great dane x mexican chihuahua
DESCRIPTION
Great Dane x Mexican Chihuahua. F1 Big (Great Danes). 3 Big : 1 Small. The Genius of Mendel. Highly inbred strains of peas Differed by single character. Round x Wrinkled (WT x mutant) F1 All Round F2 5474 Round 1850 Wrinkled 2.96:1 (3:1) Needs Statistics. - PowerPoint PPT PresentationTRANSCRIPT
Great Dane x Mexican Chihuahua
F1 Big (Great Danes)
3 Big : 1 Small
The Genius of Mendel
• Highly inbred strains of peas
• Differed by single character
Round x Wrinkled (WT x mutant)
F1 All Round
F2 5474 Round 1850 Wrinkled
2.96:1 (3:1)
Needs Statistics
Mapping in Drosophila
Ly Sb br
+ + +
Lots of variation in people
There must be a genetic component
How do we assign “traits” to genes?
Ultimately want a molecular description
Start with inherited diseases
Pedigrees……Mendel’s First Law
Autosomal Dominant Disorder
Autosomal Recessive
Disease is apparent because of consanguinity (III 5 &6)
Population GeneticsScience of Intraspecific Variation Phenotypic
GENOTYPIC
• Genotypic Variation: Alleles, Polymorphism– Ultimate Source of Variation: Mutation
• Dynamics of Variation during Population History– Changes in Allele Frequencies due to
• Drift
• Selection
– Persistence of Allele Combinations due to Linkage
• Linkage Disequilibrium
Some Basics 1
GATTACA TGTAATC GATCACA TGTGATC
Allele 1 Allele 2
= GATTACATGTAATC GATCACATGTGATCAllele 1 Allele 2
1. Only refer to one strand, and don’t confuse strands with alleles
2. Context is unimportant (unless we have linkage…next)
Allele 1: T Allele 2: C
AGACAGAAAGGAAAAGAACCTTCCATTTTTGGCTGTGCCAAGAAGCTCAGAAAGGTGATAATATAAAAAATATATAGTTAATTGGGAATTGAATTTACAAAATACATTGTGAGACAGAAAGGAAAAGAACCTTCCATTTTTGGCTGTGCCAAGAAGCTCAGAAAGGCGATAATATAAAAAATATATAGTTAATTGGGAATTGAATTTACAAAATACATTGTG
Some Basics 23. Because mutations are rare events, the vast majority of variation is
BINARY, at the base pair level.
CAAAGGAAAAGAATGCCTTCCATTTTTGGCTGTGCCAAGAAGCTCAGAAAGGTGATAATATAAAAAATATATAGTTAATTGGGAATTGAATTTACAAAATACATT
CAAAGGAAAAGAATGCCTTCCATTTTTGGCTGTGCCAAGAAGCTCAGAAAGGCGATAATATAAAAAATATATAGTTAATTGGGAATTGAATTTACAAAATACATT
Allele 1
Allele 2
GAAAGGAAAAGAAGATTTACTTCC[1396bp]GAAGCTCAGAAAGGCGATAATATAAAAAATAT[2502bp]TTGGGAATTTACAGAATAC
Haplotype 3
4. Linkage makes things more complicated but only if you actually care about linkage: Linkage equilibrium/disequilibrium.
GAAAGGAAAAGAAGATTTCCTTCC[1396bp]GAAGCTCAGAAAGGTGATAATATAAAAAATAT[2502bp]TTGGGAATTTACAGAATAC
GAAAGGAAAAGAAGATTTACTTCC[1396bp]GAAGCTCAGAAAGGCGATAATATAAAAAATAT[2502bp]TTGGGAATTTACAAAATAC
2 alleles 2 alleles 2 alleles
Haplotype 2
Haplotype 1
Some Basics 35. Alleles have frequencies in the population (which sum to 1)
Frequency of Allele 1 (T) = 0.59
Frequency of Allele 2 (C) = 0.41p = 0.59
frequency of major allele
0.35
6. We’ll be talking about diploids, and genotype probabilities (which sum to 1) can be calculated from allele frequencies.(And vice versa; and under certain assumptions)
T,T C,CT,CProb. of having:
0.48 0.17
p2 2pq q2
What about two different genes?Consider two genes A and B that each have two alleles
A a B b
Allelic frequencies are 0.5
(At the “A” locus A=0.5, a= 0.5)
(At the “B” locus B=0.5 and b=0.5)
For A and a genotype frequencies = p2 +2pq +q2
AA , Aa and aa individuals = 0.25 + 0.5 + 0.25
The same for BB, Bb and bb
How many AA BB individuals are (0.25 x 0.25) aa Bb individuals are (0.25 x 0.50)
Both genes are in “equilibrium”. (Hardy and Weinberg)
A a
a
A AA Aa
Aa aa
(p + q)2 = p2 +2pq + q2
Hardy Weinberg is the Population Equivalent of the Punnett Square
Mutation Rate per Generation
How often per generation does this happen?
Average Mutation Rates in Mammals
Point substitution (nuc) 0.5 x 10-8 per base pair
Microdeletion (1-10bp) ~10-9 per base pair
Microinsertion (1-10bp) ~0.5 x 10-9 per base pair
Mobile element ins’n ~10-11
Inversion ?? much rarer
ExceptionsHypermutable sites (CpGs)C->T = 10x avg point rate
Simple Sequence Repeats10-1000x indel rate (some 10-4!)mitochondrial DNA10-100x nuclear point rate
1 generation
Haploid Human Genome is ~2 x 109 base pairs
Most of the DNA is non-coding
Introns, Intragenic regions, LINES, SINES etc
AT the DNA level, can have tremendous variationath no phenotypic consequenses
Remember the LacI gene (the repressor)
Nonsense mutations at every codon
Substitute every AA at every position
White means no phenotype
Lesson….most mutations in coding regions are silent
Drift vs. Selection
• Drift– Change in allele frequencies due to
sampling
• Selection– Change in allele frequencies due to
function
The two forces that determine the fate of alleles in a population
Genetic Drift
Gen 0
Gen 19
This is like 107 independent populations
For every bottle: after eggs hatch pick 8 male larvae and 8 female larvae, stick in a new bottle. Repeat for 19 generations.
Genetic Drift: Size Matters
From Li (1997) Molecular Evolution, Sinauer Press
4 populations
2 at N=25
2 at N=250
Selection & Fitness
“Absolute Fitness” = “Viability” = # of survivors / total # progeny produced
= P(survival until mean reproductive age)
If Fitness depends on Genotype, then we have (natural) Selection
Selection vs Drift RecapFrom the perspective of disease severity:Given a particular selection coefficient (picture severity of disease), selection is only effective in a population whose size is large enough to overcome the effect of drift.
From the perspective of population size:Given a particular population size, only alleles that bear a large enough selection coefficient (picture severity of disease) will be strongly selected against.
A new mutation! (on the "red" chromosome)
Eager geneticist obtains samples from multiple affected individuals
Linkage disequilibrium: the big (and oversimplified) picture
• Small number (maybe one) of ancestral disease-causing mutations
• Isolation of chromosome bearing disease-causing mutation
• "Reasonable" opportunity for recombination during population history
• (Think Finland: 1000 founders 2000 years ago; consistent expansion)
• Few (maybe none) reoccurrences of disease-causing mutation
LD and time: history at work
Do we care about:
The age of the mutation or the age of the founding population?
Two common types of DNA variants
DNA haplotype
• Haplotype = a series of marker alleles on a chromosome (DNA molecule)
• E.g.: DNA sequence, a series of SNPs or microsatellites along a chromosome.