18.04.01 Genetic definitions

Question 1

Define allele frequency.

Answer 1

The proportion of a particular allele (or variant) among all allele copies at a given locus (ie: the number of copies of a particular allele divided by the number of copies of all alleles at the given locus in a population). Usually expressed as a percentage.

It is also the relative proportion of all alleles of a gene that are of a designated type.

Question 2

What is the allele frequency used for?

Answer 2

Allele frequency is used to estimate the amount of genetic diversity at the individual, population, and species level.

Question 3

What is an association study?

Answer 3

A statistical method for estimating the co-occurrence of genetic alleles with a phenotype. If an association is present, an allele will occur most commonly with the phenotype in the population than would be expected by chance. The association is independent to linkage.

Question 4

What are the main differences between linkage and association studies?

Answer 4

Linkage

1. Requires families with multiple affected individuals
2. Uses microsatellites
3. Marker needs to be linked to risk factor - can be Mb apart
4. Identifies variants of large effect typically requiring variants in the same gene in many families to detect.

Association

1. Typically employs a series of unrelated cases and controls
2. Typically tests 1.5-2 million SNPs
3. Marker needs to be in linkage disequiblibrium which means they should be within a few kb of each other
4. Requires a common risk factor that has occurred on only a few haplotypes.

Question 5

Define epistasis.

Answer 5

a phenomenon that consists of the effect of one gene being dependent on the presence of one or more ‘modifier genes’ (genetic background).

Question 6

Define genetic fitness.

Answer 6

population genetics defines fitness as a propensity or probability of survival and reproduction in a particular environment usually represented by w, where w is equal to 1- the selection coefficient.

Question 7

Define gene flow

Answer 7

The flow of genetic material between previously separate populations (of the same species), caused by migration and mating.

Question 8

Define gene pool

Answer 8

The collection of all the alleles of all of the genes found within a freely interbreeding population.

Question 9

Define genetic drift

Answer 9

A change in allele frequency in a given population over time due to chance (ie: offsprings alleles are random samples of those in parent). Not driven by adaptive pressures and more prevalent in small populations. Genetic drift can result in the loss of some alleles (including beneficial ones) from a population, and can have a significant impact when a population sharply reduces in size (following for example a natural disaster - bottleneck effect, or by populations splitting and forming a new colony - founder effect).

Question 10

Define genetic hitch-hiking.

Answer 10

When an allele changes frequency because another allele which it is in linkage disequilibrium is under selection pressures.

Question 11

Define genetic linkage

Answer 11

The tendency of genes, that are located proximal to each other on a chromosome, to be inherited together during meiosis. It has been proposed that the greater the distance between 2 linked genes, the greater the chance the non sister chromatids recombine (cross over) in the region between the genes.

Question 12

Define genetic load.

Answer 12

The difference in fitness between the optimal individual and the average of the population.

Question 13

What is a genetic screening programme?

Answer 13

Genetic screening programs: Any kind of test performed for:

1. Systematic early detection or exclusion of a genetic disease.
2. Detection of genetic predisposition or resistance to a disease.
3. Determination whether a person carries a gene variant, which may produce disease in offspring.

Question 14

Define genotype frequency

Answer 14

The number of individuals in a population with a given genotype divided by the total number of individuals in the population. Genotype frequency may be used for “genomic profiling” - to predict someone’s having a disease or a birth defect. It can also be used to determine ethnic diversity.

Question 15

What is a genome wide association study?

Answer 15

Studies looking at associations between alleles throughout the genome and phenotypes. They are effective in detecting common alleles that contribute to the inherited component of common multifactorial diseases. Typically, the alleles identified by this approach have modest effect sizes that cannot fully account for disease susceptibility. This discrepancy may exist because it is hard to identify rare alleles with a low to modest penetrance using GWAS.

Question 16

What is genomic profiling?

Answer 16

When genotype frequency is used for to predict someone’s having a disease or a birth defect. It can also be used to determine ethnic diversity.

Question 17

Define the term haplotype.

Answer 17

It is the symbolic representation of a combination of linked alleles in a cluster of related genes. The term is a contraction of Haploid Genotype.

Question 18

What is Hardy-Weinberg’s law?

Answer 18

This is an important principle in population genetics that provides a solution as to how variation is maintained in a population with Mendelian inheritance. According to this principle the frequency of alleles (gene variants) remain constant through generations in the absence of the four evolutionary forces - i.e. no natural selection, no sexual selection, no mutations, no genetic drift and no gene flow (Hardy –Weinberg equilibrium). It is used to assess risk for individuals of families with genetic disease.

Question 19

Define linkage disequilibrium.

Answer 19

It is the non-random distribution of adjacent gene alleles into gametes (by recombination). Linkage disequilibrium is the occurrence of some combinations of alleles or genetic markers in a population more often or less often than would be expected from a random distribution.
An association can only be found between alleles and disease if the disease is in LD with a marker allele.
LD is often expressed as D. If D=0 there is no association between alleles and, in this case, the distribution of alleles in the population is as expected (randomly distributed) and dependent on the allelic frequency.

Question 20

What is the LOD score?

Answer 20

Lod is the abbreviation for “logarithm of the odds” favouring linkage. The lod score method is employed in the statistical analyses of linkage. A LOD score of 3 or more is generally taken to indicate that two loci are linked and are close to one another. In practice, score calculations are done by computer software, e.g. LIPED program.

Question 21

What is a map unit (uu)

Answer 21

It is a measure of genetic distance between linked genes corresponding to the recombination frequency of 1% or 1 centiMorgan (cM).
Morgan’s observation that the amount of crossing over between linked genes differs led to the idea that crossover frequency might indicate the distance separating genes on the chromosome.

Question 22

Define minor allele frequency (MAF).

Answer 22

It is the frequency of occurrence of the least common allele at a given locus in a defined population. SNPs with MAF of 5% or more have been targeted by Hapmap project.

Question 23

What is a Morgan unit?

Answer 23

A unit used to express the distance between genes on chromosomes. One Morgan (M) indicates a recombination possibility of 100%. A crossover value (recombination) of 10% represented by a distance of deciMorgan (dM) and a crossover value of 1% is equal to centiMorgan (cM).

Question 24

Define the term mutation rate.

Answer 24

Frequency with which a gene changes from the wild-type to a specific mutant; generally expressed as the number of mutations per biological unit (i.e., mutations per cell division, per gamete, or per round of replication).

Question 25

Define natural selection.

Answer 25

Selection based on the individuals within a population who are the best fit/fittest for the environment they are in as they have a certain phenotype of group of phenotypes.

Question 26

What is meant by the term ‘odds ratio’?

Answer 26

The odds of having the disease and the risk allele divided by the odds of having the disease without the risk allele. In a case-control study this is effectively the proportion of cases with the genotype over the proportion of controls with the genotype. A higher OR or RR implies a greater effect on the phenotype.

Question 27

What is meant by the term ‘penetrance’?

Answer 27

a measure of the proportion of individuals in a population carrying a particular allele that expresses the related phenotype. Mendelian diseases tend to have a high penetrance and very rare allele frequency.

Question 28

What is population genetics?

Answer 28

Is the study of genetic composition of populations. It involves estimations of gene frequencies and the four main selective factors that determine them in natural populations; natural selection, genetic drift, mutation and recombination.

Question 29

What is meant by the terms ‘recombination frequency’ and ‘recombination fraction’?

Answer 29

Recombination fraction: A number that describes the proportion of recombinant offspring produced in a genetic cross between two organisms. (see also Recombination fraction)

Recombination fraction (θ): It is the number of recombinants over the total number of progeny. It is used to determine distance between loci in genetic map.It can take values between 0 and 0.5. When the recombination fraction is 0.0, this means the two loci are so close together on the chromosome that recombination never occurs between them.
When the recombination fraction is 0.5, this indicates the two loci are segregating independently and either are far apart on the same chromosome or are on different chromosomes.

Question 30

What is meant by the term ‘relative risk’?

Answer 30

It is the estimated probability of having the disease when the patient has the at risk allele in association studies (e.g.GWAS).

Question 31

How is ‘selection coefficient’ defined?

Answer 31

The relative fitness of a particular phenotype when compared to an individual with a more favoured phenotype. Represented as s. An s of 0 related to a phenotype which confers no advantage whatsoever to the individual. An s of 1 is lethal.

Question 32

Define selective sweep.

Answer 32

the process of hitchhiking genes changing their frequency.

Question 33

Define the term ‘single nucleotide polymorphism’.

Answer 33

It is a variation in DNA sequence in which a single nucleotide is replaced by any one of the other 3 bases. It is inherited stably so it is a very useful marker in linkage studies.

It is very prevalent in the human genome and estimated to occur every about 300bp suggesting that there are about 10 million SNPs in the human genome.

Question 34

Define speciation and species

Answer 34

Speciation: evolutionary process by which a new species comes into being. can be driven by natural selection and genetic drift.

Species: a group of organisms that can reproduce with one another to produce viable fertile offspring and is reproductively isolated from other organisms.