Molecular evolution

Question 1

Explain molecular evolution and its mechanisms

Answer 1

-conceptual foundation of evolution: descent from an ancestor which leads to speciation

-molecular evolution evolution at the nucleic acid level
-mutation
-selection
-genetic drift
-gene flow (migration)
-recombination
-gene duplication

Question 2

Explain how mutations drive evolution

Answer 2

How mutations drive evolution:
-generation of variation: introduction of new alleles due to errors, damage, radiation etc.
-variation in individuals: mutations lead to changes in appearance, behaviour, physiology
-environmental interaction: variations interact with environment and are acted upon by other forces
-evolution of the population: over time the frequency of advantageous mutations can increase within the population

Question 3

Explain natural selection

Answer 3

-organisms better adapted to their environment are more likely to survive
Positive: variants that increase fitness are selected for (LP, CCR5- A32 HIV resistance, antibiotic resistance in bacteria)

Negative/ Purifying: variants that decrease fitness are selected against removal of alleles

Balancing selection: maintenance of alleles because of heterozyogote advantage

-even enhance ability to attract a mate, some pats of the genome are resistant to change as they contain vital sequences (conservation)
-selection acts on phenotypes but the outcome is allele frequencies
-mutations happen randomly but selection is a non random process

Question 4

Explain gene flow (migration)

Answer 4

-the transfer of genetic material between populations through the movement of individuals, introducing new alleles into the gene pool
-contributes to genetic diversity within a population
-reduces genetic variation across populations
-gene flow can be adaptive, neutral, or even maladaptive, depending on the context
-interbreeding of previously isolated populations is called admixture.

Question 5

Explain genetic drift

Answer 5

-a random change in the frequency of a variant within a population due to chance
-more powerful in smaller populations
-may cause genes variations to disappear thereby reducing genetic variation or lead to fixation
-all variants are subject to genetic drift

Question 6

Explain gene duplication

Answer 6

After duplication:
-Nonfunctionalisation: one copy becomes a pseudogene
-Neofunctionalisation: one copy acquires a new function
-Subfunctionalisation: functions partitioned between copies

Mechanisms of gene duplication:
-unequal crossing over in meiosis
-retrotransposition
-whole genome duplication (WGD)

Question 7

Explain recombination

Answer 7

Homologous recombination reshuffles alleles during meiosis
-creates new combinations of variants, new genotypes
-can bring together beneficial, break apart harmful combinations
-mechanism for gene duplication and deletion via unequal crossing

Question 8

Explain sequence conservation and divergence

Answer 8

Conservation: high similarity due to purifying selection (exons, splice sites etc)

Divergence: accumulation of substitutions due to drift or adaptive change
Conservation- where selection is acting to preserve function
Divergence- where change is tolerated.

Orthologs: same gene different species
Paralogs: duplicated genes within a genome
Homologs: genes related by descent

Question 9

Explain sequence conservation patterns in the genome

Answer 9

-coding regions; high conservation
-UTRs, promoters, terminators; intermediate conservation
-Introns, 3rd base of codons; low conservation

Question 10

What can we use sequence conservation for

Answer 10

-understand disease mechanisms
-identify functionally critical DNA and protein regions
-pinpointing regulatory sequences
-predict protein structure and function
-improving computational methods
-infer evolutionary relationships

Question 11

Explain phylogenetics

Answer 11

-the study of evolutionary relationships between biological organisms
-reconstruction of evolution of genes or species
-phylogenetic trees: illustrate the relatedness of different biological entities
-distance between two entities on a tree can be used to convey the extent of relatedness
-relatedness is normally a function of both evolutionary pressure and time
-time is estimated by measuring mutation rates

Question 12

Explain infectious disease and phylogenetics

Answer 12

-SARS- CoV- 2 is thought to have emerged as a zoonotic virus

-determining the origin is important to understand how the virus emerged and to prevent similar events in future

-phylogenetic analysis of early outbreak virus isolates from Wuhan indicate that two separate viruses emerged within weeks of eachother

Question 13

Explain SARS-CoV-2 origins

Answer 13

-phylogenetic analysis indicates an origin of SARS-CoV-2 in the Huanan Seafood wholesaler market
-individuals and their locations within the market have been determined
-these have now been linked to particular species of infected animals

Question 14

Explain the globin gene family

Answer 14

-gene duplication and divergence: subfunctionalisation
-paralogs retained by natural selection, complementary roles
-stage specific expression: embryonic —-> foetal —-> adult globing
-ancestral globin gene —-> duplication—-> whole genome duplications —> a-like and B-like clusters —-> further duplications—-> stage p specific paralogs —-> pseudogenes and specialised functions

Question 15

Explain globin clusters and stage-specific expression

Answer 15

Two gene clusters; a, Beta
-Six chains of globin chains: ζ,α,ε,γ,δ,β

Alpha cluster (chr 16):3 genes/ 3 pseudogenes (ζ,α chains)

➢ Beta cluster (chr 11): 5 genes/1 pseudogene (ε,γ,δ,β chains)
➢ Humans make different Hb as they develop
➢ The genes are arranged on each chromosome in order of expression during development
Embryo: HBZ/HBE1
high O₂ affinity for early development. mutations here
not relevant.
Foetus: HBA1/2 - HBG1/2
High O₂ affinity to pull oxygen from maternal blood -
genes usually silenced after birth
Adult: HBB, HBD
optimised for oxygen delivery to tissues. Mutations here

Question 16

Explain sickle cell disease

Answer 16

Group of multisystem inherited
disorders that affect haemoglobin
➢ Normal: disk abnormal: crescent
➢ Main symptoms appear at 5-6 months
➢ Blockage of small vessels (vasoocclusion): acute pain episodes – “crises”
– due to oxygen deprivation of tissues
➢ Hemolysis: Anaemia – fatigue, restlessness, jaundice
➢ Increased frequency of infections – spleen damage, stroke, pulmonary
hypertension, gallstones, liver and kidney problems, joint problems, delayed
puberty

Question 17

Explain characteristics of sickle cell disease

Answer 17

Cause: SNV in the HBB (β-globin gene): Glu6Val
(CAG > GTG)
➢ AR genetic disease
➢ Original mutation occurred ~7300 ago
➢ If both parents have one copy of HbS then each child
has a 1 in 4 chance of having sickle cell anaemia (two
copies of HbS)
➢ One of the most common inherited life-threatening
disorders worldwide
➢ Sickle trait is common in African, Middle Eastern,
Mediterranean and Indian populations but very rare in
Northern European populations

Question 18

Discuss balancing selection and HbS

Answer 18

HbAA (normal/normal): healthy hemoglobin, but vulnerable to malaria
* HbSS (sickle/sickle): sickle cell disease, reduced survival/fitness
* HbAS (carrier): usually healthy + resistant to severe malaria
* Heterozygote advantage = balancing selection
* Explains persistence of HbS allele in malaria-endemic regions
* Classic case of evolution directly shaping human health

Question 19

Give a brief summary

Answer 19

Define molecular evolution and its mechanisms driving sequence change
* Understand the levels of sequence conservation in CDS, UTRs, introns
* Describe the principles of phylogenetic inheritance
* Discuss Gene Duplication as a major driver of genomic innovation
* Apply concepts of molecular evolution to the globin gene family and SCD
* Evaluate the concept of heterozygote advantage