genome variation

Question 1

what does human genetic variation show?

Answer 1

we are a young species

human evolution is characterised by constriction and frequent bottlenecks

Question 2

why are there fixed mutations in the human genome?

Answer 2

certain selective pressures

Question 3

what is the result of genetic bottle necks?

Answer 3

reduced diversity - the diverse population by chance will turn into a less diverse population and when this re-expands there will be reduced diversity

Question 4

what causes genetic bottlenecks?

Answer 4

speciation, migration, environment and disease

Question 5

what is the result of mutation?

Answer 5

it promotes diversity

Question 6

how can we work out how fast individuals mutate?

Answer 6

sequence the offspring and the parents - there are 50-100 new mutations in offspring that are not present in children

Question 7

what happens as paternal age increases?

Answer 7

the rate of mutation increases as there is a higher chance of passing on mutated sperms - there are some dominant genetic diseases during spermatogenesis - chance of this occurring is dependent on the age of the father

Question 8

how commonly do mutations occur in each generation?

Answer 8

a chance of 10^-8 per position per haploid genome - chance that that position will mutate every time that individual has offspring - around 70 new mutations in each diploid genome

Question 9

where are mutations higher?

Answer 9

mutations are higher in the testes and ovaries than the mutation rates for inherited disease

Question 10

how many base pairs are in the haploid genome?

Answer 10

3x10^9

Question 11

what are the origins of mutation?

Answer 11

mutation is due to failure to correct the errors that usually occur during replication but can also be down to exogenous factors

Question 12

what are uncorrected errors caused by?

Answer 12

exogenous and endogenous factors (segregation, recombination, DNA replication and inadequate DNA repair mechanisms)

Question 13

where are more mutations accumulated?

Answer 13

where there is poorly conserved DNA - 90% of our DNA is poorly conserved

Question 14

what are the two classes of mutation?

Answer 14

variation that does not change the DNA content - the nucleotides are unchanged - single nucleotide replacement or a balanced translocation or inversion
variation that results in a net loss or gain of DNA sequence - large (chromosome) or small (single nucleotide)

Question 15

what is neutral variation?

Answer 15

most DNA changes are small scale and have no obvious effect on the phenotype

Question 16

what types of variation are there and how common are these?

Answer 16

there are single nucleotide variations - rare variants are less common than 1% and single nucleotide polymorphisms that are more common that 1%

Question 17

what are restriction fragment length polymorphisms?

Answer 17

they are when the polymorphism or indel is a target of nuclease enzymes

Question 18

what are indels?

Answer 18

they are insertions or deletions of one or more nucleotides

Question 19

what are CNVs?

Answer 19

they are copy number variants - technically large indels

Question 20

what are the most common variations?

Answer 20

SNVS (include SNPs)- 90%
small (1-10 nucleotides) indels - 9%
large (10-100 nucleotides) - 0.9%
CNVs (>100 nucleotides) - 0.1%

Question 21

what is a polymorphism?

Answer 21

it is anything that is present at a frequency over over 1%

Question 22

what is the result of rare alleles that cause mendelian diseases?

Answer 22

they have a large impact on gene function and therefore are rare because these alleles are selected against in evolution

Question 23

what is the characteristic of a common genetic variation?

Answer 23

they have low or no impact on gene function

Question 24

what is the frequency of variants within a population?

Answer 24

it is determined by the functional impact - silent is common and detrimental is rare

Question 25

what are the usual two alleles for SNPs?

Answer 25

C and T

Question 26

how many possible genotypes are there for a diallelic SNP?

Answer 26

3

Question 27

what is an SNP?

Answer 27

it occurs when a single nucleotide in the genome differs between individuals of the same species resulting in a slight change to DNA sequence

Question 28

what is the minor allele frequency?

Answer 28

it is the frequency of the less common variant in a population

Question 29

when do SNPS with an MAF of >1% occur?

Answer 29

roughly every 300 bases

Question 30

how can base pair substitutions be classified?

Answer 30

missense, nonsense or silent

Question 31

how can we characterise these base pair substitutions based on their location?

Answer 31

intronic/intergenic variations - they are between genes or exons - do not directly affect the resulting protein but could affect the splicing or transcription regulation coding exonic variants - missense (AA change), nonsense (stop-gain - truncation), silent (same AA coded for)

Question 32

what are simple repeats?

Answer 32

they are part of normal human variation - there are lots of tandem repeats that are di or tri nucleotide

Question 33

what are the complications of repeats?

Answer 33

they are unstable and they are prone to replication slippage resulting in mutations that are variable

Question 34

how can STRs be used in fingerprinting?

Answer 34

there are a large number of possible sequence lengths and lots of different alleles - chance of someone being heterozygous for 2 sequences that are different in length is likely - only one individual will have the same combination of STRs in different lengths in a particular regions

Question 35

what are microsatellites comprised of?

Answer 35

simple sequence repeats, variable number tandem repeats and simple tandem repeats

Question 36

how would you type a simple repeat?

Answer 36

separation by size on a gel

Question 37

what are the characteristics of repeats?

Answer 37

they are refractive to sequencing due to poor cell rates, they can cause disease and they are subject to anticipation

Question 38

what does the copy number variation map of the human genome show?

Answer 38

it documents the extent and the characteristics of CNVs among healthy people

Question 39

where is there a particularly high rate of CNV variation?

Answer 39

subtelomeric regions and pericentromeric regions of the chromosome - they are distributed unevenly across the genome

Question 40

what are CNVs?

Answer 40

there are large regions of the genome where the number of copies of that region will vary across different chromosomes in healthy individuals

Question 41

what is the mechanism for losing and gaining in CNV?

Answer 41

recombination

Question 42

give an example of a gene family where CNVs are enriched?

Answer 42

in those gene families involved in certain functions - immune response, T cell receptor genes, olfactory receptor and drug metabolism is an example

Question 43

where is there very little variation in copy number?

Answer 43

functional groups of proteins that are integral to cellular function - signalling groups

Question 44

which genes have the most CNVs and which are least affected by CNVs?

Answer 44

most - paralogous genes | least - those genes involved in disease

Question 45

how are T cell receptor genes and Ig genes adapted for their role?

Answer 45

they are encoded by a large family of very similar duplicated genes allowing them to promote diversity and increase defence against pathogens and toxins

Question 46

what tends to be in CNS?

Answer 46

protein degradation, phosphorylation, signal transduction, transcriptional machinery and regulatory genes

Question 47

what is negative selection?

Answer 47

it is when a strongly deleterious mutation is removed by natural selection therefore it is very rare

Question 48

why may later onset disease be more common than neonatal?

Answer 48

the mutation causing this may not be eliminated by natural purifying selection as it is not immediate and therefore there may be little neonatal or early development disease but later onset

Question 49

what is the result of selection and give an example?

Answer 49

reduced diversity - inverse correlation between skin pigmentation and latitude - lighter means ability to better synthesise vitamin D where further from equator reduced diversity is apparent in regions of genome that have selective pressure on them

Question 50

what is positive selection?

Answer 50

mutations that have helped a change occur are selected for

Question 51

what is FOXp2 for?

Answer 51

the neural control of orofacial regions and vocalisation - highly conserved

Question 52

what is an example of positive selection?

Answer 52

responsible for synthesis of alpha amylase for starch digestion in saliva - those populations with a high starch diet will have a higher number of copies of gene in the CNV region of genome

Question 53

where is most variation found?

Answer 53

within populations - only around 10% extra found between them

Question 54

what variants are common to all populations?

Answer 54

those variants at a 10% frequency across combined samples

Question 55

where will rare variants often be found?

Answer 55

single population