA diversity individuals and host populations, should evolve where challenged by more pathogens

78
Q

What is an overview on HLA genes in different populations?

A

Shortest Routes between the 61 Populations Analyzed (Red Dots) and E. African origin
Neutral genetic diversity – strongly correlated to geographical distance from E. Africa

79
Q

What explains HLA diveristy in different populations?

A

HLA diversity strongly negatively correlated to geographical distance from E. Africa
Human colonisation history explains up to 39% of HLA diversity
Strong correlation between HLA class 1 diversity and pathogen species diversity (virus, bacteria and protozoans)

80
Q

What is the relationship with archaic humans and HLA genes?

A

Adaptive introgression of archaic HLA alleles in the cross breeding high prevalence for these genes

81
Q

What are the 3 hypothesises for HLA in sexual selection?

A

Good genes - Most divere HLA
Genetic compatibility - Most different HLA genes
Avoid interbreeding - Not the same HLA genes

82
Q

How did they test for HLA dependant mate choice?

A

T-shirt tests – dissimilar preferred
Hutterite couples – dissimilar preferred
Dissimilar preferred in European American couples

83
Q

What are geo evolutionary mismatches?

A

Modern migration and travel exposes us to selective pressures we’re not adapted to. I.e. factors that are different than those in our ancestral populations

84
Q

How has modern travel impacted skin colour selection through high UVR than evolved to handle?

A

Higher UVR regime than adapted to:
Skin cancers and serious sunburns
Folate breakdown – Folic acid in flour / cereals

85
Q

How has modern travel impacted skin colour selection through lower UVR than evolved to protect?

A

Lower UVR regime than adapted to:
Vitamin D deficiency - bone disease (Rickets), various cancers, cardiovascular disease, fertility
Vitamin D deficiency in Saudi women
Global health burden of low UVR – higher than that caused by high UVR

86
Q

How has global travel impacted exposure to infectious diseases?

A

Locally adapted immune responses - now maladaptive!
e.g. no malaria resistance
e.g. Sickle cell anemia in places with no malaria

87
Q

How might climate change make infectious disease mismatch worse?

A

Increase range vectors live and increase number of people at risk some might have little to no resistance to disease

88
Q

What are examples of research into ancient DNA?

A

Mapping relation of quagga to modern horses
Molecular cloning of ancient egyptian mummy DNA (though it was Svante Paabo DNA)

89
Q

When was the dark ages of research into ancient DNA?

A

Studies in the 90’s reported PCR amplification of DNA from material tens of millions of years old.

90
Q

Why was research in the 90s the dark age for ancient DNA?

A

Many results werent real ie
Isolation of 250 mya halotolerant bacterium
Amolification and sequencing of DNA from a 120-135 mya Weevil

91
Q

What are the challenges of ancient DNA?

A

Success rate is highly variable, often low, and depends on age and local conditions
The DNA is highly degraded (molecule lengths typically 20-70 bp)
The DNA contains substitutions caused by post-mortem damage

92
Q

Why does ancient DNA sucess rate vary?

A

Contamination from modern sources is a big concern –> lab work in cleanrooms

93
Q

What is an overview of DNA subsituations caused by post-morten damage in ancient DNA?

A

In particular, very high rates of C->T transitions towards the ends of molecules
Challenge in analyses, but can also be used to authenticate endogenous ancient DNA

94
Q

How has the exploration of ancient DNA across the last decade changed?

A

The advent of next-generation sequencing in the 2000’s and 2010’s has allowed ancient DNA to be
produced much more reliably and at larger scale
The rapid progress in humans has been fueled by the development of
SNP capture technology, allowing enrichment for endogenous DNA.
Only a minority of the data is whole genomes

95
Q

What is an overview of the scale of genome sequencing?

A

2017 - 714 human genes sequences 2022 - 10067
Mostly in europe with blind spots in Africa, Australia and Americas
2017 - 109 non human genes sequences compared to 1096 in 2023

96
Q

What has ancient DNA revealed about human history?

A

Before ancient DNA studies, there was a general expectation that present-day
population structure is the product of the first migration events into a region
Ancient DNA is increasingly showing that this is not the case – instead, later
processes have often overwritten the signals from the earliest events

97
Q

How has the location of the ancestors of modern day rome inhabitants changed?

A

The genetic ancestry of people in Rome (red), relative to present-day people in Europe (grey background dots), changes quite a bit between historical periods.
(This is a PCA, ”Principal Components Analysis”,
which clusters genomes based on similarity)

98
Q

What are examples of waves of admixture in Britain?

A

Late glacial population was 100% replaced by new tribe
Anatolian farmers replaced 80% of those tribes
90% of the anatolian farmers were replaced by a new contential population

99
Q

What are dead end populatuions?

A

The first people to reach a given geographical area often do not seem to have contributed any ancestry to later populations

100
Q

How has ancient DNA given insights into kinship and social structure?

A

Ancient burial showed high ranking individuals buried together in Ireland
As this person has long runs of homozygosity along the genome, indicating recent inbreeding

101
Q

What is an example of ancient DNA showing natural selection in wolves?

A

Dramatic selection acting on the gene
IFT88, involved in craniofacial development
Not presnet form 100 Kya but evolved 30-40 kya and rapidly evolved in

102
Q

What is an example of ancient DNA showing natural selection in humans?

A

Selection for the lactase persistence allele in Europe did not start right after the agricultural transition, but only really
occurred in the last ~4,000 years eg British population went form 3% to 60% in 2000 years

103
Q

How has ancient DNA showed insights into domestication of horses?

A

Domesitcation of horses was found to be roughly Ukraine and south western Russia

104
Q

How has ancient DNA showed insights into domestication of wolves?

A

2 ancestor populations one western and eastern population both contributed to different breed genetics, vary depending on breed. Shows at least two seperate domestication events

105
Q

How has ancient DNA proved different strains infect at different times?

A

Yersinia pestis that caused the black death is different to the Yersinia pestis that caused the plague of Justinian or was infecting neolithic farmers

106
Q

How has ancient DNA shown about evolution of Yersinia Pestis?

A

Early strains couldnt be spread by fleas but evoluition of ymt allowed this. All modern day branches have this gene as non flea Y.pestis have extinct

107
Q

How can ancient DNA detect the infections of ancient pathogen genomics?

A

Direct detection of infections gives us a picture of pathogen prevalence across
time and space (though false negative rate is probably very high)

108
Q

What is an example of ancient genomics changing history of infections?

A

Diversification of Mycobacterium tuberculosis was thought to have occured on the timescale of ~70 kya, co-inciding with the human out-of-Africa expansion
After ancient DNA, diversification is found to be on the timescale of ~6 kya

109
Q

How can ancient DNA give insights into past ecology?

A

Temporal sampling of environmental DNA, tracking the
presence and absence of species over time, can give an
ecosystem-level view of environmental change
Also give insights into relatedness of species

110
Q

How can metagenomics of environmental DNA be used?

A

In some exceptional environmental DNA samples, there is
enough information to go beyond just species absence/presence.
If enough DNA can be obtained from the whole genome, this can
be almost equivalent to a low-coverage genome sequence

111
Q

What are examples of environmental genomes from whole DNA?

A

Sequencing and analysis of 25,000 year olf human, wolf and bison DNA
Showing that Neanderthals lived in a cave but also a new population replaced the original population

112
Q

How old can you get DNA from?

A

a maximum survival of DNA of <1 million years. However, that limit has recently
been broken by real data (oldest is 2 mya with Kap Kabenhavn DNA also 1.2 mya Krestovka mammoth DNA)

113
Q

How can DNA from objects show evolutionary history?

A

Human DNA from pendant showed it was a woman
Whole genome allowed allowed for tracing of her to DCP1 group and where the DCP1 placed on the phylogeny

114
Q

How can ancient proteins be used for DNA analysis?

A

Bone can also contain intact protein molecules, which can be sequenced using massspectrometry technology

115
Q

What are the advantages of using ancient proteins instead of ancient DNA?

A

Protein preserves much better than DNA, such that success rates are higher and you can
go deeper into the past (perhaps 10-20 million years)

3s1: Evolution of health and disease (10 decks)

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