20.01.12 Normal variation in human genome Flashcards
What is normal genomic variation
Genetic variants which are not associated with adverse phenotypic effects.
What are microscopically visible variations
- Normal variants that are visible at the resolution of a light microscope. Also known as heteromorphisms.
- ~5% genome is structurally variable.
Can balanced chromosomal rearrangements be carried with out phenotypic affect
Yes
Examples of normal inversions
inv(3)(p11q11), inv(3)(p11q12), inv(3)(p13q12)
What are supernumerary marker chromosomes (SMCs)
a structurally abnormal chromosome that cannot be clearly characterized by conventional banding cytogenetics alone
- Not technically heteromorphisms as ther are additional to normal karyotype.
- Show karyotypic variation without phenotypic effect.
What is constitutive heterochromatic variation
- Constitutive heterochromatin is permanently condensed/inactive (darkly stained regions in C-banding, AT rich). 6.5% of genome.
- Can vary in length (h+ is increase, h- is decrease)
- e.g. 1qh, 9qh, 16qh (due to inversions) and Yqh (due to translocations)
- Due to the instability of satellite DNA.
What is acrocentric p-arm variation
- Often no phenotypic effect.
- NOR (Nucleolar organising region) translocations can be pathogenic is there is a concomitant deletion at the tip of the recipient chromosome or gene disruption.
Copy number polymorphisms
- Pathogenicity of CNVs is dependent on the gene content or position of breakpoints/insertion sites within or near genes and regulatory elements.
- > 1% in general population
- Inherited from an unaffected parent (unless reduced penetrance etc)
- Functional redundancy= due to additional or related copies outside of imbalanced region that can compensate
What are euchromatic variants
- Variation of regions containing genes or pseudogenes, which are polymorphic and present in general population. Usually duplications
- e.g. var(9)dup(9)(q13q21.12) or var(9)del(9)(q13q21.12)
Repeat sequence polymorphisms
- 50% genome consists of repeated sequence
- Most are interspersed (across the genome, e.g. transposable elements), rather than clustered (e.g. tandem repeats)
What are transposable elements
- Units of DNA that move within the genome
- Retrotransposons: replicate themselves prior to transposition (copy and paste)
- DNA transposons: transpose without replication (cut and paste)
Accumulation of transposition events over evolution results in what
- Repetitive sequences of DNA interspersed throughout the genome.
- 45% genome
What is the most common transposable element
-Most common is the Alu sequence (SINE)
- SINEs= Short interspersed nuclear elements.
- LINEs= Long interspersed nuclear elements
How can transposable elements cause disease
- Disrupt gene function by insertion into coding region
- Homologous recombination between elements can induce structural chromosomal rearrangements.
What are variable number tandem repeats (VNTR)
- Satellite DNA
- Units of DNA sequence which are replicated and located adjacent to each other.
What are the subgroups of VNTRs/satellite DNA
- Satellite (3 subgroups, alpha, beta, gamma)
- Mini-satellite: cluster in telomeric regions
- Micro-satellite (Short tandem repeats): High mutation rate, due to slippage of DNA polymerase during DNA replication. Means they are highly variable with many alleles.
What are low copy repeats/ segmental duplications
Block so of 10-400kb with >97% identity. Can predisposed to structural variation with NAHR, which could be pathogenic.
What is epigenetic variation
- Methylation and acetylation of DNA
- Could be heritable. e.g. methylation pattern of 15q11-13 region associated with Prader-Willi and Angelman syndromes.
What are fragile sites
- Segments of uncoiled chromatin that is liable to show gaps and breaks in chromosomes.
- Low in gene content and high in LINE content
- In regions where genes are silenced by hypermethylation.
- Arise when DNA is exposed to factors that perturb DNA replication (e.g. folate- inhibits DNA elongation, BrdU- inhibits DNA polymerase)
What classes of fragile sites are there
- Rare, intermediate and common (based on frequency in the population).
- Rare and intermediate are variants, but common fragile sites form normal chromosome architecture so not classified as variants.
Examples of fragile sites
- FRAXA= Xq27.3. FMR1 gene
- FRAXE= Xq28. AFF2 gene
- FRA11B= 11q23.2, within CBL2 proto-oncogene.
What is a polymorphism
-a site with 2 or more possible alleles with a minor allele frequency of at least 1%
What is heterozygote advantage
-When a heterozygous genotype has a higher relative fitness than either homozygous wild type or mutant genotype
What is a SNP
- Single nucleotide polymorphism
- Most abundant variation
- Involve a single nucleotide
- Occur more frequently in non-coding regions.
- More stable over evolution so mark alternative ancestral chromosome segments.
What two types of SNP are there in coding regions
- Synonymous: don’t change amino acid sequence
- Non-synonymous: change amino acid sequence
What are restriction fragment length polymorphisms (RFLPs)
- Cleavage of DNA with restriction enzymes results in different lengths of DNA
- Due to the existence of VNTRs between cleavage sites or SNPs within cleavage sites.
- Originally used for DNA profiling
Examples of normal variation databases
- dbSNP
- ExAC
- gnomAD
- DGV
- Decipher
