Download Human Genomic Variation

Human Genomic Variation
The Story of SNPs
Single Nucleotide
Polymorphisms (SNPs)
 In addition to variation in microsatellites
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(VNTRs), genetic variation takes the form
of SNPs (point mutations)
The SNP Map Working Group has
identified about 1.5 million SNPs
There is about 1 SNP / 2 kb of genome
Each ethnic group has its own collection
SNPs have been classified as major or
minor, depending on frequency
Is a SNP really a SNP?
 False positives can result from 1) inclusion of
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paralogs and 2) errors in sequencing
Warren Gish at Wash U. developed a
procedure to minimize false SNPs
Initially, 80,469 SNP candidates were found in
1.3 Mb of finished sequence
Paralogs were identified by their high frequency
of variation (1 base in 50, instead of 1 in 1000)
This left 69,756 positions, only 59 of which were
given a high probability of not resulting from
sequencing error (20 were later confirmed)
SNP Prevalence & Importance
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98% of all genes are within 5 kb of a SNP
93% of all genes contain at least 1 SNP
59% of all genes have 5 or more SNPs
39% of all genes have 10 or more SNPs
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How is SNP data useful?
the study of evolution
DNA fingerprinting
markers to map polygenic traits
developing genotype-specific medication
SNPs and Disease
 Linkage- how close 2 loci are on a chromosome
 Linkage disequilibrium- when 2 alleles are
inherited together more often than expected
 Haplotype- the set of alleles on a chromosome
Each person has 2 haplotypes in a given region
If we track SNPs that are in linkage disequilibrium
and correlate this with a disease phenotype, we
have identified SNP markers that form a
particular haplotype associated with this disease
Two Populations with Different
Frequencies of a Disease
Polygenic Traits
 For monogenic traits, there are 3 different
genotypes
 For polygenic traits, there are 3N different
genotypes
 Traits that are polygenic but can be measured in
some quantitative way can be mapped to QTL
(Quantitative Trait Loci)
 Traits such as schizophrenia, high blood
pressure, diabetes, cancer and Alzheimer’s may
someday be mapped to QTL
One Polygenic Trait:
Hypomagnesemia
 People with this disease are unable to maintain
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sufficient levels of Mg in their blood
One contributing factor is the Na/K pump
ATPase of this protein is composed of a, b & g
subunits (the former is the actual pump)
A family which carried this disease had a SNP
which mapped to 11q23 (the g subunit)
The SNP changed Gly to Arg in the only
transmembrane domain.
Caused all 3 subunits to localize to cytoplasm
Mitochondrial SNPs
 >50 disease-causing SNPs map to mitochondria
 Phenotypes mostly affect cardiac & skeletal
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muscle
13 genes required for ETC are encoded by
mitochondria, as are 22 tRNA and 2 rRNA
2000 patients suspected of having diseases
caused by mitochondrial SNPs were screened
108 had known SNPs
More SNPs may be yet to be discovered or
some diseases may not be due to SNPs
Incorrect mRNA Splicing
 BRCA1 has been linked to breast cancer
 SNPs which do not alter the aa sequence of a
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protein are considered “silent”
Adrian Krainer (CSH) identified SNPs which
lead to alternate splicing
5’, 3’ ends of exons as well as internal
sequences contribute to splicing
ESEs are exonic splicing enhancers and ESSs
are exonic splicing silencers
SNPs in these regions lead to breast cancer
Nondisease SNPs
 “What is food to some men may be fierce
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poison to others” - Lucretius Caro
About 10% of people experience RBC
lysis upon consuming fava beans
These people lack G6P dehydrogenase
Fava beans act to increase a RBC’s
sensitivity to oxidants such as H2O2
NADPH is required to break down H2O2
RBC’s produce NADPH using G6PD,
which is encoded on the X chromosome
G6PD SNPs
 20% of Mediterranean population has
563C » T (no activity)
 20% of African population has 202G » A
(reduces activity by 10%)
 20% of African males have 376A » G
(produces normal activity)
Response to Medications
 Many drugs must be metabolized to
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intermediates before they become active
Optimum dosage for drugs is determined
for the “average” person
People can typically be divided into poor,
typical, and ultra-rapid metabolizers
Cytochrome P450 is one enzyme used for
drug metabolism
This enzyme is encoded for by two genes,
2C19 & 2D6
SNPs in Cytochrome P450
 2D6 has 12 SNPs that have been identified
 G » A in exon 4 is the most common, it
leads to inactivity
 >40 different drugs require 2D6 to become
active, including: antiarrhythmics, opioids,
antidepressants, and antipsychotics
 2C19 is required to metabolize
mephenytoin, an epilepsy drug
 While only 2% of Caucasians have a 681G
» A SNP, 23% of Asians have this SNP
Pharmacogenomics
 The study of a gene which affects drug
metabolism, transport, or reception is
called pharmacogenetics
 The study of all genes in this category is
another of the “omics” sciences
 Traditional drug development was aimed
at delivering medications which were safe
and effective for everyone
 Now, genome-specific medicine may be
developed which is more effective in
individuals with specific SNP combinations
Two Classes of Drug
Metabolizing Enzymes
Efficacy vs. Toxicity for a Drug
 Drug response is usually polygenic
 Response determined by just 2 alleles (ie.
metabolism & receptor) will have 9 (32)
genotypes
 Different #s of people will experience a
therapeutic vs. a toxic effect, depending on
genotype
mmRR
mmRr
mmrr
MmRR
MmRr
Mmrr
MMRR
MMRr
MMrr
You Don’t Need a SNP to
Inactivate Cytochrome P450!
 Cytochrome P450 3A is used to convert
drugs to a form that will be excreted
 Grapefruit juice contains an unknown
component which destroys this enzyme
 1 glass can block activity for about 24 hours
 While normal breakfast amounts slightly
elevated levels of a cholesterol-lowing drug,
concentrated juice 3 times a day increased
concentrations by 12 fold!