20.01.12 Normal variation in human genome

Question 1

What is normal genomic variation

Answer 1

Genetic variants which are not associated with adverse phenotypic effects.

Question 2

What are microscopically visible variations

Answer 2

• Normal variants that are visible at the resolution of a light microscope. Also known as heteromorphisms.
• ~5% genome is structurally variable.

Question 3

Can balanced chromosomal rearrangements be carried with out phenotypic affect

Answer 3

Yes

Question 4

Examples of normal inversions

Answer 4

inv(3)(p11q11), inv(3)(p11q12), inv(3)(p13q12)

Question 5

What are supernumerary marker chromosomes (SMCs)

Answer 5

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.

Question 6

What is constitutive heterochromatic variation

Answer 6

• 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.

Question 7

What is acrocentric p-arm variation

Answer 7

• 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.

Question 8

Copy number polymorphisms

Answer 8

• 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

Question 9

What are euchromatic variants

Answer 9

• 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)

Question 10

Repeat sequence polymorphisms

Answer 10

• 50% genome consists of repeated sequence

- Most are interspersed (across the genome, e.g. transposable elements), rather than clustered (e.g. tandem repeats)

Question 11

What are transposable elements

Answer 11

• 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)

Question 12

Accumulation of transposition events over evolution results in what

Answer 12

• Repetitive sequences of DNA interspersed throughout the genome.
• 45% genome

Question 13

What is the most common transposable element

Answer 13

-Most common is the Alu sequence (SINE)

• SINEs= Short interspersed nuclear elements.
• LINEs= Long interspersed nuclear elements

Question 14

How can transposable elements cause disease

Answer 14

• Disrupt gene function by insertion into coding region

- Homologous recombination between elements can induce structural chromosomal rearrangements.

Question 15

What are variable number tandem repeats (VNTR)

Answer 15

• Satellite DNA

- Units of DNA sequence which are replicated and located adjacent to each other.

Question 16

What are the subgroups of VNTRs/satellite DNA

Answer 16

• 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.

Question 17

What are low copy repeats/ segmental duplications

Answer 17

Block so of 10-400kb with >97% identity. Can predisposed to structural variation with NAHR, which could be pathogenic.

Question 18

What is epigenetic variation

Answer 18

• Methylation and acetylation of DNA

- Could be heritable. e.g. methylation pattern of 15q11-13 region associated with Prader-Willi and Angelman syndromes.

Question 19

What are fragile sites

Answer 19

• 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)

Question 20

What classes of fragile sites are there

Answer 20

• 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.

Question 21

Examples of fragile sites

Answer 21

• FRAXA= Xq27.3. FMR1 gene
• FRAXE= Xq28. AFF2 gene
• FRA11B= 11q23.2, within CBL2 proto-oncogene.

Question 22

What is a polymorphism

Answer 22

-a site with 2 or more possible alleles with a minor allele frequency of at least 1%

Question 23

What is heterozygote advantage

Answer 23

-When a heterozygous genotype has a higher relative fitness than either homozygous wild type or mutant genotype

Question 24

What is a SNP

Answer 24

• 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.

Question 25

What two types of SNP are there in coding regions

Answer 25

• Synonymous: don’t change amino acid sequence

- Non-synonymous: change amino acid sequence

Question 26

What are restriction fragment length polymorphisms (RFLPs)

Answer 26

• 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

Question 27

Examples of normal variation databases

Answer 27

• dbSNP
• ExAC
• gnomAD
• DGV
• Decipher