Week 4 Flashcards

Question

What is the functional genetic variation among humans?

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

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

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

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

Answer 20

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

Answer 21

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

Answer 22

Genetic basis of variation in drug metabolism and response - Pharmogenetics

Answer 23

Codeine (an opioid) – widely used painkiller

Answer 24

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

Answer 25

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)

Answer 26

Need for population/individual specific treatments

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

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

Answer 32

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

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

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

Answer 40

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

Answer 41

Malaria spreads unchecked

Answer 42

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

Answer 43

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

Answer 44

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

Answer 45

Human Leukocyte Antigen (HLA)

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

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

Answer 50

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

Answer 51

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

Answer 52

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

Answer 53

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

Answer 54

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

Answer 55

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)

Answer 56

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

Answer 57

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

Answer 58

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

Answer 59

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

Answer 60

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

Answer 61

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

Answer 62

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

Answer 63

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

Answer 64

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

Answer 65

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

Answer 66

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

Answer 67

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

Answer 68

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

Answer 69

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

Answer 70

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

Answer 71

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

Answer 72

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

Answer 73

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)

Answer 74

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

Answer 75

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

Answer 76

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

Answer 77

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

Answer 78

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

Answer 79

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

Answer 80

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

Answer 81

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

Answer 82

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

Answer 83

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

Answer 84

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

Answer 85

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

Answer 86

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

Answer 87

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

Answer 88

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)

Answer 89

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

Answer 90

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

Answer 91

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)