Linkage Analysis Flashcards
What is genetic variation?
Genetic variation refers to difference in the DNA sequence between individuals in a population.
The variation can be inherited or due to environmental factors (e.g. drugs, exposure to radiation, etc.)
What are some effects of genetic variation?
Genetic variation can have different effects:
- alteration of the amino acid sequence (protein) that is encoded by a gene
- changes in gene regulation (where and when a gene is expressed)
- physical appearance of an individual (e.g. eye colour, genetic disease risk)
- silent or no apparent effect
Why is genetic variation important?
- Genetic variation underlies the phenotypic differences among different individuals
- Genetic variations determine our predisposition to complex diseases and responses to drugs and environmental factors.
- Genetic variation reveals clues of ancestral human migration history.
List and describe the mechanisms of genetic variation.
MUTATION/POLYMORPHISM: errors in DNA replication. This may affect single nucleotides or larger portions of DNA.
- germ-line mutation: passed on to descendants
- somatic mutations: not transmitted to descendants (e.g. due to external environmental conditions like smoking or radiation)
- de novo mutations: new mutation not inherited from either parent
HOMOLOGOUS RECOMBINATION (a.k.a. genetic recombination): shuffling of chromosomal segments between partner (homologous) chromosomes of a pair during meiosis.
GENE FLOW: the movement of genes from one population to another (e.g. migration) is an important source of genetic variation.
What is the difference between a mutation (rare variant) and a polymorphism (common variant)?
Difference is mainly based around frequency in general population.
A mutation is a rare change in the DNA sequence that is different to the normal (reference) sequence. The ‘normal’ allele is prevalent in the population and the mutation changes this to a rare ‘abnormal’ variant.
By contrast, a polymorphism is a DNA sequence variant that is common in the population. In this case, no single allele is regarded as the ‘normal’ allele. Instead, there are tow or more equally acceptable alternatives.
The arbitrary cut-off point between a mutation and a polymorphism is a minor allele frequency (MAF) of 1% (i.e. to be classed as polymorphism, the least common allele must be present in ≥1% of the population).
How does homologous (genetic) recombination occur in meiosis?
Homologous recombination occurs in prophase I, when the two homologous chromosomes (i.e. maternal and paternal) line up together and this is when crossing over can occur between the sister chromatids. Homologous chromosome pair with each other and undergo genetic recombination, in which DNA is cut and then repaired, which allows them to exchange some of their genetic information.
- Non-recombinant alleles: original to the chromosome
- Recombinant alleles: a mixture of maternal and paternal material
How does crossing over occur?
Crossing over occurs in which the reciprocal breaking and re-joining of the homologous chromosomes occurs. This results in the exchange of chromosome segments and new allele combinations. This creates physical links known as chiasmata between the homologous chromosomes.
These crossing over events result in the production of recombinant chromosomes where there is the exchange of genetic information between maternal and paternal chromosomes. This is highly informative and can be utilised for linkage analysis studies.
Define genotype.
The genotype is the genetic makeup of the individual.
A genotype details the two alleles an individual carries for a specific gene or marker.
Define phenotype.
The phenotype is the physical expression of the genetic makeup.
Define alleles and locus.
Genes are found in alternative versions called alleles.
For each characteristics, an organism inherits two allele, one from each parents; the alleles can be the same or different.
A locus is the specific physical location of a gene or other DNA sequence on a chromosome.
What is the difference between a homozygous and a heterozygous genotype?
A homozygous genotype has identical alleles.
A heterozygous genotype has two different alleles.
Define haplotype.
A haplotype is a group of alleles that are inherited together from a single parent.
We can track what has been inherited in the maternal and paternal haplotype.
What are the 3 different classifications of genetic disease?
MENDELIAN/MONOGENIC: disease that is caused by a single gene, with little or no impact from the environment (e.g. PKD). - Linkage analysis can only be used here.
NON-MENDELIAN/POLYGENIC: diseases of traits caused by the impact of many different genes, each having a small individual impact on the final condition (e.g. psoriasis).
MULTIFACTORIAL: diseases or traits resulting from an interactions between multiple genes and often multiple environmental factors (e.g. heart disease).
Linkage analysis can only be applied to the Mendelian/monogenic types.
What is linkage analysis?
Linkage analysis is the method used to map the location of a disease gene in the genome (using genetic markers) - essentially a fishing experiment to identify the 1 gene (out of the 20,000 in our genome) that is causing disease.
The term ‘linkage’ refers to the assumption of two things being physically linked to each other. We can identify the location of a disease gene based on their physical proximity between the genetic markers we are testing and the actual disease gene.
Linkage analysis is used to map the likely location of genes causing Mendelian/monogenic (single gene) disorders.
Here, a mutation in a single gene is sufficient to cause disease - as these disorders are caused by very rare variants with high effect (penetrance).
Whereas in Polygenic (many genes) and common complex diseases, the common variants each have low penetrance and is the cumulative effect of multiple variants in different genes that cause the disease. - linkage analysis can’t be used here.
What is the importance of maps, and what are the two types of maps used in linkage analysis?
Maps provide a context to orientate yourself and calculate distance between landmarks.
The two types of maps used in linkage analysis are:
- Genetic maps look at the information in blocks or regions (similar to zones on a tube map i.e. zone 1, 2 etc).
- Physical maps provide information in the physical distances between landmarks (e.g. stations on a tube map) based on their exact location. Can pinpoint specific markers.
