Genome variation

Question 1

Explain the human genome and how big the human genome is

Answer 1

Gross structure- 23 pairs of chromosomes
Molecular structure- DNA sequences within

There are 3 billion bases (3000Mb)
Roughly 20,000 genes
-roughly 1.5% genome codes for a protein= exome

Question 2

Are we all identical?

Answer 2

-major macro-level differences generally associated with disease (aneuploidy, translocations etc)
-also micro or molecular level pathogenic difference sometimes associated with disease.
-99.7% DNA is roughly the same between any 2 people
-any position in the genome that varies between individuals is considered polymorphic= a variant.

Question 3

Explain single nucleotide variant (SNV)/ polymorphism (SNP)

Answer 3

-high frequency: 1 every 300 nucleotides in reference genome
-one individual: 1 every 1000 bases
-millions SNVs identified in human genomes
-majority not in exome
-generated by mismatch repair during DNA replication

Question 4

Explain what happens during DNA mismatch repair and SNVs

Answer 4

-during DNA replication sometimes the wrong base is inserted and the DNA repair machinery pathway needs to identify which base is wrong.
-if the mismatch isn’t corrected before replication, one daughter strand keeps the original base pair and the other daughter strand keeps the mutated base pair.

Question 5

What may SNVs be in?

Answer 5

SNVs may be in:
-gene
-might alter amino acid sequence in protein
-might not alter protein

-promoter
-could affect gene expression

-non coding region

-without a deleterious effect, SNVs can spread in population

Question 6

How to tell if theres a mutation or polymorphism

Answer 6

-If minor allele frequency > 1% (atleast 1 in every 100 chromosomes has non-reference allele)= polymorphism
-rare polymorphism: MAF 1-5%
-common polymorphism: MAF > 5%

• If MAF <1% (fewer than 1 in every 100 chromosomes has non-reference allele)= mutation

-all variants start off rare
-evolutionary forces affect whether or not a variant remains rare
-rare variant may be damaging and or/recent

Question 7

Explain evolutionary forces

Answer 7

-mutation:
-new allele arises, we now have a variant

Gene flow:
-migration leading to introduction of that variant into another population

Genetic drift:
-random change in variant allele frequency between generations

Selection:
-non random change in variant allele frequency between generations because presence of one allele/genotype is pathogen (negative selection) or beneficial (positive selection)

Question 8

Give a summary of SNVs/ SNPs

Answer 8

-millions in genome
-a position in genome at which the base can vary
-can be anywhere in the genome (genic or non-genic)
-may do nothing, may affect a trait, may be associated with disorder
-genetically bi-allelic
-due to mutation and mismatch repair
-these are base substitutions
-when pathogenic, may call point mutations

Question 9

Explain microsatellite alleles and inheritance of them

Answer 9

microsatellite also known as a short tandem repeated DNA sequences.
People inherit different numbers of repeats from their parents.
This makes microsatellites very useful for genetic fingerprinting (like in forensics and paternity testing) because they are highly variable between individuals.

Question 10

Explain the polymerase slippage model

Answer 10

-during replication, polymerase slippage and subsequent reattachment may cause a bubble to form in the new strand
-slippage is thought to occur in sections of DNA with repeated patterns of bases.

-then DNA repair mechanisms realign the template strand with the new strand and the bubble is straightened out. The resulting double helix is thus expanded.

-polymerase slippage, as theorised cannot occur in DNA without repeating patterns of bases

Question 11

Where may microsatellites be in?

Answer 11

Microsatellites may be in:
-genes (could lead to extra amino acids in protein)
-non coding DNA

Question 12

Give a summary of microsatellites in summary

Answer 12

-1000s in genome
-repeat units
-varying numbers of repeats
-alters actual size of that region of the genome
-multiallelic
-can be anywhere in genome
-may do nothing..

Question 13

Explain copy number variation

Answer 13

-the simplest type of copy number variation is the presence or absence of a gene
-an individual’s genome could therefore contain two, one or zero copies

-duplication of a genomic segment
-could result in diploid copy numbers of two, three, or four.

• Pair of homologous chromosomes (e.g. 2 copies of chromosomes)
• every locus (gene, base, genomic region) in theory is present as diploid

Question 14

Explain non-allelic homologous recombination in meiosis

Answer 14

Normal recombination:
In meiosis, homologous chromosomes line up and exchange DNA.
This is called allelic recombination — it shuffles alleles and increases genetic diversity.

Non-allelic recombination:
Sometimes, chromosomes misalign at regions of repetitive DNA (red bands in the figure).
Instead of swapping matching alleles, a crossover happens at the wrong place.
This is called non-allelic recombination.

Consequences:
One chromosome ends up with a duplication (extra copies of a gene or region).
The other ends up with a deletion (missing genes).
This changes copy number (how many copies of a gene/region you have).

Why it matters:
Copy number changes can lead to genetic disorders (e.g. some developmental disorders, susceptibility to disease).
But this same mechanism also drives evolution (new genes can arise from duplications).

Question 15

CNVs may be?

Answer 15

CNVs may be…
-intergenic (non coding)
-but quite large (>1Kb) so often affect on (or more) genes
-roughly 12% genome= CNV
->2000 identified

Question 16

Explain types of common genetic variant

Answer 16

-single nucleotide polymorphisms (SNPs)= roughly 17 million identified and 3 million/ genome

-microsatellites= roughly 3% of the genome

-copy numbers variants (CNVs) >2000 identified; roughly 100 per genome

Question 17

What is common?

Answer 17

-if biallelic (SNP/SNV), the frequency of the minor allele is relatively high (>1%)
-population frequency

-or multiallelic (microsatellites and CNVs)

Question 18

Explain common variants and disease/trait association

Answer 18

-most common variants not causing Mendelian, monogenic disorders
-majority are probably neutral
-but, may well impact complex, non Mendelian disorders and undoubtedly contribute to general individual variation

Question 19

Explain variant effects

Answer 19

-can be beneficial
-can be pathogenic
-most are neutral
-it can be used to as markers to help find disease-causing genes and mutations
-autozygosity mapping and linkage studies
-genome-wide association analysis (SNPs, CNVs)