Human Genetic Variation

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Human Genetic Variation
SNPs
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Human Genetic Identity

• 99.9 identical
• 3,196,800,000 nucleotides identical
• 3,200,000 nucleotides different

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Relevance Variation Bears Difference

• Physiological and anatomical differences based on
  molecular differences
• Exception Trauma, environmental impacts
• Genetics Inherited contribution to phenotypic
  variation

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Relevance Important applications

• Identify inherited contribution to
• Disease risk
• Reactions to environmental triggers
• Reactions to treatments
• Cognitive abilities
• Requirements
• Ontology Phylogeny
• Evolution

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Types - macro

• Chromosome numbers
• Segmental duplications
• Segmental rearrangements
• Segmental deletions

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Types - medium

• Sequence Repeats
• Transposable Elements
• Short Deletions
• Short Sequence Length Polymorphisms
• Short Tandem Repeat Polymorphisms
• Sequence Tagged Sites

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Types - micro

• SingleNucleotidePolymorphisms
• Single Nucleotide Insertions
• Single Nucleotide Deletions
• (Indels)

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SNPs in Biomedicine

• Medical Conditions
• Diagnosis and treatment
• Gene therapy
• Pharmacogenomics
• Individualized drugs
• Less drug side effects
• Faster clinical trials

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Traditional Approach

• Linkage or recombinatorial mapping
• Successful for single gene disorders
• Little success for common complex traits, such as
  heart disease, diabetes, asthma, mental disorders

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Human Genetic Variation

• Single base differences in genomes between any
  two individuals 2-5 million
• Amino acid differences in proteomes between
  between any two individuals about 100,000

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

Most abundant SNPs-Single Nucleotide
Polymorphisms GATTTAGATCGCGATAGAG GATTTAGATCTCGAT
AGAG
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SNPs

• Single base pair variations among alleles
• Least abundant allele has frequency gt 1
• Not all single base pair differences are SNPs

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Occurrence

• Ca. 1/1300 bp in genomic DNA from two equivalent
  chromosomes
• Ca. 1/300 bp in whole 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

• Causative SNPs
• coding SNPS (non-synonymous)
• non-coding SNPs
• Linked SNPs
• usually non-coding SNPs

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TSC SNPdb

• A/G C/T 33
• A/C A/T C/G G/T 8
• A/C/G A/C/T A/G/T C/G/T 0.006
• A/C/G/T 0.002

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• Transitions c?t g?a

Transversions c?a g?t c?g g?c t?a a?t
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SNPs - Identification

• Sequence comparison
• PCR
• Microarrays
• Databases

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In Silico SNP Identification

• Mine existing sequence resources
• Genomic sequences
• ESTs
• BAC-end sequences
• Cost-effective genome-wide SNP discovery by
  examining regions of redundant sequence coverage
• Rare alleles difficult to spot (below error rate)

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SNPs in Overlapping Genomic Sequences
Overlapping BACs from library
50 of overlaps contain polymorphisms
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De Novo SNP Identification

• Select candidates
• Establish cell cultures
• Isolate DNA, digest, gel fractionate, clone
• Sequence, kill if repeats gt 50
• Blast against each other select gt99 id
• Run SNPFinding Program

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GATTTAGATCGCGATAGAGGATTTAGATCTCGATAGAG

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

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

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GATTTAGATCGCGATAGAGGATTTAGATCTCGATAGAG

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

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

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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

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• 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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Validation

• Correlation between phenotype and SNP
• Recombinatorial linkage vs. SNP association