Lecture 04 Flashcards
International HapMap Project
a. What is the objective of this project?(1)
b. When was phase 1 published and what was its goal?(1)
c. How many individuals?(1)
d. How much was the ID?
e. What did phases 2 and 3 do?(1)
International HapMap Project
a.Objective: collect and curate haplotype distributions from several human
populations
b. Phase I (published Oct 2005) goal: measure distribution of at least 1 SNP/5 kb
across entire genome
c. 269 individuals from four continents (see Box 1.6)
d. ID > 1 million SNPs of significant frequency (>5%); further, ten selected 500-kb
regions were fully sequenced from 48 samples
e. Phases II & III: determine an additional 4.6 million SNPs from same samples
Discuss What did the international HapMap Consortium reveal?(5)
International HapMap Consortium revealed that:
a. most variations appear in all populations sampled; some inter-population diff’s reflect
different relative amounts of the same SNPs
b. very few SNPs are unique to specific popu’s – e.g. 11 were consistently diff. between
all individuals of European origin and all Chinese or Japanese origin
c. genomes of individuals from Japan and China were very similar – more recent common
ancestry than other population pairs in the study
d. among chr’s, X chr varied more between different populations than others – this may
arise because males contain only one X chr, whose genes are subject to more
selective pressure; X chr’s recombine in females only (faster-X effect)
e. length of haplotype blocks varied among diff. sources of samples – tend to be shorter
among African populations (‘out of Africa’ theory) – the older the population (many
generations), the greater the chance of recombination
Discuss the clinically important haplotype which is the Major Histocompatibility complex as best as you can.(5)
A clinically important haplotype: the major
histocompatibility complex
Major Histocompatibility Complex (MHC)
a. Human Leucocyte Antigen (HLA) system; ~4 Mb region on chr 6
b.in vertebrates, individuals express a set of MHC proteins selected from a
diverse genetic repertoire of the species
c. highly polymorphic system, with 50 – 150 alleles per locus; higher sequence
variation than found in most polymorphic proteins
d.set of expressed MHC proteins defines a partial haplotype of an individual
e. compared with other haplotype blocks, the MHC region shows unusually
wide individual variation
MHC region contains over 120 genes, coding for proteins that?(3)
- provide the mechanism by which the immune system distinguishes ‘self’ molecules – i.e. those to be tolerated – from ‘non-self’ molecules – i.e.
those recognized as foreign invaders that must be repelled - determine individual profiles of competence for resistance to diseases
- are useful markers for determining relationships among populations of humans and animals, and for tracing large-scale migrations and population interactions
List the applications of MHC region(4)
Discuss each application in detail(4)(2)(3)(3)
Applications of MHC region
a.MHC haplotypes control donor–recipient compatibility in transplants
* if not immunosuppressed by drugs or unless the donor is an identical sibling, transplanted organs are recognized as foreign and rejected
* MHC proteins bind peptides and present them on the cell surface
* specifically, T-cell receptors of MHC proteins bind foreign proteinderived
peptides and trigger the cleavage of foreign protein
* MHC-peptide complexes are also involved in removing self-complementary T-cells in the thymus during development, at the stage when the
distinction between self and non-self is being ‘learnt’
b. MHC haplotype influences autoimmune diseases
* thus, breakdowns in self-/non-self-distinguishability that result in a person’s immune system attacking his/her own tissues
* rheumatoid arthritis, multiple sclerosis, type I diabetes and systemic lupus erythematosus (SLE
c. MHC haplotypes determine patterns of disease resistance
* different MHC molecules have different binding specificities and can present different sets of peptides
* individuals whose MHC molecules do not effectively present epitopes from a particular pathogen will be more susceptible to infection
* for instance, MHC haplotype is a predictor of survival horizon in people infected by HIV (i.e. HLA-B and HLA-C)
d.MHC haplotypes influence mate selection
* opposites attract: people will tend to find other as romantically attractive
if they have different MHC haplotypes
* association between MHC haplotype and body scent
* effect will result in production of offspring with MHC molecules that can present a broader repertoire of peptides, thus, broader resistance to infection
Populations
a. Define a population?(1)
b. How do genomes differ in a population?(3)
c. Discuss the Macaques(2)
a.Population – an interacting and interbreeding group of individuals of the same species inhabiting the same geographical area
b.How do genomes differ in a population?
- variation reveals population structure and its history (see Box 1.7)
- little variation: (genetic) bottleneck or isolation from a larger population (i.e. ‘founder’ effect)
- high variation: longer evolutionary history – argument for ‘out of Africa’
theory
Box 1.7 – Application of haplotypes to infer relationships
between populations: the Barbary macaques
c.The macaques (Macaca sylvanus)
- island of Gibraltar; introduced in WWII; four individuals in 1943; Winston Churchill ordered that the population be restocked and maintained as 24
individuals
- Modolo et al. 2005: 428 bp of mtDNA; individuals from Gibraltar, Morocco and Algeria -> 24 diff. haplotypes; 1 – 26 diff. mutations (all but one were SNPs
List the 3 major clusters(3)
Three major clusters
*Molecular dating – the Moroccan and Algerian populations separated >1.2 MYA
*Likely that the female line in the current Barbary macaques originated from both the Moroccan and Algerian population
*Morocco – main
haplotype + several
others; likely the
oldest population!
Species
a. List the 2 fundamental issues in relation to the idea of species(2)
b. Discuss the species concept(3)
c. Why have many groups of higher organisms coalesced into a hierarchy of discrete groups, with differentiating sets of features(2)
a. Two fundamental issues in relation to idea of species
* many living things can be classified into discrete non-overlapping groups (i.e. species)
* a catalogue of these groups can be organized into a hierarchy/tree based on similarities
b. Species concept
* long-standing commitment to the idea of species; Linnaeus and Darwin –virtually unchallengeable
* satisfactory definition of term has remained elusive – see Box 1.8
* non-trivial exceptions challenge all the definitions that have been proposed
c.Why have many groups of higher organisms coalesced into a hierarchy of discrete groups, with differentiating sets of features evolution
* discreteness of the evolutionary niches for which different populations
compete
*emergence of reproductive isolating mechanisms, incl. both geographic
barriers and genomic ones
Species
a.Evolution
How is variety generated?
How do diploids and haploids generate variety
b.Compare Eukaryotes vs prokaryotes
c. State the role of genomics
- Give a pro and con
a.Evolution
- requires a mechanism to generate variety in a population of reproducing
individuals, thus, mutations
- diploids – independent assortment and recombination
- haploids – gene transfer
Eukaryotes vs prokaryotes
- eukaryotes: sexual reproduction; ancestors vs descendants, thus, hierarchical organization
- prokaryotes: exchanging genetic material doesn’t fit into hierarchical classification scheme of classical taxonomy
c.Role of genomics
- raised opportunities and challenges to the idea of species
- pro: DNA seqs of members of diff. species differ more than the variation
among individuals of the same species
- con: extent of seq. diversity to distinguish species is quite variable across taxa; genomic distance also doesn’t help; in microbiology, bacterial species
are those that maintain > or = 97% seq. ID in 16S rRNA
The biosphere
a. What do genomes also contain?(1)
- What are organisms on Earth products of?
- Examples
b. What did the G. E. Hutchinson (1965): The Ecological Theater and the Evolutionary Play emphasize?
c. Extinctions
- 1859
- 1796
- 65Mya
- Current extinction
The biosphere
a. Genomes also contain records of evolutionary history
- organisms on Earth are products not only of response to imposed environment, but also show interactions among individuals and species
- examples: photosynthesis and aerobic metabolism; pathogenic viruses and bacteria
b. G. E. Hutchinson (1965): The Ecological Theater and the Evolutionary Play
- emphasized the interdependence of environment and living things, which reciprocally affect each other
c. Extinctions
- Darwin (1859): new species arise
- Cuvier (1796): species go extinct – major natural catastrophes (see Fig. 1.6 & Box 1.9)
- ~65 MYA: asteroid landed in the Yucatan Peninsula of Mexico
- current extinction: mainly human activity – excessive hunting,pathogen extermination, habitat destruction; others are natural events – elm yellow, white nose disease and transmissible cancer
