1. Non-Mendelian Genetics
Chapter Five

2. Altering Mendel’s Ratios
Two different types of complications:
Genotypic ratios follow Mendel’s laws, but phenotypes do not
Somehow the underlying genotypic ratios are hidden
Mendel’s laws do not apply
Both genotypes and phenotypes are not following Mendel’s laws

3. Type 1 – Laws in effect:
Insert figure 5.2

4. Type 2 – Mendel’s Laws No Longer Apply
Mitochondrial Inheritance
Mitochondria have their own DNA, which is solely maternally inherited
Linkage
Two genes that are close together physically
Linkage Disequilibrium
Two alleles that are not inherited separately

5. 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

6. Two alleles segregate randomly during
1. Mitochondrial Genes
Maternal Transmission:
Genes don’t follow Mendel’s 1st law:
Insert figure 5.6
Two alleles segregate randomly during
formation of gametes

7. 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

8. 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

9. Mendel’s Dihybrid cross:
YyRr
4 different
possible gametes Y R y r
(¼)
= 1 +

10. Mendel’s Dihybrid cross:
With two independent genes F2 looked like:
Four Phenotypes:
9 : : : 1

11. Mendel’s Dihybrid cross:
F2 offspring of Dihybrid cross
Four Phenotypes:
new phenotypes
recombinants
original phenotypes
parental or non-recombinant

12. Two Linked Genes: 3 : 1 Only produce 2 gametes
YyRr
Only produce
2 gametes YR yr
(½)
YYRR
YyRr YR yr
(½)
3 : 1
yellow
round
green
wrinkled
Two Phenotypes
YyRr
yyrr
Traits transmitted together

13. Dihybrid with Linked Genes
F2 offspring with two linked genes:
Two Phenotypes:
new phenotypes
recombinants
original phenotypes
parental or non-recombinant
Recombinants are not present, or they are reduced.

14. 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

15. Recombination Mapping
Number of recombinations will tell you how close two genes are genetically to each other
Examine offspring and count number of recombinant individuals
Divide by total number of offspring to calculate recombination frequency
1 % RF = 1 centimorgan (cM)

16. Example – Calculate RF In 100 offspring: 4/100 = 4%
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

17. 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”]

18. 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

19. 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?

20. How To Calculate Linkage?
Determine whether two loci segregate independently in meiosis.
If two loci are linked the number of non-recombinant meioses (parental) would be larger than recombinant meioses.
In Model Organisms, just count traits in offspring, calculate Recombination Frequency (RF or cM) directly.
Recombinant – try two genes, with two alleles each. Do we see more of the parental genotype or more of the non-parental (Recombinant) genotype? Expect by chance

21. 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

22. Pedigree for
Huntington’s Disease

23. 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

24. 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

25. 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?

26. 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?

27. LOD Score LOD = Logarithm of ODds Ratio
Calculate a LOD score for every single marker tested
and
add up the LOD scores of each separate pedigree in one study

28. 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

29. Questions?
What are two types of complications that form non-Mendelian 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?

30. Next Class:
Read Chapter Six
Homework – Handout Problems