In-depth notes on 5BBG0203 Human and Molecular Genetics A containing all detail mention in class and extra. Notes written after rewatching lecture and details were added when content wasn't clear. FAQ were asked when not sure and responses were added on to the lecture notes
L01/L02: Inheritance of genes
• Genotype- the genetic make up of an individual the alleles (variants) of all genes
• Phenotypes- the observable or detectable characteristics or traits that are the outward
expression of an organism’s alleles
• The inheritance of single genes follows classic Mendelian inheritance and generally
follow Mendel’s rules.
• Genes are contained on chromosomes.
• Most eukaryotic organisms have two copies of each chromosome, one from the father
(paternal) and one from mother (maternal), present in their somatic cells. The two
chromosomes are separated from one another in meiosis during the production of germ
cells. When a sperm fertilises an egg cell the developing animal has two copies of each
chromosome.
• These alleles are often identical but can vary from one another, ie there are variant
alleles.
• A variant allele occurs when there is a change (mutation) to the DNA sequence of the
gene allele causing a variation to occur to the protein that the gene encodes, leading to
a change in phenotype.
• Different alleles have different properties.
• The most common allele is often known as the wild type. A wild type allele usually
encodes a functional protein. Thus wild type alleles will normally act dominantly over a
variant allele that produces an inactive form of the protein.
• Variant or mutant alleles occur when there is a change or mutation in the allele DNA
sequence. A variant allele can change the function of the protein it encodes. This change
can cause a loss-of-function, there is no functional protein or a gain-of-function, the
protein gains additional activities. Both of these changes can create new phenotypes or
be the cause of genetic disease.
• New phenotypes (due to mutations) result from changes in functional activity of the
cellular product specified by that gene.
o Mutation may change overall enzyme shape and thus reduce affinity for
substrate- Loss-of-function allele
o Mutation may cause a complete loss of function, e.g elimination of substrate
binding- Null allele
o Some mutations may enhance allelic function.
▪ Usually increases quantity of gene product by affecting regulation of
transcription of the gene- Gain-of-function allele
o Some mutations do not show any change in function- Neutral mutation
• Types of alleles
o Wild type- normal allele
o Recessive allele- alleles whose phenotype can be masked. Recessive alleles
are often loss of function or null alleles
, o Dominant- allele whose phenotype can mask a recessive alleles
o Wild type alleles generally act as dominant when in combination with a null
allele - the normal wild type allele dominants over a loss of function
• Dominant alleles can also be gain of function alleles that enhance gene activity, This can
occur as a result of an increase in activity of the gene. Alternatively a dominant allele can
have a new activity that can mask the activity of a wild type allele
o Oncogenes often alleles with increased activity and drive increased cell
division
• Semidominant/ incomplete allele- allele that creates an intermediates phenotype when
heterozygous. Allele is not fully dominant, a single copy of the semidominant allele not
completely mask (or compensate for) the recessive allele. One copy of the semi-
dominant allele causes a phenotypic affect but its not the same as when the dominant
allele is homozygous, also known as co-dominance. In some cases the wild-type alleles
can be semi-dominant if one copy is insufficient to provide full activity, for example petal
colour in Antirrhinum
o a/a- recessive
o A/a - intermediate phenotype
o A/A- dominant phenotype
• Co-dominance- allele can be distinguished in the phenotype in the presence of another
allele. Co-dominance produce different gene products both of which are detectable in
the phenotype.
o Blood groups A and B alleles are co-dominant since when both are present
they can both be detected. Both A and B alleles are dominant over O allele
but co-dominantly with each other
o Different alleles leads to addition of alternative sugar to glycolipid
• Conditional alleles- alleles whose phenotypic consequence varies with environmental
conditions, most commonly temperature sensitive alleles
o The DNA mutation produces a change in the protein such that the protein is
active at low temperatures bit loses its function at higher temperatures:
Himalayan rabbit and Siamese cat
• Lethal alleles- many genes are essential for survival and loss of gene activity results in
death of the animal. Alleles that disrupt these genes are known as recessive lethals since
the animal will live when the allele is heterozygous.
o Gene required for development
o Time of death will dependent on when gene is required
o Approximately 1/3 of genes are essential for survival
o Rare dominant lethal exist- an example is the dominant allele that causes
Huntington’s disease. Individuals with this allele die prematurely but often
reproduce before the disease presents, resulting in the maintenance of the
allele in the population
• Alleles can be described based on how they produce their phenotype
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, o Amorph- an amorphic allele is one where is a complete loss of gene product
function, and are generally recessive to wild type alleles
o Hypomorph- a hypomorphic allele is one where there is a reduction in the
activity of the gene product, and are usually recessive to the wild type allele
o Hypermorph- a hypermorphic allele is one that has an increase activity of the
gene product, these are generally dominant over the wild type allele
o Neomorph- a neomorphic allele is one that has a new function that differs
from the wild type allele, these are generally dominant over the wild type
o Antimorph- an antimorphic allele is one that blocks the activity of the normal
gene product and are often known as a ‘dominant-negative’
• Penetrance- describes whether a particular genotype displays its associated phenotype
• Expressivity- describes the level or intensity of phenotype seen for a particular genotype
o Eyeless shows variable expressivity- some individuals inheriting the eyeless
allele have partially reduced eyes while others have complete loss of the eye
o Polydactyly shows variable penetrance and expressivity
▪ Variable penetrance- not all individuals inheriting the polydactyly
mutation have extra digits
▪ Variable expressivity- some individuals inheriting the polydactyly
mutation have complete extra digits while other only have partial
increases
• Types of mutations
o Missense- single nucleotide change results in the substitution of the amino
acid
o Nonsense- single nucleotide change resulst in a stop codon
o Frameshift- when nucleotide is added or removed causing a shift in the
reading frame
• Genes can have many different alleles
o The white gene of drosophila encode a protein necessary for the normal
production of the red pigment in drosophila eyes. Alleles of white that
abolish protein function cause white-eyed flies while alleles that only partially
affect protein activity results in eyes with different shades of red
o The epidermal growth factor receptor (EGFR) gene encodes a protein that
regulates cell growth and differentiation. Recessive alleles of EGFR that
reduce protein function cause developmental defects and cell death.
Dominant alleles of EGFR cause over-activity of the protein resulting in
uncontrolled cell growth and cancer
• Pleiotropy- some alleles of the same genes can have different phenotypic effects. A loss
of function allele can affect multiple characteristics or cell types. If gene product is
required in many different cells or tissues then a loss of function allele can give rise to
multiple phenotypes. However different variant alleles may not produce same spectrum
of phenotypes
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, o Example : Gene “shaky” expressed in muscle, brain, gut- multi-domain
protein
▪ Domain I lost activity- kinase function only needed in brain – only
brain affected, hence shaky
▪ Domain II lost activity- GTPase function needed in brain and muscle-
phenotypes in brain and muscle
▪ Domain III lost activity- actin-binding activity needed in muscle and
gut- Muscle and gut phenotypes
▪ Truncated protein- no activity –phenotypes in muscle brain and gut
o Example: Gene A encoding an enzyme at high levels in skin (compound 1 )
and lower levels in CNS neurones (compound 2)
▪ Hypomorphic allele of gene A leads to the reduction in activity- may
produce phenotype only in CNS where levels of synthesis of
compound 2 drop below critical threshold
▪ Null allele of gene A may produce skin pigmentation and CNS
phenotypes as both compounds are not synthesises
• Multiple alleles exist in populations- Many different alleles of each gene can exist in a
population. Basis of genetic diversity and natural selection. If an allele improved gene
function it may be retained within a population and its frequency could increase
• Generation of new alleles- can occur spontaneously due to damage, a failure of DNA
replication or repair. Once they occur they can remain in the population at certain
frequencies, for example if they are carried as heterozygous. Can form basis of natural
selection. The frequency of an allele is the proportion of that allelic form among all the
copies of the gene in the population, some are quite common like cystic fibrosis 1 in 23
is a carrier (0.043)
• Deliberate generation of new alleles is the base of genetic screens to identify genes
responsible for biological processes and metabolic pathways. Having large numbers of
alleles allows a geneticist to describe in more detail the roles of an individual genes.
• New alleles also be generated by exposure to mutagen examples chemical or X
irradiation. Different mutagens cause different DNA damage
o Alkylating agents, base analogs- Base mutations
o Acridines, nitrogen mostards- frameshift
o Transposable elements- insertions
o X- ray- Chromosomal rearrangements: deletions, duplications, inversion,
translocation
• Use of genetic screens- to identify genes involved in a specific biological process it is
possible to perform genetic screens for mutations affecting single genes necessary for
that process. Model organisms such as yeast, nematode worms, fruit flies. Screens have
been used to identify single genes affecting vision, embryonic development, nervous
system development, cell cycle control, courtship behaviour
• Genetic screens/ mutagenesis identifies genes required in different processes
o 1. Mutagenesis: mutant collection
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