Transcript YYRR

Non-Mendelian Genetics
Chapter Five
Altering Mendel’s Ratios
Two different types of complications:
1. Genotypic ratios follow Mendel’s laws,
but phenotypes do not
•
Somehow the underlying genotypic ratios
are hidden
2. Mendel’s laws do not apply
•
Both genotypes and phenotypes are not
following Mendel’s laws
Type 1 – Laws in effect:
Insert figure 5.2
Type 2 – Mendel’s Laws No
Longer Apply
1. Mitochondrial Inheritance
•
Mitochondria have their own DNA, which is
solely maternally inherited
2. Linkage
•
Two genes that are close together physically
3. Linkage Disequilibrium
•
Two alleles that are not inherited separately
1. Mitochondrial Genes
• Mitochondria contains it’s own DNA
• 37 genes
• Offspring’s mitochondria come only from
the oocyte, not from the sperm
• Therefore, mitochondrial genes are only
inherited from the mother
– Maternal Transmission
1. Mitochondrial Genes
• Maternal Transmission:
Insert figure 5.6
• Genes don’t follow Mendel’s 1st law:
Two alleles segregate randomly during
formation of gametes
2. Linkage
Genes are located so close together on
same chromosome that they don’t
separate during meiosis (or less often)
• These two genes don’t follow Mendel’s 2nd
law:
Two genes will assort independently and
randomly from each other
Linkage
• Two genes that are too
close together physically to
follow Mendel’s law of
independent assortment.
• They will always go into the
same gamete together
during meiosis
Gene A
Gene B
Mendel’s Dihybrid cross:
YyRr
4 different
possible gametes
YR
(¼)
Yr
+
yR
(¼) + (¼)
yr
+
(¼) = 1
Mendel’s Dihybrid cross:
With two independent genes F2 looked like:
Four Phenotypes:
315
108
9 :
3
101
:
3
32
:
1
Mendel’s Dihybrid cross:
F2 offspring of Dihybrid cross
Four Phenotypes:
new phenotypes
recombinants
original phenotypes
parental or non-recombinant
Two Linked Genes:
Only produce
2 gametes
YyRr
YR
(½)
yr
(½)
YyRr
YR (½)
yr (½)
YYRR
YyRr
¼
Two Phenotypes
¼
YyRr
¼
yyrr
¼
3 : 1
yellow
green
round wrinkled
Traits transmitted together
Dihybrid with Linked Genes
F2 offspring with two linked genes:
Two Phenotypes:
original phenotypes
parental or non-recombinant
new phenotypes
recombinants
Recombinants are not present, or they are reduced.
Summary of Linkage
• Two genes are so close together
physically that they are inherited together
• This will lead to breaking Mendel’s 2nd Law
• Causes a huge increase in the amount of
parental offspring
Or a huge decrease in the amount of
“recombinant” offspring
– Offspring that do not look like parents
Recombination Mapping
Number of recombinations will tell you how
close two genes are genetically to each
other
1. Examine offspring and count number of
recombinant individuals
2. Divide by total number of offspring to
calculate recombination frequency
3. 1 % RF = 1 centimorgan (cM)
Example – Calculate RF
• In 100 offspring:
– 96 have parental genotypes
– 4 have recombinant genotypes
•
•
•
•
4/100 = 4%
Recombination Frequency = 4%
Genetic distance = 4 cM
Two genes are linked because genetic
distance is less than 50% or 50 cM
Genetic vs. Physical Distance
• Genetic Distance = how often two genes
will be inherited together (cM)
– Close together, inherited often/always
• Physical Distance = how many base pairs
are actually physically separating two
genes (Mb)
– Larger physical distance, larger genetic
distance
– However, correlation is not perfect [“hot spots”]
Linkage Mapping
• Two genes that are too
close together physically to
follow Mendel’s law of
independent assortment.
• Use this concept to help
identify disease causative
genes.
Disease
Marker
Linkage Mapping
• Start with a trait of interest
• Phenotype a large group of individuals (or
families) for trait
• Genotype everyone for markers across
entire genome
• Is there any correlation between any of the
markers and the trait?
How To Calculate Linkage?
• Determine whether two loci segregate
independently in meiosis.
• If two loci are linked the number of nonrecombinant meioses (parental) would
be larger than recombinant meioses.
• In Model Organisms, just count traits in
offspring, calculate Recombination
Frequency (RF or cM) directly.
Humans:
• Good for changing light-bulbs, bad for
genetics
– Can’t set up crosses
– Few offspring
– Few simple traits to follow
• Find and use pedigrees
– Well-documented
– As large as possible
Pedigree for
Huntington’s Disease
Polymorphisms:
• Regions of genome that have two or
more alleles, all of which are neither
harmful or helpful (“anonymous”)
• Marker - Used to locate a point on the
genome (Like a sign on the side of the
freeway – 300 Miles to LA vs. 30 cM to
HLA gene)
• Genotype everyone in the pedigrees for
all polymorphisms
Genotyping
• Type with 300 markers to
cover entire genome every 10 cM
• Using molecular biology determine
every individual’s genotype for every
marker
• Match up each individual’s genotypes to
their phenotypes for trait of interest
Linkage Analysis
• Determine whether two loci segregate
independently in meiosis
– Disease locus and marker locus
• If two loci are linked the number of parental
meiosis would be larger than recombinant
meiosis
• Test: whether marker-locus genotype is
independent of disease phenotype
• Is disease phenotype carried together with
marker locus genotype?
Genotype of Markers to
Identifying Disease Loci?
• 300 tests of linkage - between known
marker loci and unknown disease loci
• Disease locus must sit somewhere in
genome right?
• Therefore will find linkage between one of
these markers and disease loci…
• Possible problems?
LOD Score
LOD = Logarithm of ODds Ratio
(likelihood of genotype/phenotype data assuming linkage)
LOD =
log10
(likelihood of genotype/phenotype data assuming no linkage)
Calculate a LOD score for every single marker tested
and
add up the LOD scores of each separate pedigree in one study
Significant LOD Score
• General: LOD ≥ 3.0 is considered
significant
• LOD ≥ 3.0 means observed data is 1000
fold more likely to be linked than unlinked
• Lander: LOD ≥ 3.6 actually gives 5%
chance of false positive in whole genome
scan
Questions?
• What are two types of complications that form nonMendelian phenotype ratios?
• Which are breaking Mendel’s Laws?
• Which are actually still following Mendel’s laws?
– How does each of them still follow Mendel’s
Laws if they are producing non-Mendelian
ratios?
• What is Linkage?
• How is genetic distance different than physical
distance?
• How is Linkage Analysis/Mapping done?
Next Class:
• Read Chapter Six
• Homework – Handout Problems