T2: Normal Genetic Variation

Question 1

How can variation exist between normal individuals?

Answer 1

Origins of genetic variation:

• Exogenous factors (radiation, chemicals - mostly somatic).
• Endogenous factors:
  
  • Segregation (Aneuplodies e.g. Down’s syndrome, Edward’s syndrome)
  • Recombination (Translocations)
  • DNA replication errors (mispaired bases, slippage)l
  • Inadequate DNA repair mechanisms (e.g. mismatch repair, base excision repair).

Variation can either mean the overall DNA content has not changed (i.e. single nucleotide replacements or balanced translocations or inversions ) or the there is a let loss of gain of DNA sequences.

Question 2

How can normal and pathogenic variation be distinguished?

Answer 2

Pathogenic variation is rare, however normal generation is common.

Question 3

What is the difference between SNP and SNV?

Answer 3

This is a substitution of a single nucleotide for another. A SNV can be rare in one population but common in a different population. To qualify as a SNP, the variant must be present in at least 1% of the population.

Question 4

What are CNVs?

Answer 4

CNVs are distributed unevenly across the genome. Pericentromeric and sub telomeric (near the telomeres) regions of the chromosomes show high rates of CNV.

Genes that are associated with disease are the least affected by copy number variants whereas paralogous genes (Paralogous genesaregenesthat are related via duplication events in the last common ancestor (LCA) of the species being compared) have the most copy number variants. More than 100 genes can be completely removed from the genome without having no obvious phenotype repercussions.

Question 5

What are simple repeats?

Answer 5

Microsatillites - variable number of tandem repeats, short tandem repeats, simple sequence repeats.

These repeats are unstable and prone to replication change. They are highly variable and informative - can be used in genetic finger printing. The repeat regions are unstable so you can see slippage and alteration in the size from one generation to the next. This occurs in somatic and germline cells. You can distinguish two individuals using different sizes of repeats. The repeated length can increase meiosis. The repeat gets bigger as it gets passed on from parent to child leading to a decrease in onset of the disorder from parent to child.

Question 6

What are the types of variation?

Answer 6

• Single nucleotide variation (SNV)
• Single nucleotide polymorphisms (SNPs) - C to T is the most common
• Indel -insertion or deletion of one or more nucleotides
• CNVs (technically large indels changes in copy number of sequences greater than 100 nucleotides in length).

Question 7

What is a minor allele frequency?

Answer 7

The frequency of the less common variant in a population.

Question 8

What is the most common SNP?

Answer 8

C to T

Question 9

Where are CNVs enriched?

Answer 9

CVNS are enriched in some gene groups. Immune response genes, drug metabolism and olfactory receptor genes are enriched with CNVRs. Immunoglobulin and T-cell receptor genes are encoded by large families of very similar duplicated genes promoting diversity and increasing defence against pathogens and toxins. Genes involved in protein complex assembly and the cell clearly not commonly affected by CNV showing that cells that are essential for survival are not nearly as affected as those that are not.

Question 10

Where is variation found?

Answer 10

Most mutations are neutral. Most variations are found within populations, very few is found between populations. Individuals are much more similar to people of other populations that those within there population.