BIODATA ANALYSIS

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BIODATA ANALYSIS
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KNOWLEDGE BASE

• Descriptive vs Inferential - assumed
• Parametric/Non-Parametric - focus on choice
• Data Types/Levels of Measurement - types of
  statistic/basis for testing
• Importance of Normal Distribution
• (Non-Normality, Transformation - e.g.
  lab-based)
• Precision/Accuracy
• Differences
• Confidence, Significance - probability basis

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STRUCTURE
1,2, manysamples E.D., Regn., C.T.
Replication, Assays, Counts
Estimation/H.T.
H.T.
Study techniques
Lab. techniques
Non-Parametric
Parametric
Distributional Assumptions, Probability Basis
Size/Type of Data Set
DESCRIPTIVE ORDERED
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CONTEXT

• GENETICS 5 branches- Laws of Chemistry,
  Physics, Maths. in Biology
• GENOMICS Study of Genomes (complete set of DNA
  carried by Gamete) by integration of 5 branches
  of Genetics with Informatics and Automated
  systems
• PURPOSE of GENOME RESEARCH Info. on Structure,
  Function, Evolution of all Genomes past and
  present
• Techniques of Genomics from molecular,
  quantitative, population genetics Concepts and
  Terminology from Mendelian genetics and
  cytogenetics

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CONTEXT GENOMICS -LINKAGES
Mendelian
Cytogenetics
Molecular
GENOMICS Genetic markers DNA Sequences Linkage/Phy
sical Maps Gene Location QTL Mapping
Population
Quantitative
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CONTEXT GENETICS - BRANCHES

• Classical Mendelian Gene and Locus, Allele,
  Segregation, Gamete, Dominance, Mutation
• Cytogenetics Cell, Chromasome, Meiosis and
  Mitosis, Crossover and Linkage
• Molecular DNA sequencing, Gene Regulation and
  Transcription, Translation and Genetic Code
  Mutations
• Population Allelic/Genotypic Frequencies,
  Equilibrium, Selection, Drift, Migration,
  Mutation
• Quantitative Heritability/Additive,
  Non-additive Genetic Effects, Genetic by
  Environment Interaction, Plant and Animal Breeding

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GENOMICS - FOCUS
CLASSICAL Genetic Markers, Linkage
Analysis, Gene Ordering, Multipoint Analysis,
Genetic and QTL mapping
INFORMATICS Databases, Sequence
Comparison,Data Communications, Automation
DNA SEQUENCE ANALYSIS Sequence
Assembly, Placement, Comparison
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GENOMICS KEY QUESTIONS

• HOW do Genes determine total phenotype?
• HOW MANY functional genes necessary and
  sufficient in Biosystems?
• WHAT are necessary Physical/Chemical aspects of
  gene structure?
• IS gene location in Genome specific?
• WHAT DNA sequences/structures needed for
  gene-specific functions?
• HOW MANY different functional genes in whole
  biosphere?
• WHAT MEASURES of essential DNA sameness in
  different species?

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STATISTICAL GENOMICS

• UNUSUAL FEATURES
• Mixtures discrete/continuous variables e.g.
  combination of genotypes of genetic markers (D)
  and values quantitative traits (C)
• Empirical Distibutions needed for some Test
  Statistics e.g. QTL analysis, H.T. of locus order
• Size databases very large e.g. molecular marker
  and DA protein sequence data
• Intensive Computation e.g. Linkage Analysis, QTL
  and computationally greedy algorithms in locus
  ordering, derivation of empirical distributions
  etc.
• Likelihood Analysis - Linear Models typically
  insufficient alone

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EXAMPLE Mendelian Genetics - Cytogenetics

• GENE unit of heredity. Single gene passed
  between generations by Mendelian Inheritance
• DIPLOID Individual two copies (alleles) of each
  gene (A)
• HOMOZYGOSITY AA aa
  (genotypes)
• HETEROZYGOSITY Aa
  (genotype)
• (multiple alleles possible for a gene)
• PHENOTYPE -appearance /measurement gene
  characteristic
• - AA,Aa,aa
  (codominant)
• - AA,Aa same (A
  dominant allele)

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Example contd.

• Common Mating schemes
• Single gene haploid gene cell (AA,aa) gamete
• AA A(gamete) aa a F1 hybrid diploid
  genotype Aa
• then F1 x 1 parent (AA or aa) (Backcross)
• F1 x F1 (self-pollination - or sibs if two
  sexes) (F2)
• Mendelian Laws
• 1. Segregation Single gene trait, simple
  heredity
• Genotypic segregation ratio 11
  codominant (Backcross)
• G.S.R.
  121 (F2)
• P.S.R.
  31 (dominant alleles in F2)

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Example contd.

• 2. Independent Assortment (Inheritance of
  unlinked multiple genes). Each pair of alleles of
  a gene segregate independently of the segregation
  of alleles of another gene)
• e.g. A, B and 2 alleles for both
• 9 genotypes (AABB, AABb, Aabb, AaBB, AaBb,
  Aabb,aaBB,aaBb and aabb) in F2 progeny
• Expect G.S.R. 1212
  121242121
• For Dominant genes 4 phenotypes
• P.S.R. 9331 (A_B_, A_bb, aaB_, aabb)
• where _ ?either dominant
  or recessive allele

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EXPERIMENTAL OUTCOME

• Estimation of Expected frequency of specific
  genotype/ phenotype in population
• e.g. Freq A_b_ in F2 9/16 in previous example
• e.g. 4 independent loci
• AaBBccDd in F2
• (with parental groups of cross AAbbCCdd
  aaBBccDD)
• Clearly
• PAaBBccDd (1/2)(1/4)(1/4)(1/2)
  1/64
• N.B. Basis for estimation/testing how closely
  observed segregation fits expected segregation
  chi-squared

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No. of genotypes/phenotypes for genes in F2
progeny under Hardy-Weinberg ?m
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Mechanisms of MENDELIAN HEREDITY Gene Linkage -
genomic mapping

• Cell division and chromasomes - mitosis, meiosis
• Genetic Linkage association of genes located on
  the same chromasome. (Seg. Ratios depart from
  Mendelian. Parental (non-recombinant) types more
  frequent when recombination frequency low. Result
  of recombination (meiosis) is the existence of
  non-parental chromaosmes in cellular meiotic
  products). Each crossover (or exchange of
  chromasomal segments between homologs) creates
  two reciprocal recombinant (non-parental gametes)
• Recombination in general is random on chromasomes
  and recombination between loci is associated with
  distance between them. (Basic premises of genetic
  mapping).
• (Note relationship varies between and within
  organisms)
• Models, Linkage phase (codominance,
  experimental data), factors affecting
  recombination, (genetics, environment and
  methods, manipulation (genotypes with new gene -
  so manipulation potential)
• Measurement recombinant fraction

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Example

• For 2 loci, A and B, same chromasome
• A a B b segregation
  - two alleles each locus
• Ab, Ab, aB, ab gametes by
  meiosis
• if AB, ab possible
  Parents
• then Ab, aB recombinants
• Sampling from population, observe nr recombinant
  gametes ( Ab and aB) out of total of n samples
• Recombinant Fraction r nr/n
• Notes Usually observe phenotypic rather than
  gamete frequencies. Estimation of R.F.
  using phenotypic data involves constructing the
  likelihood. Estimation using M.L.E.
• More than 2 or 3 loci - several R.F.,
  crossover interference and relationship complex
  -use a Mapping Function, based e.g. on Poisson.
• General theory of genetic mapping -
  dependence on graining

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Example Population genetics

• Focus - frequencies, distributions, origins of
  genes in populations,
• and changes - due to mutation,
  migration, selection
• Allelic frequency (Prob) of crossover between two
  parents
• Cross Comment Allelic freq.(Prob.)
  
• A1
  A2 A3 A4
• abxcd 4 0.25
  0.25 0.25 0.25
• abxcc 3 0.25
  0.25 0.5 0
• abxab 2 (F2) 0.5
  0.5 0 0
• abxaa Backcross 0.75 0.25
  0 0
• Aaxaa Fixed 1.0 0
  0 0

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QUANTITATIVE GENETICS

• Focus - inheritance of quantitative traits. As
  number of genes controlling a trait increases, as
  effects on phenotype increase, ability to model
  through Mendelian inheritance diminishes.
• Single Gene Model
• Single-locus A two alleles A and a, three
  possible genotypes AA, Aa ad aa. Three values
  a,d, and -a assigned arbitrarily to each of
  genotypes. Population assumed to be in
  Hardy-Weinberg equilibrium (gene and genotypic
  frequencies constant generation to generation),
  and two alleles have frequencies of p and (1-p)
  q
• where population mean in terms of allelic
  frequencies and genotypic values

Aa
aa
AA
-a
d
a
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Measures of Interest

• Deviation of genotypic value from population mean
  (e.g. a-? for AA in example)
• Average effect of gene substitution (? )
  average effect on trait of one allele being
  replaced by another (e.g. for the two-allele
  system described, a gamete containing allele A
  ?progeny with genotypes AA and aa with
  frequencies p and q respectively. Similarly for a
  gamete containing allele a ?progeny with
  genotypes Aa and aa with frequencies p,q
  respectively. Mean values of each from
  probability rules and difference between the two
  gives ?. Note can also use regression of
  genotypic value (as deviation from mean)on number
  of copies of target alleles.

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Quantitative Genetics measures contd.

• Breeding Value average genotypic value of
  progeny(e.g. progeny having genotype AA receive 2
  copies of allele A etc.).
• Dominance deviation - D.D. part of genotypic
  value not explained by breeding value.
• Variances Total Genetic Variance in a Population
  Variance of genmotypic values, (usual
  probability rules) Sum of variances for B.V.
  and D.D.
• Heritability ratio of genotypic/phenpotypc
  variances
• Trait Models (Linear Model e.g. of a continuous
  trait
• where yij is trait type for genotype i in
  replication j, ? the population mean, Gi the
  genetic effect for i and ?ij the error term
  associated with genotype i in replication j