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

9 :

108

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

LOD =

log10

(likelihood of genotype/phenotype data assuming linkage) (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