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L19 - Genetic Variation I
Understand the terms variant and polymorphism…
L19 - Genetic Variation I
- Understand the terms variant and polymorphism and the scale of human variation
- Be able to describe SNVs, SNPs, indels & CNV
- Be able to describe different types of satellite regions within the genome, how replication slippage affects copy number and how/why they are used in genetic mapping
- Be able to describe the concept of structural variation i.e. balanced vs unbalanced
- Understand we now have databases to curate human genetic variation
- Be able to describe the aims of the HapMap project
- Understand the 1000 genomes project and what data can be accessed
- Understand genetic variation may/may not have functional consequences
- Describe the various databases used to assess functional genetic variants
- Define the term population genetics and the forces that influence genetic change in populations
- Describe the effect of mutation on allele frequencies in populations
- Understand that mating patterns have a large effect on allele frequencies in populations
DNA Variatiance
Within Populations
~85% of total genetic variation is found within populations
~33% of protein-encoding loci are polymorphic
There is additional nucleotide diversity in introns, regulatory sequences and flanking sequences
Between Populations
Variation impacted by differential frequencies of alleles especially for morphological traits
Human Genetic Variation are changes to Base Sequence
- Most Genetic variation is small
- Does not always impact phenotypic features
1. Do not affect DNA content but sequence is influenced (number nucleotides unchanged)
- Mostly - Single nucleotide is replaced - SINGLE NUCLEOTIDE POLYMORPHISM (SNPS)
- Rarely – multiple nucleotides move location without net loss/gain (translocations/inversions)
Single Nucleotide Substitutions (Typically biallelic variation)
SNS are the most common cause of genetic variation
- Variance results in **single
nucleotide variants** (SNVs).
- Sould the frequency of the SNV exceed 0.01 in population = single nucleotide polymorphism
Pattern of SNV in Human Genome is Not-Random
- Different regions within can undergo different rates of mutation.
Certain snips provide insight into our ancestral chromosome, and others are spontaneous
- Mitochondrial DNA higher rates of mutation than nuclear DNA
- Majority of SNS are related to C-T substitutions (methylation)
2. Causes a net loss/gain of DNA conent and sequence
- Change in copy number of DNA sequence (large or small)
- Small sequences changes are typically classed as - SNPS
- Abnormal chromosome segregation
- Deletion/insertion of a single nucleotide or short sequences to Mb DNA*
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DNA Variants and Polymorphism
- Rare Variant = Mutations resulting in alternative forms of sequnce DNA which are uncommon in a population(less frequent than 0.01)
- Polymorphism = When a DNA variant is common in the population (above frequency of 0.01)
Extent of Variation in Human Genome?
Craig Venter & James Watson seuqence each of their genomes
- 44% CraigV genes had sequence variant
- 17% of these sequence variants encoded an altered protein
Comparison Found;
290,000 heterozygous insertion/deletion variants
559,000 homozygous insertion/deletion variants
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Origins of DNA Variation
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2. Errors in chromosome segregation results in abnormal gametes, with fewer or more chromosomes than normal.
5. Spontaneous and naturally occuring errors may give rise to altered copy number of specific gene sequence within a DNA strand. Crossover errors may cause this
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MicroSatellites/Short Tandem Repeats and Other Polymorphisms
- A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times
Tandem copies (1bp to 200bp) are quite common, and have a higher mutation rate than other areas of DNA leading to high genetic diversity.
- Unlike SNVs, microsatellites can have multiple alleles
- Mapping and finding micro satellites was more helpful than finding snips during the human genome project
Satellite DNA
– (length = 20kb to many 100’s kb
- Located at centromeres, heterochromatic regions)*
Minisatellite DNA
- (length = 100bp to 20kb;
- located primarily at telomeres and subtelomeric regions)*
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Microsatellite DNA
– (length = fewer than 100bp;)
- Widely distributed through euchromatin*
Genotyping Microsatellites
More informative than SNPs for distinguishing between individuals or following chromosome segments through pedigree
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Structural Variation and Low Copy Number Variation
Variation due to large-scale changes in DNA is very common
Balanced Structural Variation
Large Scale DNA variance between chromosomes which is due to incoherent order of nucleotide sequence across homologs. The number and proportion of individual nt constituents are the same, however, the sequence in which they appear on the genome is different
Aetiology
Chromosomes break and fragments are incorrectly rejoined, w/out loss or gain of DNA = inversions and translocations
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Unbalanced Structural Variation
Rare instances where variance across chromosomes is due to loss or gain of an entire chromosomal region, thereby influencing DNA content. One individual may have gained/lost DNA => often results in disease.
Also includes commonly occurring CNV, where variants differ in number of copies from moderately-long to very-long DNA sequence. Some CNVs contribute to disease, others normal
Copy Number Variants
(Different numbers of copies within a specific regions)
1. Insertion/deletion of an entire nucleotide sequence
2. CNV due to tandem duplication
3. Normal orientation
4. inversion of copy