Human Genomic Variation

The Story of SNPs

 Single Nucleotide
Polymorphisms (SNPs)
 In addition to variation in microsatellites
(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
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
 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

 How is SNP data useful?

1) the study of evolution
2) DNA fingerprinting
3) markers to map polygenic traits
4) 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
sufficient levels of Mg in their blood
 One contributing factor is the Na/K pump
 ATPase of this protein is composed of ,  & 
subunits (the former is the actual pump)
 A family which carried this disease had a SNP
which mapped to 11q23 (the  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
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
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
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
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!