Human Genetic Variation

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Human Genetic Variation

• http//www.genome.gov/10001551

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Handout

• Understanding Human Genetic Variation
  NIH/NHGRI
• http//science.education.nih.gov/supplements/nih1/
  genetic/guide/genetic_variation1.htm
• http//science.education.nih.gov/supplements/nih1/
  genetic/guide/genetic_variation2.htm
• http//science.education.nih.gov/supplements/nih1/
  genetic/guide/genetic_variation3.htm

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DNA Variation-Polymorphisms

• Restriction fragment length polymorphism-RFLP
• Microsatellites-STRs-Short tandem repeats
• Dinucleotide repeats (CA)n, Tri- and
  Tetranucleotide repeats
• Minisatellites VNTR-Variable number of tandem
  repeats
• Single nucleotide Polymorphisms-SNPs
• Insertion/deletions

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Terms

• Genotype
• Phenotype

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Genetic Mapping of Mendelian Characters

• Board work
• Informative meioses
• Haplotypesalleles of linked loci in phase
• Recombinants
• Linkage analysisLOD Scores

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Complex Disease Phenotypes
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Gene Discoveries for Common Complex Diseases
Type 2 Diabetes Prostate Cancer Systemic Lupus
Erythematosus Myocardial Infarction Inflammatory
Bowel Disease Macular Degeneration
Breast Cancer Alzheimer's Disease
Macular Degeneration
Type 2 Diabetes Psoriasis
Colon Cancer
YR
90
91
92
93
94
95
96
97
98
99
00
01
02
03
04
05
06
07
HapMap Project Completed
Genes and Environment Initiative Launched
Genetic Association Information Network Launched
HapMap Project Initiated
The Cancer Genome Atlas Launched
Human Genome Project Completed
Human Genome Project Begins
NIH Research Initiatives
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Why study the etiology of complex diseases?

• 1.) Identification of susceptible individuals
• 2.) Lower risk by modifying environmental
  interactions
• 3.) Early diagnosis
• 4.) Efficacious treatment--pharmacogenetics

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Genetic analysis of phenotype

• Monogenic Trait
• Oligogenic Trait
• Polygenic Trait

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Identifying the Phenotype

• In natural populations, variation in the
  phenotype of a trait takes the form of a
  continuous phenotypic range rather than discrete
  phenotypic classes.

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Discontinuous Variation

• Tall vs. Short Pea plants

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Continuous Variation

• Class Exercise
• Human Heightvolunteers?
• Write height on the board
• Who is tall? Who is short?
• How did your group determine the phenotypic trait
  of tall?
• Short?

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Human Height Distribution
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Quantitative Trait Loci (QTLs)

• 1. Traits are quantified by measurement rather
  than qualitatively (yes/no affected/unaffected).
• 2. Two or more genes contribute to the
  phenotype each gene (allele) contributes in an
  additive way.
• 3. The effect of an individual allele may be
  small, with some alleles making no contribution.
• 4. Phenotypic expression of polygenic and
  multifactorial traits varies within a wide range.

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Distribution of F2 ratios involving QTLs

• Class Exercise
• In this case, the single quantitative trait is
  controlled by 2 genetic loci, each of which has a
  dominant and recessive allele.
• Each dominant allele is additive and contributes
  equally to the trait.
• P1 (AABB) x P2 (aabb)
• F1 (AaBb)
• F2?
• How many phenotypic classes in the F2 are
  present?
• What are the phenotypic ratios?

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Continuity of a phenotype

• 1.) Each genotype does not have a single
  phenotypic expression, but a normal distribution
  that covers a wide phenotypic range. As a
  result, the phenotypic differences between
  genotypic classes become blurred.

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Continuity of a phenotype

• 2.) Many segregating loci may have alleles that
  make a difference to the phenotype being observed.

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Continuity of a phenotype

• 3.) Epistasisinteraction of several loci

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Continuity of a phenotype

• 4.) Epigenetic variation
• DNA methylation
• X chromosome inactivation
• regulation of gene expression
• imprinting

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Natural phenotypic variation

• Function of
• The presence of different genotypes in members of
  the population
• The presence of different environments in which
  all the genotypes have been expressed

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Genotype/Phenotype correlations

• Confounded by
• Incomplete penetrance
• Variable expressivity
• Phenocopies
• Genetic heterogeneity
• Pleiotropy
• Modifier locienhanced risk and protective alleles

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Threshold Effects

• A threshold model is often used to interpret the
  discontinuous distribution of multifactorial
  traits.
• Assigning affection states and risk categories.

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Complex Genetic DiseaseQuantitative vs.
Qualitative Trait

• Frequency

Genotype
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Complex Genetic Disease
Continuously variable Polygenic Environmental
influence
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Liability Classes

• Age
• Sex
• Family history

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QTL Analysis

• Twin Studies
• Any phenotypic difference between MZ twins is
  likely to be due to environmental factors.
• The greater in frequency of the same trait in
  both members of MZ pairs who share the same
  environment in comparison to DZ pairs who share
  the same environment, the greater the likelihood
  that the trait has a genetic component.
• When a MZ concordance value is high and much
  greater than the DZ concordance, the trait is
  thought to have a genetic basis.

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• Caveats of Concordance Value Predictions
• Degree of heritability (H)
• Genetic Variance
• Environmental Variance
• Correlation coefficients (rMZ and rDz)

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Case Control Association Studies

• Case Control Studies
• Detect non-random co-occurrences between alleles
  and traits.
• Control groupunaffected
• Affected group
• Association of a particular allele with the
  phenotypeapply statistical measures, Chi Square
  test to determine statistical significance of
  association of the allele with the phenotype

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Sib Pair Analysis

• Affected sib pair linkage analysisdetermine
  whether large numbers of sib pairs with the same
  trait share one or more polymorphic loci.
• Identity by State vs. Identity by Descent