Linkage Analysis Flashcards
What is meant by genetic variation?
→ differences in the DNA sequence between individuals in a population
What can variation be due to?
→ Inherited
→ Environmental factors
What are the 4 effects that genetic variation can have?
→ Alteration of amino acid sequence
→ changes in gene regulation
→ Physical appearance
→ silent or no apparent effect
What are the 3 reasons genetic variation is important?
→ Underlies phenotypic differences among individuals
→ Determine predisposition to complex diseases, drugs and environmental factors
→ Genetic variation reveals clues of ancestral human migration history
What is a mutation/polymorphism and what does this affect?
→ An error in DNA replication
→ It can affect single nucleotides of larger portions of DNA
What are the three types of mutations?
→ Germline
→ Somatic
→ De Novo
What is the difference between germline and somatic mutations?
→ Passed onto descendants - germline, occurs in gametes
→ Not transmitted to descendants - somatic- can lead to cancers
What is a de novo mutation?
→ a new mutation that is not inherited from either parent
→they occur spontaneously, either in one of the parental gametes or in the fertilized egg during early embryogenesis
What is gene flow?
→ The movement of genes from one population to another
What is genetic recombination?
→ Shuffling of chromosomal segments between partner (homologous) chromosomes of a pair
What is a mutation?
→ a rare change in the DNA sequence
→ different to the normal sequence
→ there is a normal allele present in the population
What is a polymorphism?
→ A DNA sequence variant that is common in the population
→no single allele is regarded as normal
→ two or more equally acceptable alternatives
What is the cut off point between a mutation and a polymorphism?
→ Minor allele frequency of 1%
What does the common allele frequency need to be for it to be classed as a polymorphism?
→ 1%
At what phase does genetic recombination occur?
→ Prophase
What happens during genetic recombination?
→ Maternal and paternal chromosomes line up together
→ exchange of genetic information between them
What is crossing over?
→ Reciprocal breaking and re-joining of the homologous chromosomes during meiosis
What does crossing over result in?
→ Exchanges of chromosome segments and new allele combinations
What is the genotype?
→ The genetic make up of an individual
What is the phenotype?
→ The physical expression of the genetic make up
What does being homozygous mean ?
→ The genotype has two identical alleles
What does being heterozygous mean?
→ The genotype has two different alleles
What is a haplotype?
→ A group of alleles that are inherited together from a single parent
What is a chromosome pair?
→ Homologous chromosomes with genes at the same loci
What is Mendelian genetic disease?
→ Disease that is caused by a single gene with little or no impact from the environment (PKD)
What is Non Mendelian genetic disease?
→ Diseases or traits caused by the impact of many different genes each having a small individual impact o the final condition
What is Multifactorial genetic disease?
→ Diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors
What is linkage analysis?
→ A method used to map the location of a disease gene in the genome
What does the term linkage refer to?
→ The assumption of two things being physically linked to each other
What is genetic linkage?
→ The tendency for alleles at neighbouring loci to segregate together at meiosis
→ to be linked loci have to be very close together
What does a haplotype define?
→ Multiple alleles linked at loci
When are crossovers more likely to occur?
→ between loci separated by some distance than those close together
1) a disease gene is far away from a genetic marker
2) a disease gene is close to a genetic marker
In which scenario is recombination more likely to occur?
→ 1) because if the genes are further away they are more likely to be separated
What is the advantage of using SNPs as markers?
→ 6000 SNPs → data is returned within 1-2 months →biallelic →lower heterozygosity than microsatellites but spaced much closer together →highly automated
Why are microsatellites not used?
→ 400 microsatellites
→ Whole genome scan 2-3 months
→relatively widely spaced apart so they don’t offer good coverage for linkage analysis
→high heterozygosity. Microsatellites may differ in length between microsatellites
→ manual handling
In what situations are microsatellites used?
→ Paternity testing
→ linkage analysis for gene identification
→ DNA fingerprinting from small amounts of material
If a marker is linked to a disease locus what does this mean?
→ the same marker alleles will be inherited by two affected relatives more often than expected by chance
What does it mean if the marker and the disease locus are unlinked?
→ If the marker and the disease locus are unlinked then the affected relatives in a family are less likely to inherit the same marker alleles
What are SNP genotyping arrays used for?
→ Linkage analysis in families
→ homozygosity mapping
→ GWAS in populations
→ Non-mendelian disorders and multifactorial traits
What can the probability of linkage be assessed by?
→ LOD score
What is a LOD score?
→ Logarithm of the odds score
→ the probability of observing same test data between two linked loci to the likelihood of observing the same data purely by chance
What ratio does a LOD score calculate?
→ observed vs expected
What does a high LOD score mean?
→ The higher the likelihood of linkage
→Positive LOD scores favour the presence of linkage, whereas negative LOD scores indicate that linkage is less likely.
Why can a LOD score not be higher than 0.5 /50%?
→ There is a 50/50 chance that you inherit maternal or paternal genes anyway
What can LOD scores be calculated with?
→ Across the whole genome using genotype data for many genetic markers in multiple members of a family
Why is the overall score increased if different families are linked to the same disease locus?
→ LOD scores are additive
What LOD score is considered evidence for linkage?
→ >3 is evidence for linkage
→Equivalent to odds of 1000:1 that the observed linkage occurred by chance
Translates to a p-value of approximately 0.05
→more likely to represent genuine linkage between the marker and disease gene
What LOD score is considered evidence against linkage?
→ <2
→These regions of the genome can be excluded from further analysis as they are highly unlikely to contain the disease gene.
What are associated features of Adams Oliver syndrome?
→ Neurological anomalies
→ Cardiac malformations
→ Vascular defect
How can we filter variants?
based on zygosity (autosomal dominant = heterozygous) and allele frequency (rare = less than 1% in control populations)
What is a non-recombinant chromosome?
chromosomes have not changed
What is the difference between genetic and physical maps?
→Genetic maps look at information in blocks or regions (similar to zones on a tube map)
→Physical maps provide information on the physical distances between landmarks based on their exact location
What will happen if the genetic marker and disease are in close proximity?
→There is less likelihood of recombination between the two loci
→Affected individuals will have the same allele for the genetic marker, indicating that it is close to the disease gene
→ the genetic marker and disease gene are co-segregating
What does a peak on represent on fluorescent tagged primers?
→one allele: single peaks are homozygous;
→double peaks are heterozygous for the marker
