What is genetic variation?
differences in the DNA sequence between individuals in a population
Variation can be either:
- inherited
- due to environmental factors( e.g. drugs, radiation exposure)
Importance of Genetic Variation
- underlies phenotypic differences among different individuals
- determines predisposition to complex disease and responses to drugs + environmental factors
- reveals clues of ancestral human migration history
Mechanisms of Genetic Variation
Mutation/Polymorphism
- errors in DNA replication which may affect single nucleotides or larger portions of DNA
- e.g. Germline, Somatic or de Novo mutations
Gene Flow/Migration
-movement of genes from one population to another
Genetic Recombination
-shuffling of chromosomal segments between homologous chromosomes of a pair
Difference between mutation and polymorphism
Mutation is a rare change in the DNA sequence, whereas a polymorphism is a common change in the DNA sequence
Polymorphism minor allele frequency >1%
Mutation minor allele frequency <1%
Genetic Recombination/Crossing Over
The exchange of genetic material between non-sister chromatids of maternal and paternal homologous chromosomes during prophase 1 in meiosis, which results in new allelic combinations in the daughter cells.
What can genetic recombination be used in?
linkage analysis to track regions of the genome that are being transmitted throughout a family
Haplotype
a combination of alleles on a single chromosome that are inherited as a single unit
Mendelian monogenic inheritance
disease that is caused by a single gene, with little or no impact from the environment (e.g. PKD)
Non-Mendelian polygenic inheritance
diseases or traits caused by the impact of many different genes, each having only a small individual impact on final condition (e.g. psoriasis)
Multifactorial inheritance
diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors (e.g. heart disease)
Variant frequency and penetrance in mendelian and non-mendelian disorders
Mendelian single gene disorders:
- rare variant frequency (mutation)
- high penetrance/effect
Non-mendelian polygenic complex disorders:
- common variant frequency (polymorphism)
- low penetrance/effect
Gene linkage
the tendency of DNA sequences that are close together on a chromosome to be inherited together during meiosis
What is linkage analysis?
method used to map the location of a disease gene in the genome by searching for the chromosomal segments that co-segregate with the disease phenotype through families
> we can use genetic markers to identify the location of a disease gene based on their physical proximity
Process of linkage analysis
If each family member with a particular disease or trait inherits a particular DNA marker, then it is very likely that the gene responsible for the disease or trait lies near that marker
*the more DNA markers there are on a genetic map, the more likely it is that at least one marker will be located close to a disease gene- and the easier it will be for researchers to narrow down on that gene
Maps used in linkage analysis
Genetic Maps
-information based on the recombination frequency between DNA markers; maps are population specific
Physical Maps
-information on physical distance between loci, with distance measured in base pairs
Genetic Markers and Linkage
If marker linked to disease locus, the same marker alleles will be inherited by affected relative more often than expected by chance because they will likely stay together during crossing over and be passed on to descendants
If maker unlinked to disease locus, the affected relatives in the family are less likely to inherit the same marker alleles
Types of Genetic Markers
Microsatellite Markers
Single Nucleotide Polymorphism Markers
Microsatellite Markers
- highly polymorphic STRs
- heterozygous
- widely spaced apart
- 400(200) markers
- PCR based system
- fluorescently labelled markers
- manual assignment of genotype
- labour intensive
- whole genome scan takes 2-3 months
Single Nucleotide Polymorphism Markers
- single base variants
- biallelic (SNP will be one of two possible bases)
- less heterozygous than microsatellites
- spaced much closer together + more informative
- ~6000 SNPs can be genotyped
- spaced throughout the genome
- microarray based system
- genotypes assigned automatically
- highly automated
- data returned within 1-2 months
Uses of microsatellite genotyping
DNA fingerprinting
Paternity testing
Linkage analysis
Uses of SNP Genotyping Microarrays
Provides genome-wide coverage of SNP markers
Can amplify thousands of markers in a single experiment
Alleles are identified by relative fluorescence:
- homozygous for allele 1: green signal
- homozygous for allele 2: red signal
- heterozygous: yellow signal
Typically used for:
- linkage analysis
- GWAS studies in populations (unrelated cases vs matched controls)
LOD score
The ratio of probabilities that two genes are linked to the probability that they are not linked,
the higher the LOD score, the higher the likelihood of linkage
LOD scores are additive, meaning different families linked to the same disease locus will increase the overall score
expressed as a log10:
- Scores of 3.0 or higher are taken as establishing linkage.
- Scores of
Adams-Oliver Syndrome
autosomal dominant disease where children are born with terminal transverse limb defects and scalp aplasia cutis congenital
Associated features also include:
- neurological anomalies
- cardiac malformations
- vascular defects (e.g. cutis marmorata telangiectatica congenita, dilated veins)
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DNA hybridisation58
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PCR and its role in diagnostics47
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Molecular Evolution25
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genome structure30
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genome variation39
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inheritance patterns22
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enzymes and restriction mapping0
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Recombinant DNA and cloning vectors12
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DNA sequencing6
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association analysis22
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microarrays24
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using the results of genetic studies0
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DNA sequencing15
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The metagenome27
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The functional genome26
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The mitochondrial genome36
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The epigenome29
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Mapping mendilian disease27
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genetics of common disease18
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linkage analysis23
