lecture 03

Question 1

Single-nucleotide polymorphisms (SNPs)…continued!

a. How many mutations do various DBs contain?
b. How many percent of how many genes?
c. What do individuals have of SNPs? what do these reflect?
d. How are groups of SNPs co inherited?
e. How are mutations separated on chromosomes? What is the difference between these processes?(1)

Answer 1

a. various DBs (see Box 1.4): contain over 100,000 mutations from 3,700 genes + more are still being reported
b. 6.2% of the ∼23,000 genes
c.individuals have an accumulated collection of SNPs, reflecting mutations that occurred in our ancestors
d.some groups of SNPs are co-inherited as blocks; others not
e. note: mutations on different chr’s will be separated by independent assortment within 1 generation; same chr -> recombination, albeit a slower
process (no recombination on haploid sequences of Y chr or mtDNA

Question 2

List the 8 mechanisms by which mutations can affect human health(8)

Answer 2

By what mechanisms can mutations affect human health?
* some mutations led to protein inactivity (e.g., FVIII or IX in haemophilia; Phe-
OH in PKU, converts Phe to Tyr)
*other mutations cause disease only when in combination with unusual lifestyle
features or triggered by specific eventsZ-mutation of a1-antitrypsin (Glu342->Lys), where smoking enhances its tendency to cause emphysema
* loss-of-function mutations: homozygous recessive (lethal) vs heterozygous
(carriers)
* insoluble aggregates of misfolded proteins – classical amyloidoses, Alzheimer’s,
Huntington’s, a1-antitrypsin, prion diseases (e.g., mad cow disease) and insulin
* some deleterious mutations carry compensating advantages due to protein
interactions – they are not selected out of the populations (see Box 1.5)
* mutant regulatory protein or receptor can disorganize the operation of a
pathway even if all components of the pathway regulated are normal
*some abnormal regulatory proteins cannot be activated at all vs. constitutive
activation
* physiological (G prot-coupled receptors) or developmental (Laron synd) defects

Question 3

Discuss sequence variations within individuals-cancer genomics(4)

Answer 3

Sequence variations within individuals – cancer genomics

• healthy cells accumulate mutations at a modest rate
• cancerous cells have lost the ability to control DNA accuracy
• research strategy: compare healthy cells with cancerous ones-distinguish between variations arising from disease vs healthy cells in same individuals

Question 4

Discuss

a. Glucose-6-phosphate dehydrogenase(2)
b. Drugs and beans(5)
c. The malaria parasite story-drugs and beans(3)

Answer 4

a.Glucose-6-phosphate dehydrogenase (G6PDH)
* produces glutathione, which disposes H2O2
* RBCs lack nuclei and mitochondria; lack of active G6PDH = H2O2 build-up, oxidize
and denature haemoglobin; RBCs destruct  haemolytic anaemia

b. Drugs and beans
* fava beans
* anaemic episodes in G6PDH patients – food taboo (Pythagoras)
* metabolized products + O2 = H2O2  oxidative stress of cells
* drugs
* antimalarial drugs or large doses of VitC  oxidative stress of cells in G6PDH patients

c.Drugs and beans: The malaria parasite story…
* malaria parasite infects RBC, and akin to drugs, cause oxidative stress 
destroy entire cell + pathogen
* fava beans – antimalarial effect in healthy individuals + G6PDH patients (are at
an advantage, until Plasmodium produces G6PDH to destroy H2O2)
* malarial link explain prospering fava beans in farming + mutant G6PDH gene in
human populations

Question 5

Haplotypes

a. Discuss mutations in diploids(3)
b. Discuss haplotypes in humans(3)
c. What is a haplotype(1) and what does it provide?(2)

Answer 5

a. Mutations in diploids
* when on same chr, become unlinked thru recombination
* recombination: affected by distance + vary in the genome, and thus ‘hot’ vs. ‘cold’ spots
* when on different chr’s separate within a single generation (assortment!)

b.In humans
* 100-kb regions remain intact, with expected number of SNPs and
relatively few of the possible combinations
* ave. SNP density = 0.1% or 1 SNP/kb, meaning ~100 SNPs per 100-kb
region; if all present  large number of combinations (2100)
* discrete combinations of SNPs in recombination-poor regions define a
haplotype or ‘haploid genotype

c.Haplotype: local combination of genetic polymorphisms (e.g., SNPs)
that tend to be co-inherited as a block
* provide a cost effective way to characterize entire genomes
* enable ID of phenotype–genotype correlations; detection of migratory and
interbreeding patterns in populations (e.g., Y chr or mtDNA haplotypes

Question 6

Exercise 1.4(do it whether you like it or not you must like it)
Suppose that there are ten SNPs in a 50-kb region.
a) If the region is on the Y chromosome, how many possible haplotypes
are there?
b) If the region is on a diploid chromosome, how many possible
haplotypes are there?
c) Assuming a typical SNP density of one SNP/5 kb in a human genome,
and only two possible bases observed at the position of any SNP,
how many sequences could you expect to find throughout a
population, within a 100-kb region, if recombination were common at
every position in the region?
d) If only three of the possible combinations of SNPs – that is, three
haplotypes – are observed, what fraction of possible sequences does
this represent?

Answer 6

Answer on a paper