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Pedagogical Objectives Bioinformatics/Neuroinformatics Unit

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Pedagogical Objectives Bioinformatics/Neuroinformatics Unit Review of genetics Review/introduction of statistical analyses and concepts Introduce QTL analysis – PowerPoint PPT presentation

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Title: Pedagogical Objectives Bioinformatics/Neuroinformatics Unit


1
Pedagogical Objectives Bioinformatics/Neuroinforma
tics Unit
  • Review of genetics
  • Review/introduction of statistical analyses and
    concepts
  • Introduce QTL analysis
  • Introduce bioinformatic tools
  • Review/introduction of molecular techniques

2
So, now the gametes of the F1 have some of the
DNA from each F0 strain. So, the F2 generation
will have a collage of the F0 DNA
3
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4
Hey! We have at Least three maps! Chromosomal, li
nkage, physical.
Linkage map is in centimorgans.
5
This is a PCR product for a marker or Locus
(remember Quantitative Trait Loci?) it is a small
stretch of DNA that is different between the two
different strains. A marker can be in any aspect
of the DNA gene, promoter, expressed
sequence, intron, junk, etc., etc..
6
Qualitative vs Quantitative Traits
  • Qualitative Traits
  • Influenced by a single gene
  • Typically follow simple patterns of inheritance
  • Phenotypes fall into distinct categories (nominal
    scale)
  • Trait expression is typically unaffected by
    environment
  • Quantitative Traits
  • Influenced by multiple genes, perhaps interacting
    genes
  • Do not follow simple patterns of inheritance
  • Phenotype is measured on continuous scale
    (interval scale)
  • Trait expression may be affected by environment

7
Pedagogical Objectives Bioinformatics/Neuroinforma
tics Unit
  • Review of genetics
  • Review/introduction of statistical analyses and
    concepts
  • Introduce QTL analysis
  • Introduce bioinformatic tools
  • Review/introduction of molecular techniques

8
What is key in using regression to control for
various extraneous variables is the additive
model of variance.
s2total s2sex s2body weight s2brain weight
s2age s2error s2olfactory bulb genes
9
Thus, the total variance can be partitioned into
the variance associated with each of these
extraneous variables such as sex, body weight,
brain weight, and age. Then we can successively
remove the variance associated with each of
these variables and hopefully just have residual
variance that only pertains to olfactory bulbs.
10
Let us first consider the case of simple linear
regression before we tackle the problem of
multiple regression.
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Residual (error)
_

Y
OB Volume
Y
Variance predicted by X
Body Weight (grams)
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The variance left over after the variance from
the other variable(s) has been removed is the
residual variance. This residual variance
is precious to us because it has the variance
specific to gene effects on olfactory bulbs.
15
So the SSE SSyy is our
treasure, yet anothers trash.
16
By using multiple regression, We can remove the
variance associated with extraneous variables
and so statistically control for these variables.
17
How to make mistakes with statistics
  • Type II (beta) errorsAKA false negatives
  • Small effect size
  • Small n
  • Greater variance in scores
  • Greater the error variance, the more Type II
    errors
  • Type I (alpha) errorsfalse positives
  • Stringency of the alpha error rate
  • Significant Individual point p 1.5 x 10-5 for
    genome-wide
  • a .05
  • Suggested individual point p 3 x 10-4 for
    genome wide a .63

18
Thus, lots of error variance will give us false
negatives (Type II errors) when we do QTL
analyses!
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23
Pedagogical Objectives Bioinformatics/Neuroinforma
tics Unit
  • Review of genetics
  • Review/introduction of statistical analyses and
    concepts
  • Introduce QTL analysis
  • Introduce bioinformatic tools
  • Review/introduction of molecular techniques

24
QTL is good for detecting the approximate locus
of multiple genes affecting a phenotype across
all the chromosomes, except Y.
This is a graph that displays the likelihood
ratio statistic as a function of locus on the
various chromosomes, which are numbered at top.
25
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26
This is a PCR product for a marker or Locus
(remember Quantitative Trait Loci?) it is a small
stretch of DNA that is different between the two
different strains. A marker can be in any aspect
of the DNA gene, promoter, expressed
sequence, intron, junk, etc., etc..
27
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LRS is High
D
D
D
D
D
D
D
D
D
D
D
D
Phenotypic Measurement (Residual)
B
B
B
B
B
B
B
B
B
B
B
B
D
B
29
LRS is LOW
B
D
B
D
B
B
D
D
B
X
B
B
B
D
Phenotypic Measurement (Residual)
D
B
X
D
B
D
D
D
B
D
D
B
D
B
D
B
30
This line is the criterion for suggested level of
significance.
This line denotes the criterion for significance
p lt .05.
Squiggly blue line is the LRS.
31
Clickable track to corresponding display in UCSC
Genome Browser.
Zooming in on Chromosome 6
Each Small colored box represents a known gene
Likelihood ratio statistic
SNP Density
32
QTL is good for detecting the approximate locus
of multiple genes affecting a phenotype across
all the chromosomes, except Y.
This is a graph that displays the likelihood
ratio statistic as a function of locus on the
various chromosomes, which are numbered at top.
33
Pedagogical Objectives Bioinformatics/Neuroinforma
tics Unit
  • Review of genetics
  • Review/introduction of statistical analyses and
    concepts
  • Introduce QTL analysis
  • Introduce bioinformatic tools
  • Review/introduction of molecular techniques

34
QTL is good for detecting the approximate locus
of multiple genes affecting a phenotype across
all the chromosomes, except Y.
This is a graph that displays the likelihood
ratio statistic as a function of locus on the
various chromosomes, which are numbered at top.
35
Clickable genes!
36
For Gabarap, Dr.Gs gene.
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Bioinformatics Tools
  • GeneNetwork--performs a QTL analysis and reveals
    LRS as a function of markers on chromosomes
  • UCSC Genome Browser-- reveals known genes over a
    given region of chromosome--also gives--also
    provides relative expression levels of genes via
    gene chips
  • Allen Brain Atlas provides in situ hybridization
    data--cell layers cells in which gene is
    expressed.
  • Entrez gene--sequence of given genes including
    coding sequence.
  • PubMed--articles about given genes ( other
    stuff)

46
Pedagogical Objectives Bioinformatics/Neuroinforma
tics Unit
  • Review of genetics
  • Review/introduction of statistical analyses and
    concepts
  • Introduce QTL analysis
  • Introduce bioinformatic tools
  • Review/introduction of molecular techniques

47
This is a PCR product for a marker or Locus
(remember Quantitative Trait Loci?) it is a small
stretch of DNA that is different between the two
different strains. A marker can be in any aspect
of the DNA gene, promoter, expressed
sequence, intron, junk, etc., etc..
48
For Gabarap, Dr.Gs gene.
49
Gene Chips DNA microarrays
  • Can use fluorescent cDNAs (mRNAs or RNAs) as
    probes.
  • Yield the pattern of gene expression across 2
    different conditions.
  • Can examine many (thousands) of genes at once.
  • Does not give cell-by-cell resolution.

50
In situ hybridization
  • Finding out which cell(s) express a gene by
    probing for mRNA.
  • Probes to mRNA can be made of antisense DNA or
    RNA (sense is control).
  • Probes are labeled.
  • Probes hybridize with specific mRNAs being made
    in a cell.
  • Can only examine expression of one or two genes
    at a time.

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