The Co-Evolution of Genetics and

StatisticsBio-Stat seminar 2 February 2011

From the First

•Gregor Mendel is recognized as the founder of genetics

•Was the first to use “math” to define a biologic process.

Role of Biostat

•Fisher suggested in 1936 that Mendel’s data was a little too good.

•Fisher is thought of as a geneticist.

The Chemistry of DNA

Structure of DNA

Double helix=2nm10 Base pairs/turn=10nm

140 BP/nucleosome

How Has “Math” Driven Genetics?

Genotype

GG=0.25Gg=0.50gg=0.25

PhenotypeGx=0.75gg=0.25

Some Questions in Genetics

•There are 4 bases in DNA

•There are 20 amino acids

•How do you order 4 to code for 20?

Simple Math

4=44X4=16

4X4X4=64So 3 bases required

at a minimum

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

Example

•TTCCTTCCTTCCTTCCTTCC

•Boxcar Sequential

•TTC=Phe TTC=Phe

• TCC=Ser CTT=Leu

• CCT=Pro CCT=Pro

• CTT=Leu TCC=Ser

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

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

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

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

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”!

Other Terms

•InDel

•VNTR

•marker

•Coding

•Non-Coding

•synonymous

•promoter

•epigenetic

•imprinting

•mitochondrial

•Intron/exon

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

Help From the “Math”Gifted!

•These are complex datasets

•Analysis can be “simple”, it shouldn’t be!

•Getting in early is critical

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.