lecture 7 - population genetics 1 Flashcards
what is population genetics?
the study of the distributions and changes of allele frequency in a population as the population is subject to the 4 main evolutionary processes such as mutations, selection, gene flow and genetic drift
what is the population genetic diversity
90% of human variation is in all humans, 10% is population specific
Only a small proportion of additional differences will be found between
individuals from two different continents.
what is the hardy-weinburg equilibrium?
this principle states that within sufficiently large populations, the allele frequencies remain constant from 1 generation to the next unless the equilibrium is disturbed by migration, genetic mutation or selection
a population in H-W equilibrium will be expected to maintain near identical allelic frequencies from 1 generation to the next
a population is said to be in H-W equilibrium if the population is large, mating is random, all matings are fertile and the population is closed
a population will maintain equilibrium unless an agent of change enact upon it
Allele frequency – p + q = 1
what are mutations?
mutation is the ultimate source of genetic variation in the form of new alleles
mutation can result in several different types of change in DNA sequences, these can either have no effect, alter the product of a gene or prevent the gene from functioning
no mutation, no change and no evolution
what is selection?
selective pressure can be the result of many things
-competition for food, habitat or mates (ecological and sexual)
-pressure exerted through predation
-death or illness do to parasitic organisms or infectious disease
natural positive selection = sickle cell and malaria
as a result of there pressures, due to genetic variability, some phenotypes may have a selective advantage
-greater contribution to the next generation = greater fitness
-no phenotype has a set fitness level - depends on the circumstances
what is selection sweep?
occur when an allele becomes more common in a population as a result of positive selection
a selective sweep can occur when a new mutation occurs that increase the fitness of the carrier relative to other members of the population. natural selection will favour individuals that have a greater fitness and with time the newly mutated variant (allele) will increase in frequency relative to other alleles
one of the most famous examples of an incomplete sweep is that at the lactase loss in European populations. variants in this gene influence whether the ability to produce lactase, which enables the digestion of milk, persists in adulthood. lactase persistence is thought to have increased in frequency as a result of positive selection during the past 10,000 years after the emergence of dairy farming
what is artificial selection?
Selection for high oil content in maize. Experiment running since 1896.
Maize kernel oil is a valuable source of nutrition
Original population of 163 corn ears.
Selection for breeding - 24 ears with high oil content and 12 ears for low.
The low oil content plants reached 0% oil production after around 80 generations, i.e. all the individuals in the population had the same genotype encoding for low oil content.
For high % oil content, it continued to increase past a 100 generations. WHY?
A complex trait, >70 genes involved. It depends on the combination of alleles in these genes – indicating that the additive effect is important in oil synthesis and accumulation.
Phenotypes with super high oil content may have combinations of genes that weren’t present in the initial population
Difficulties can arise when a species reaches its desired form.
In the case of crops, this can create a “monoculture” where each individual has the same advantages and disadvantages
An example of this going wrong was the case of the great potato famine in Ireland.
International seed and sperm banks have been created in an effort to maintain genetic diversity.
what is gene flow?
-gene flow can change the frequency and/or the range of alleles in the population
-migration is capable of changing allele frequencies far more rapidly than selection
-immigration = disproportionate quantity of certain alleles are Brought into a population
-emigration = the departing group do not represent the population as a whole with regard to allelic proportions
what is a chance event?
A change in the population’s allele frequency due to chance, NOT selection, which may result in the loss of alleles from the gene pool.
what is a bottleneck type of genetic drift?
-natural disasters do not favour any particular phenotype
-the resultant reduced population may be unrepresentative of the original population
a bottleneck essentially wipes out thousands of years worth of divergent evolution resulting in the next generation having very few mating options and as a result the growing population will be genetically very similar
an example is a typhoon which wiped out all but 30 inhabitants on an island in a S.PACIFIC. one male survivor was heterozygous for total colourblindness gene (recessive). today 2,000 inhabitants = 10% are homozygous for the colour blind gene
what is the founder effect of genetic drifting?
where popultions experience a strong influence of genetic drift if some portion of the population leaves to start a new population in a new location or if a population gets divided by a physical barrier of some kind.
in this situation, it I improbable that those individuals are representative of the entire population, which results in the founder effect
the founder effect occurs when the genetic structure changes to match that of the new populations founding fathers and mothers
eg The Amish are a group descended from 30 Swiss founders.
One of the founders had Ellis-van Crevald syndrome, extra fingers and toes, and heart defects.
Today 1 in 200 Amish are homozygous for this syndrome, which is very rare in the larger US population.
what is genetic drift?
Causes random fluctuations in allele frequencies in a population
Includes the bottleneck effect and founder effect
Is most obvious when population size is small.
May result, over many generations, in the fixation of one allele in the population, with the loss of the second.
what is cystic fibrosis?
a hereditary disorder characterised by lung congestion and infection and malabsorption of nutrients by the pancreas
Researchers have traced the origins of the mutation to two separate events. It was first introduced into European populations about 50,000 years ago, possibly through the Basques of Spain.
A second introduction of the gene occurred with the inception of agriculture in Europe, about 10,000 years ago.
Ireland has among some of the most severe strains of CF and also has the highest incidence (per head of population) of CF in the world, with three times the rate of the United States and the rest of the European Union.
what are cystic fibrosis genetics?
Cystic Fibrosis is the most common single-gene disorder in Europeans
1 in 20 people of European descent are carriers (+/-)
1 in 625 couples of European descent are both carriers (+/- x +/-)
1 in 2500 newborns of European descent have Cystic Fibrosis (-/-)
why do people still get cystic fibrosis?
The lethal disease strikes people with mutations in both copies of a particular gene. Historically, such people died before reproductive age – so the mutant genes would be expected to have gradually died out.
Instead the genes have persisted for thousands of years, especially in people of European descent. Other racial groups have a far lower incidence.
Previous studies into the potential benefit of a single cystic fibrosis (CF) mutation focused on cholera or typhoid, because these diseases involve the protein that is mutated in CF.
Research has shown that cholera and typhoid simply did not kill enough people to explain the CF gene’s persistence. Even if one CF gene gave total protection against either disease, this would not be enough selective advantage to push the gene to modern European levels.
However, between 1600 and 1900, TB caused 20% of all deaths in Europe, an epidemic unparalleled elsewhere. The model showed that even if it gave only partial protection against TB, the CF gene would easily have reached its current levels in Europeans.
what is the CF gene?
Organisation of the Human Cystic Fibrosis Gene: DNA (230,000bp)
Organisation of the Human Cystic Fibrosis Gene: pre-mRNA
Organisation of the Human Cystic Fibrosis Gene: mRNA (just exons left)
The first mRNA transcript contains intron (yellow) and exons (red)
These are removed (spliced) before the mRNA leaves the nucleus
The protein is 1500 amino acids long
what is the cystic fibrosis gene?
Gene found in 1989. It encodes a chloride ion pump called CFTR
(Cystic Fibrosis Transmembrane Regulator)
normal CFTR = moves chloride ions to the outside of the cell whereas
mutant CFTR = does not move chloride ions, causing sticky mucus to build up on the outside of the cell
what is the cystic fibrosis mutation?
Many Genetic conditions have mutations that are specific to one family (or families related by descent)
However, 75% of CF mutations are a three base pair deletion of the 508th amino acid phenylalanine ((triangle)F508)
Tests have been developed that allow us to diagnose the (triangle)F508 mutation
The other 25% of CF mutations are very variable but can be diagnosed
how can Population & evolutionary genetics help in understanding the pandemic?
it can tell us…
where did SARS-CoV-2 originate?
How many introductions have there been to a region?
What are the implications of mutations for public health (e.g. vaccine development, changes in infectivity or virulence)?
Can we predict whether these mutations will spread?
What human genetic factors and what environmental factors affect the severity of the disease?
From Monogenetic to Oligogenic Disease: Modifier Genes. Complexity in monogenic diseases…
CF categorized as “oligogenic” rather than “polygenic,“ only a relatively small number of genes involved.
Mutations in CFTR almost always cause the CF phenotype.
Diverse population studies of CFTR mutations have shown mutations in additional genes could perhaps modulate the severity and type of disease-related phenotypes.
CFM1 = cystic fibrosis modifier,
HLA-II = MHC class II antigen,
MBL2 = mannose-binding lectin (protein C) 2 NOS1 = nitric oxide synthase 1,
TGFB1 = transforming growth factor-a1
TNFA = tumour necrosis factor-a encoding gene.)
Identification of 5 modifier loci of lung disease severity in CF…
Y-axis – relative association of SNPs on Chrm regions of affected individuals compared to controls. The higher the peak the higher the association.
P value – observation occurs by chance but with negative Log scale this shows the SNP is very unlikely NOT to be associated with CF.
Patients with the same variants in CFTR exhibit substantial variation in severity of lung disease, of which 50% is explained by non-CFTR genetic variation
Genome wide association meta-analysis of 6,365 CF patients and non-CF siblings with over 8 million variants was conducted.
Individuals were from the USA and France.
65% were Phe508del homozygotes and 95.5% were of European ancestry.
Functional analysis of associated SNPs and genes at each modifier locus could identify novel targets for treating CF.
The discovery of modifier loci that are strongly associated with severity of CF lung disease provides an opportunity to enhance individualized treatment in CF.
The five associated loci contain genes of compelling biologic plausibility based on extensive understanding of CF pathophysiology.
MUC4andMUC20, SLC9A3 , HLA II, EHF/APIP and AGTR2/SLC6A14
All have been implicated in a variety of pulmonary and intestinal functions.
Identification of the gene or genes, and associated SNPs, responsible for the modifying effect of each locus will require functional study.
All 5 regions remained significant when only individuals of European decent were considered.
EHF transcription factor is reported to modify the CF phenotype by influencing p.Phe508del processing, and to modulate epithelial tight junctions and wound repair.
what are treatments of cystic fibrosis?
The discovery of modifier loci that are strongly associated with severity of CF lung disease provides an opportunity to enhance individualised treatment in CF. Small molecule targeting, CRISPR-Cas9
what is the route of HIV infection?
-CCR5 is a g-protein coupled receptor that normally controls migration of white blood ells from the blood to inflamed tissue
-CD4 is a receptor in t-cells
-HIV entry requires CD4 and CCR5 (chemokine (C-C motif) receptor 5)
-some chemokine, such as RANTES, block HIV entry
-we know that different people have different susceptability to hiv, what causes this?
