the co-evolution of genetics and statistics bio-stat seminar 2 february 2011
TRANSCRIPT
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The Co-Evolution of Genetics and
StatisticsBio-Stat seminar 2 February 2011
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From the First
•Gregor Mendel is recognized as the founder of genetics
•Was the first to use “math” to define a biologic process.
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Role of Biostat
•Fisher suggested in 1936 that Mendel’s data was a little too good.
•Fisher is thought of as a geneticist.
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The Chemistry of DNA
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Structure of DNA
Double helix=2nm10 Base pairs/turn=10nm
140 BP/nucleosome
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How Has “Math” Driven Genetics?
Genotype
GG=0.25Gg=0.50gg=0.25
PhenotypeGx=0.75gg=0.25
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Some Questions in Genetics
•There are 4 bases in DNA
•There are 20 amino acids
•How do you order 4 to code for 20?
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Simple Math
4=44X4=16
4X4X4=64So 3 bases required
at a minimum
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More Questions
•If 3 required, spacing?
Boxcar= ATGCAGTSequential=ATGCAGT Spaced=ATGaCAGaT
Solution First a homo-polymer (TTTTTTT)This produce a peptide of phenylalanine
Then a co-polymer TTCCTTCCTTCCThe pattern of AA would allow dissection
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Example
•TTCCTTCCTTCCTTCCTTCC
•Boxcar Sequential
•TTC=Phe TTC=Phe
• TCC=Ser CTT=Leu
• CCT=Pro CCT=Pro
• CTT=Leu TCC=Ser
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How Did We Get Here?
•Genetics is the study of variation
•“Easy” genetics involved variation by genes of major effect.
•Sickle cell, cystic fibrosis are examples of single gene diseases
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Finding Single Genes
•Collect families that show the trait
•Analyze their DNA find sections that are common with trait
•Assess the probability that these are shared randomly LOd ratio
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How is DNA Measured?
•Before the age of the genome, centimorgans
•Humans have 22 paired chromosomes
•These segregate at cell division independently
•Along a chromosome the probability that a trait is near something is measured in centimorgans
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DNA is in Base Pairs Now
•The chromosomes are numbered largest to smallest (1-22)
•Positions are now located by Chr # and position along that Chr. (Chr2:108234125)
•There are a little more than 3x109 BP
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Mutations vs. SNP•Currently the trend is to talk of
“variation” not mutation.
•SNP=Single Nucleotide Polymorphism
•Most SNP are dimeric (A/G) and have a frequency (0.895/0.105)
•SNP’s mark positions not “mutations”!
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Other Terms
•InDel
•VNTR
•marker
•Coding
•Non-Coding
•synonymous
•promoter
•epigenetic
•imprinting
•mitochondrial
•Intron/exon
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Data Sets•Arrays
•SNP
•ExpressionGenotype
SNP - Looking for regions of
DNA associated with a trait
PhenotypeExpression - What
genes are “produced”
How the biochemistry is changed
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Help From the “Math”Gifted!
•These are complex datasets
•Analysis can be “simple”, it shouldn’t be!
•Getting in early is critical
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Next Big Challenge•Network analysis• •Andrew Mugler, Boris Grinshpun, Riley Franks, and Chris H.
WigginsStatistical method for revealing form-function relations in biological networksPNAS 2011 108 (2) 446-451; published ahead of print December 23, 2010, doi:10.1073/pnas.