CNVs Flashcards
What are CNVs?
Copy number variants
- 50bp upto submicroscopic
- 5-10% of the genomes
- common
- unstable due to duplicated regions
- coding and non-coding regions
- > 99% inherited
- beneficial and detrimental examples
- unevenly distributed ; pericentromeric and subtelomeric usually
- genes associated with disease are least affected
What is a CNP?
Copy number polymorphism
CNV that occurs in more than 1% of population
How common are CNVs in human genome?
Every human has ~250 CNVs that’s are more than 10Kb in size
12% of human genome associated with CNVs
What role do CNVs play in developmental delay?
~25% children with developmental delay have CNVs of > 400Kb compared to 8% of normal people
Why are CNVs so abundant?
Large repeat sequences are located at the breakpoints of the duplications or deletions
25fold enrichment for breakpoints to occur in these regions
Human genome is enriched for them
What are low copy number repeats?
10-500Kb in size
- > 95% sequence identity between repeats
- also called segmental duplications or paralogous repeats
- susceptible to NAHR
- give rise to CNVs
What are the four recombination mechanisms to generate CNVs?
NAHR
NHEJ
FoSTeS
L1 Transposition
What types of NAHR can occur between Low Copy repeats?
Direct, inverted, complex
Can be interchromosal, intrachromosomal or interhchromatid
How can CNVs be detected?
- Karyotyping : for gross rearrangements. >5Mb
- FISH: need to know where to look. >0.5Mb
- aCHG: >10Kb
- next gen sequencing : gold standard
What are advantages and disadvantages of array CGH?
Advan:
- whole genome or targeted
- quantitative data
- resolution depends only on probes
- oligonucleotide probes can give 2-10Kb resolution
Disadvantages:
- can’t detect balanced rearrangements
- gives no information on chromosomal location of extra material
How can array CGH be validated?
QFPCR
FISH
Tiled oligonucleotide microarrays
What is Williams-Beuren syndrome?
Dysmorphic face, cardiovascular abnormalities, hoarse voice abnormal gait,short stature, infantile hypercalcaemia. Low IQ, friendly personality, hyperacusis. Caused by hemizygous 1.5Mb micro deletion on 7q11.23. Affects approx 30 gene. Instability in the region due to flanking repeats
What is speech dyspraxia syndrome?
Deep set eyes, long nose, speech delay. Normal Karyotype. De novo duplication on 7q11.23. Over expression of 28 genes. Duplications not as clinically severe as deletions
What is CHARGE syndrome?
Coloboma, heart malformation, atresia of choanae, retardation of growth an development, genital hyperplasia and eat abnormality including deafness.
Array showed due to 4.8Mb deletion of chromosome 8q12. And FISH confirmed .
Also found mutation in CHD7 gene that causes truncated protein and disrupts chromatin remodelling and regulation of gene expression
Why study structural variation?
Common in normal genome and is a major cause of phenotype variation
8-15% rare disease
Underlie susceptibility to complex disease
Common in cancer
