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GENE3340 MOLECULAR GENETICS > Genetic variation > Flashcards

Genetic variation Flashcards

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1
Q

What are the 2 categories of human genetic variation?

A
  1. Do not affect DNA content (no nts unchanged)
  2. Causes a net loss/gain of DNA sequence
    - change in CNV
    - abnormal chromosome segregation
    - deletions/insertion
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2
Q

What are DNA variants?

A

Alternative forms of DNA resultant of mutations

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3
Q

What is a polymorphism and what is a rare variant?

A

Polymorphism is if more than 1 DNA variant is common in population (freq>0.01).

Rare variant if less than 0.01

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4
Q

What is the most common variation due to?

A

Single nucleotide substitutions - produces single nt variants (SNVs).

If more than 2 alternative DNA variants exceed freq of 0.01 = SNP

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5
Q

Why is the pattern of SNV not random?

A
  • different regions undergo different mutation rates
  • mtDNA higher than nuclear
  • excess of C-T substitutions
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6
Q

Why are C-T transitions so common?

A

Deamination of C = U. Uracil DNA glycosylase (base excision repair) removes them. However, if C methylated = T. Stable GC replaced by TG (escapes mismatch repair). If replication T form TA base pair (C-T mutation)

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7
Q

What is the difference between indels and CNV?

A

Some point mutations create variants that differ by presence/absence of nt.

Indels describes deletions/insertions up to 50 nts

CNV is when a change in cipy number of sequences result in larger deletions/insertions (more than 100 nts)

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8
Q

What does variation in copy number result from?

A

Replication slippage and unequal crossover

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9
Q

What are the 3 types of tandem repeats?

A

Tandem copies:
- satellites DNA: 20kb-1000kb; centromeres and heterochromatic regions

  • minisatellites: 100bp-20kb; telomeres and sub telomeric regions
  • microsatellites: fewer than 100bp; widely distributed through euchromatin
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10
Q

How does slippage cause insertion/deletion?

A

During replication, new strand partially dissociates from template, then associates. New strand may mis pair (has more repeat units)

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11
Q

How does unequal crossover work? Misaligned chromatids can either be?

A

Meiotic recombination between mis-paired repeats = change in unit number.

Misaligned chromatids can be either on a homologous chromosome (unequal crossover) or on a sister chromatid (unequal sister chromatid exchange)

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12
Q

Why are microsatellites used to genotype families and individuals?

A
  • to track chromosomes of DNA

- more informative than SNPs for distinguishing between individuals

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13
Q

What causes DNA variation?

A
  • errors in DNA replication/recombination
  • various natural errors
  • various endogenous/exogenous sources
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14
Q

What are the 4 mechanisms that cause chemical damage to DNA?

A
  1. Strand breakage: cleavage of covalent bonds in sugar-P backbone
  2. Base deletion: cleavage of N-glycosidic bond, base to sugar
  3. Base modification: replacing certain groups of bases, adding chemical group
  4. Base-crossing linking: formation of covalent bonds between 2 bases
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15
Q

What are the three types of endogenous chemical damage?

A
  1. Hydrolytic: disrupts bonds that hold bases to sugars. Also strips amino acid groups from some bases
  2. Oxidative: metabolism generates ROS. Attack covalent bonds in sugars, strand breakage.
  3. Methylation: SAM, methyl donor
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16
Q

What are the three types of repair?

A
  1. Base excision repair
  2. Nucleotide excision repair
  3. Homologous recombination-mediated repair
17
Q

Describe base excision repair

A

Lesions where single base modified or excised. Replace modified base, specific DNA glycosylase cleave sugar-base bond to delete base (abasic site). Residual sugar-P removed by endonuclease and phosphodiesterase. Gap filled by DNA pol and ligase

18
Q

Describe nucleotide excision repair

A

Repair of bulky, helix-distorting DNA lesions. Lesions detected, damaged site opened, DNA cleaved some distance either side (~30bp removal). Synthesis of DNA performed using opposite strand as template. DNA pol and ligase.

19
Q

Describe homologous recombination-mediated DNA repair

A

Repair lesions that affect both strands. DSB repaired using undamaged strands in sister chromatid as template. Cut back 5’ ends at DSB to leave protruding ss with 3’ ends. Each ss region forms duplex with undamaged complementary strand from sister chromatid. Ends sealed by DNA ligase

20
Q

What are the health consequences?

A

Cancer susceptibility, progeria (premature aging), neurological features and immunodeficiency

21
Q

What are the two types of structural variation?

A
  1. Balanced SV: DNA variants have same DNA content but differ where DNA sequences are located (inversions and translocations)
  2. Unbalanced SV: DNA variants differ in DNA content. Includes CNV (variants differ in number of copies of moderately long DNA sequences)
22
Q

What are the databases used to curate data on genetic variation?

A
  • dbSNP: SNPs and other short genetic variation
  • NCBI: SNPs
  • dbVar and DGV: genomic structural variation
  • ALFRED: allele frequencies in human populations
23
Q

What is the HapMap project?

A

A genetic map of SNPs as a common resource.

Phase I: 1 million common SNPs genotyped from 4 populations.

Phase II: additional 4.6 million SNPs genotyped

24
Q

What is the 1000 genomes project?

A

HapMap evolved into the 1000 genomes project.

Phase I: genotyped 1092 individuals across 14 populations (whole genome and exome sequencing)

Phase III: 2535 individuals across 26 populations (exome and low coverage data)

25
Q

What is a selective sweep?

A

When variants become fixed in a population

26
Q

What are MHC proteins?

A

MHC genes important in immune response and are extremely polymorphic

27
Q

What is MHC pathogen polymorphism driven by?

A
  • strong selective pressure, by mutant pathogens that seek to evade MHC-mediated detection
  • gene duplication = multiple MHC genes with different peptide binding specificities
  • Many MHC genes are extraordinarily polymorphic

GENE3340 MOLECULAR GENETICS (20 decks)

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