BMS2062 Lecture Notes - Lecture 9: Protein Folding, 1000 Genomes Project, Universities Admission Index
30 May 2018
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Week 5. Exploiting genomic information and from
mRNA to functional protein
WHAT MAKES AN INDIVIDUAL? GENOME FINGERPRINTING, FASTER SEQUENCING
AND THE ROUTE TOWARDS PERSONIALISED MEDICINE
• How can we use information from the HGP?
o Understand basic complex genetic disease
o Predict susceptibility to complex disease
o Diagnose disease and monitor disease
o Manage and cure disease
• What makes an individual?
o Except perhaps twins, no two individuals are genetically identical
o The more closely related two people are, the more similar their genomes
o DNA sequence variation underpins phenotypic differences
• SNP (single nucleotide polymorphisms)
o 90% of human genome variation is in the form of SNPs
o Theoretically, a SNP could have four possible alleles but most SNPs have only 2
o Human genome collectively contain more than 18 million SNPs
o Mapping an individual's SNPs can provide physiological information
o Eg. ApoE i Alzheie’s holesteol taspot
- an individual who inherits at least one E4 allele will have a greater chance of getting
Alzheie’s
-iheitig the E allele idiates that a idiidual is less likely to deelop Alzheie’s
o Determining the SNP pattern or haplotype of an individual will be useful to test for
susceptibility – drg responses and side effects to specific SNP profiles may also allow
treatments to be specifically tailored to individuals
o Many SNP do not cause disease but presence or absence can be used to flag the
presence of nearby defective genes and help assess risk of developing a disease
o Genetic linkage analysis: identify SNPs associated with disease
• Recombination between paternal chromosomes during meiosis is non-random
- occurs at hot spots so that discrete segments of DNA are shuffled during meiosis
-each recombined DNA segment is known as a haplotype block and has a unique SNP pattern
• Using SNP pattern to barcode different haplotype blocks reduces the complexity of an
idiidual’s geotype – e do’t eed to physially seuee the etie geoe o ap eey
SNP to fingerprint an individual
-often a subset of tag SNPs will discriminate between haplotypes
find more resources at oneclass.com
find more resources at oneclass.com
• Personalised medicine :
o Haplotyping of individuals via SNP analysis
Producing risk profiles for broad range of diseases and treatment will require:
o Reference map of SNPs – sequencing
o Developing rapid and cheap screening methods to map at least 10,000 SNPs in patients –
also need to be reliable
Customising medical care for each individual by:
o predicting susceptibility to complex disease
o Diagnosing complex disease or syndromes
o Classifying disease – can start to tailor treatment to patient
o Managing disease – individualised treatment via pharmacogenetics
o Curing disease by gene therapy
o
• International Haplotype map project:
o Characterised 600,000 SNPs
o Identified SNPs in genomes of 270 individuals from 4 ethnic groups
o Such SNP sequencing has allowed the development of SNP microarrays
• Principle of SNP arrays:
o Allows lab to quickly figure out patterns of SNPs
o Microscope slide -> spot thousands of DNA
o Set up targets and at each position of matrix, 4 different alleles that corresponds to
variation -> can isolate DNA -> hybridise and ask which of these dots do you see a signal
o A gene chip contains thousands of spots, each containing ss 25 base reference DNA
molecules (oligonucleotides)
o Each SNP position is represented by up to 40 different but overlapping (tiled) DNA
sequences which allows for high degree of accuracy (reduces false positives)
o Hybridisation on chips -> a ask if thee’s a patte that eeges aog idiiduals ->
can be used for diagnosis
• SNP analysis is powerful but does not give all the genetic information on an individual
• Only sequencing he entire genome will give the complete picture
• Pharmacogenetics:
o Study of relationship between genetic variation and response to medications
o Individuals will react to drugs differently
o May require differing doses
o May be more or less susceptible to side effects
o Eg. use of warfarin in people with clotting diseases:
Warfarin (coumarins) are commonly used to inhibit VKORC1 and prevent
clotting but too much leads to serious side effects such as bleeding
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Exploiting genomic information and from mrna to functional protein. An individual who inherits at least one e4 allele will have a greater chance of getting. Occurs at hot spots so that discrete segments of dna are shuffled during meiosis. Often a subset of tag snps will discriminate between haplotypes: personalised medicine , haplotyping of individuals via snp analysis. Producing risk profiles for broad range of diseases and treatment will require: reference map of snps sequencing, developing rapid and cheap screening methods to map at least 10,000 snps in patients also need to be reliable. International haplotype map project: characterised 600,000 snps. Individuals will react to drugs differently: may require differing doses, may be more or less susceptible to side effects, eg. use of warfarin in people with clotting diseases: Warfarin (coumarins) are commonly used to inhibit vkorc1 and prevent clotting but too much leads to serious side effects such as bleeding.
