Linkage analysis Flashcards
What does genetic variation refer to?
Refers to differences in the DNA sequence between individuals in a population
What are the different effects caused by genetic variation?
- Alteration of amino acid sequence
- Changes in gene regulation
- Physical appearance
- Silent or no apparent effect
Why is genetic variation important?
Important because:
- Underlies phenotypic differences among different individuals
- Determine over predisposition to complex diseases and responses to drugs and environmental factors
- Reveals clues of ancestral human migration history
What are the 3 mechanisms by which genetic variation arises?
- Mutations/Polymorphism
- Genetic Recombination
- Gene flow
Mutations/Polymorphism
-Errors in DNA replication
Germline mutation-Passed onto descendants
Somatic mutation-Not transmitted to descendants
De novo mutation-New mutations
Genetic recombination
Shuffling chromosomal segments between partner chromosomes of a pair
Gene flow
Movement of genes from one population to another
What type of change is a mutation?
A mutation is a rare change in the DNA sequence
What type of change is polymorphism?
Polymorphism is a DNA sequence variant that is common in the population
What is the arbitrary cut off point between a mutation and polymorphism?
Arbitrary cut off point between a mutation and polymorphism is a minor allele frequency of 1%
What is created by meiosis?
Creation of haploid gametes
What do gametes contain?
Gametes contain a mixture of maternal and paternal material
What occurs in homologous recombination and when?
During meiosis, Crossing over occurs where there is reciprocal breaking and re-joining of the homologous chromosomes
What does crossing over result in?
Results in exchange of chromosome segments and new allele combinations
What does the term haplotype mean?
A group of alleles that are inherited together from a single parent
What are the 3 terms used in the classification of genetic diseases?
- Mendelian/Monogenic
- Non-mendelian/polygenic
- Multifactorial
What is mendelian/monogenic?
Disease that is caused by a single gene with little or no impact from the environment
What is non-mendelian/polygenic?
Diseases caused by the impact of many different genes
What is multifactorial?
Diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors
What method is linkage analysis?
Method used to map location of a disease gene in the genome
What is the importance of maps?
Maps provide a context to orientate yourself and calculate distance
Genetic maps
Look at information in blocks or regions
Physical maps
Provide information on physical distance between landmarks based on their exact location
What are the principals of genetic linkage?
- Genetic linkage is the tendency for alleles at neighbouring loci to segregate together at meiosis
- Therefore to be linked, two loci must be very close together
- A haplotype is defines multiple alleles at linked loci
- Cross overs are more likely to occur between loci separated by some distance than those close together
Linkage mapping using genetic markers
- If a marker is linked to a disease locus, the same marker alleles will be inherited by two affected relatives more often than expected by chance
- If the marker and disease locus are unlinked, the affected relatives in a family are less likely to inherit the same marker alleles
What 2 markers are used as genetic markers?
- Micro-satellite markers
- Single nucleotide polymorphisms
What are micro-satellite markers?
Highly polymorphic short tandem repeats
What is the difference of micro-satellites between chromosomes?
May differ in length between chromosomes
Comment on the arrangement of micro-satellites
Relatively spaced apart
SNP’s as genetic markers
-Bi-allelic
A SNP will be one of two possible bases
-Less heterozygous than micro-satellites
-Spaced much closer
-More informationHow can the probability of linkage be assessed?
Probability of linkage can be assessed using a LOD score
What does the LOD score assess?
Assesses the probability of obtaining test data if the 2 loci are linked, to the likelihood of observing the same data purely by chance
When is there no linkage in reference to the theta score and why?
When theta=0.5 there’s no linkage because its just independent assortment
Relationship between LOD score and linkage
The higher the LOD score, the higher the likelihood of linkage
LOD score greater than or equal to 3 is considered evidence for linkage
LOD score less than or equal to -2 is considered evidence against linkage
