The Genome Access Course Sequence Variation: SNPs, etc.

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TheGenomeAccessCourseSequence
VariationSNPs, etc.
Marilyn Monroe, Andy Warhol
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Human Genetic Identity

• 99.9 identical
• 3,200,000 nucleotides different
• Single base differences in genomes between any
  two individuals ca. 3 million
• Amino acid differences in proteomes between any
  two individuals ca. 100,000

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Variation Types

• Macro
• Chromosome numbers
• Segmental duplications, rearrangements, and
  deletions
• Medium
• Sequence Repeats
• Transposable Elements
• Short Deletions, Sequence and Tandem Repeats
• Micro
• Single Nucleotide Polymorphisms (SNPs)
• Single Nucleotide Insertions and Deletions
  (Indels)

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Relevance Important applications

• Identify inherited contribution to
• Disease risk
• Reactions to environmental triggers
• Reactions to treatments
• Cognitive abilities
• Requirements
• Forensics (incl. WTC)
• Ontology Phylogeny
• Evolution

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Most common diseases are caused by a combination
of genes and environment
Stroke
Manic-depression
Myocardial Infarction
Breast cancer
Hypertension
Diabetes
High Cholesterol
Obesity
Schizophrenia
Inflammatory Bowel Disease
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Roles for variation in genome analysis

• Physical Mapping
• enriched marker set
• Population Structure
• haplotype analysis
• evolutionary studies
• Association Studies
• population stratification
• metabolic pathways
• Functional Analysis
• Pharmacogenomics
• protein structure

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Raw Genome Data
Biological variation vs. sequence variation
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• Human Genetic Variation

Most abundant type SNPs-Single Nucleotide
Polymorphisms GATTTAGATCGCGATAGAG GATTTAGATCTCGAT
AGAG

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SNPs in Overlapping Genomic Sequences
Overlapping BACs from library
50 of overlaps contain polymorphisms
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SNPs What they are (and arent )

• Single base pair variations among allelic
  sequences
• Least abundant allele has frequency 1
• Not all single base pair differences are SNPs
• Nor are all point mutations (indels are not)

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SNP - Identification

• Sequence comparison
• Genomic sequences
• ESTs
• BACs
• Rare alleles difficult to spot (below error rate)
• PCR
• Microarrays
• Databases (in silico)

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Occurrence

• Ca. 1/1300 bp between two alleles
• Ca. 1/300 bp between populations
• In intergenic regions, introns exons
• Functionally constrained DNA less diverse
• 50 of CDS SNPs synonymous
• Frequency varies by variation type

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Types of SNPs

• Genic, coding SNPs
• non-synonymous
• Maintaining vs. altering protein
  structure/function
• synonymous
• Maintaining vs. altering splicing
• Genic, non-coding SNPs
• Regulatory SNPs
• Maintaining vs. altering gene expression
• Intronic SNPs
• Maintaining vs. altering gene expression/splicing
• Linked SNPs
• usually intergenic

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GATTTAGATCGCGATAGAGGATTTAGATCTCGATAGAG

• Rare Alleles
• ---o--------------------
• -----o------------------
• -------o----------------
• -----------o------------
• ---------------o--------
• -------------------o----
• Many

• Common Alleles
• ----o-------------------
• ----o-------------------
• ----o-------------------
• --------------------o---
• ---------o----------o---
• --------------------o---
• Few

Rare Alleles ---o-------------------- -----o------
------------ -------o---------------- -----------o
------------ ---------------o-------- ------------
-------o---- Many
Common Alleles ----o------------------- ----o-----
-------------- ----o------------------- ----------
----------o--- ---------o----------o--- ----------
----------o--- Few
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Sites for Viewing SNPs

• UCSC Browser (http//genome.ucsc.edu)
• SNP Consortium (http//snp.cshl.org/)
• NCBI dbSNP http//www.ncbi.nlm.nih.gov/SNP)

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Aaron the Lemba
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NCBIs dbSNP - variation and polymorphism
Variant position A/G
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Variations mapped onto protein structures
3,868 variations (6 of coding region variations)
have been mapped to a 3D structure
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SNPs vs. Haplotypes
GATTTAGATCGCGATAGAGGATTTAGATCTCGATAGAG
CGGGTATCGATTTAGATCGCGATAGAGTTGCCTACA CGAGTATCGATTT
AGATCTCGATAGAGTTGTCTACA
Many polymorphisms make a type
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• Responders
• tcgaggaacagggctcttaaaaatgctttatccgcttag
• tcgaggaacagggctcttaaaaatgctttctccgcttgg
• tagagcaacagggctctaaaaaatgctttctccgcttag
• Non-responders
• tagtgaaacagggctctgaaaactgctttatccgattcg
• tagtggaatagggctctgaaaactgctttatccgattgg
• tcgtggaacagggctctgaaaactgctttgtccgattgg

Responders -c-a-g--c--------t----a------a----c--a-
-c-a-g--c--------t----a------c----c--g- -a-a-c--c
--------a----a------c----c--a- Non-responders -a-t
-a--c--------g----c------a----a--c- -a-t-g--t-----
---g----c------a----a--g- -c-t-g--c--------g----c-
-----g----a--g-
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Haplotypes in NCBIs MapViewer
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