L9&10: Linkage and Recombination

Question 1

How are the inheritance patterns of two genes related to location on chromosomes?

Answer 1

If genes are located on the same chromosome, the law of independent assortment would mean that the two traits would always be inherited together.

If they are on different chromosomes, they can be independently assorted into all possible combinations

Question 2

What is crossing over?

Answer 2

Crossing over of homologous chromosomes occurs in prophase 1, where sister chromatids align and undergo synapsis - the process of forming a tetrad (the structure containing two homologous chromosomes )

Crossing over can occur more than once within non-sister chromatid pairs.

Question 3

Describe the Holliday model of crossing over.

Answer 3

1. Homologous chromosomes align in synapsis.
2. Endonuclease cleaves one DNA strand from each non-sister chromatid
3. Broken DNA strand from each chromatid invades the other chromatid.
4. Invasion of DNA strands is completed through sealing by DNA ligase, forming the Holliday junction
5. The Holliday junction moves along the chromosome, away from the break site.
6. Holliday junction is resolved to form non-recombinant (East-West cleaving) or recombinant (North-South)

Question 4

What happens when crossing over goes wrong?

Answer 4

Homologous chromosomes can mis-align, and non-homologous chromosomes can pair.

This results in:

• Deletions and duplications
• Translocations
• Inversions

Question 5

How can we use offspring ratios to determine whether genes are assorting independently or not?

Answer 5

If two genes for two characteristics (e.g. Leaf shape and colour) are unlinked, we would expect 1:1:1:1 ratios for the possible outcomes.

However, if this ratio isn’t evident, then the two genes are NOT assorting independently - they must be close on the chromosome.

Gene distance is relative to the probability of crossing over, so the frequency of recombinant offspring (RF theta) can be used as a measure of the distance between two gene loci.

RF theta = % of total offspring that are recombinant

Question 6

What are the limitations of using offspring ratios to see if genes are close together?

Answer 6

• Can’t tell if genes are on different chromosomes or just really far apart.
• Doesn’t revealdouble crossovers (second crossover reverses the effect of the first).
• 2, 3 or all 4 chromatids could take part in crossing over.

Question 7

What are the cis and trans configurations of chromosomes?

What are the offspring results of each type?

Answer 7

Cis = Both dominant alleles are on the same chromosome, and both recessive alleles are on the same chromosome.

Trans = One dominant and one recessive allele on each chromosome.

In cis configuration, the most common geno/pheno-types will be those of the mum and dad.

In trans configuration, the most common geno/pheno-types will be those of half mum and half dad.

Question 8

What is linkage mapping?

Answer 8

If a disease is rare and inheritance is dominant, we assume affected individuals to be heterzygous.

Linkage mapping allows us to map the linkage of genes from pedigrees to identify Mendelian disease genes.

Linkage mapping is limited:

• Requires disease phenotype to be linked with another easily observable trait
• Only a few generations to map means very few meiosis/recombination events (poor resolution)
• Not all people are ‘informative’ for linkage - e.g. could be have inherited either X or Y from dad.

Question 9

What is the more accurate alternative to linkage mapping?

Answer 9

Using molecular markers, such as microsatellite DNA, to track inheritance.

• No issues with having to have easily observable phenotypes
• Allow distinction between heterzygous and homozygous individuals
• DNA markers can be rapidly typed using sequencing tech.

Question 10

What is the LOD score (Z)?

Answer 10

To get significant evidence for linkage, we can combine data from multiple families.

θ = 0 means complete linkage

θ = 0.5 means no linkage (bc on average, unlinked loci will segreate together 50% of the time)

An LOD score of 1.099 means the probability of disease being linked to a gene is 10^1.099 times greater than the probability they are unlinked. (~12.6x)

An LOD score of 3 is considered to be the cut-off to say with statistical certainty that two loci are linked (1000x greater chance)