lecture 5 - mendelian inheritance Flashcards
what is mendelian inheritance?
Mendelian inheritance describes inheritance patterns that obey two laws
– Law of segregation
– Law of independent
assortment
Simple Mendelian inheritance involves
– A single gene with two
different alleles
– Alleles display a simple
dominant/recessive
relationship.
what are mendelian ratios? - monohybrid
Trait affected by a single gene
For a self cross
F2 Genotypic ratios = 1:2:1
- 1/4 YY + 1/2 Yy + 1/4 yy
F2 Phenotypic ratio = 3:1
- 1/4 YY + 1/2 Yy= 3/4 dominant yellow
- 1/4 yy = recessive green
For a Test Cross Yy x yy
F2 Genotypic ratios = 1:1
- 1/2 Yy + 1/2 yy
F2 Phenotypic ratio = 1:1
- 1/2 Yy (yellow) + 1/2 yy (green)
Do Monogenetic Disorders Follow Mendelian Inheritance?
The basic laws of inheritance are important in understanding patterns of disease transmission.
The inheritance patterns of single gene diseases are often referred to as Mendelian such as - Myotonic Dystrophy, sickle cell anaemia, haemophilia, Rett syndrome…
The inheritance patterns of these monogenetic disorders still obey Mendelian laws, or nearly…
– However, they are more complex
and interesting than Mendel had
realised.
Mendelian pedigree patterns are autosomal dominant, autosomal recessive and X-linked.
what is classic mendelian inheritance?
In reality there are very few clear cases of classic Mendelian inheritance of human traits
The earwax determining gene,ABCC11(for ATP-binding cassette, subfamily C, member 11).
A SNP leads to a change in the amino acid sequence changing a Glycine to an Arginine.
AA homozygotes have dry earwax.
GA heterozygotes and GG homozygotes have wet earwax.
The dry earwax allele is very common among people of Asian descent, relatively rare among those of Western European descent and extremely rare among people of African descent (Ohashi et al, 2011)
Earwax type is not used very often to illustrate basic genetics, but unlike most human characters that are used (tongue rolling, attached earlobes, etc.), it really is controlled by a single gene with two alleles.
what are the symptoms of Myotonic Dystrophy Type 1?
Symptoms
Myotonia. Difficulty relaxing muscles.
Muscle weakness. Face, neck, arms, legs. Speech can also be affected.
Heart problems. Abnormal rhythm.
Chest and breathing problems. Chest infections and disturbed sleep
Digestive problems. Digestive muscles affected
Eye problems. Cataracts.
Thinking and planning. Brain may be affected. In children with congenital myotonic dystrophy can cause learning and behavioural issues.
what is Myotonic Dystrophy Phenotype?
Surprisingly, the DM1 inheritance pattern is autosomal dominant even though the expansion mutation occurs in a region of the DMPK gene that does not encode a protein.
There is very strong correlation between the size of the CTG repeat and the severity of the phenotype.
Why does the CTG repeat get longer on the Myotonic Dystrophy Phenotype?
Once there are more than 38 repeats in the DMPK gene the expanded sequence becomes unstable.
Leads to issues with DNA replication and repair mechanisms. The molecular mechanisms underlying repeat instability are currently not well understood.*
what causes the Myotonic Dystrophy Phenotype?
Myotonic Dystrophy was the first autosomal dominant disease found to be caused by a repeat expansion that is transcribed into mRNA but is NOT translated into a protein.
One mechanism is RNA induced toxicity
The nucleotide repeats cause the RNA strands to form abnormal hairpin folds.
These hairpins then bind splice-regulating proteins forming RNA protein complexes that accumulate within nuclei.
Accumulation can disrupt the biological function by altering the available amounts of two classes of RNA-binding splice regulators
Muscleblind-like (MBNL1) splice regulators are sequestered in the nuclear foci resulting in depletion and loss of function.
Increased levels of other proteins such as CUG triple repeat RNA-binding protein (CUGBP1) leads to mis-regulation of global splicing events.
The disruption of these splice regulators interferes with the processing of transcripts in more than twenty other genes.
what is myotonic dystrophy?
One of the most complex disorders known
Clinical symptoms are highly variable
Anticipation – The disease symptoms tend to get more severe and occur earlier with each successive generation.
Somatic mosacism – Genetic defect can be different in various tissues in a single individual and can change over time.
Penetrance - the proportion of persons with a repeat expansion for DM who will actually develop symptoms of the condition.
how do you alter mendels ratios?
Genotypic ratios follow Mendel’s laws, but phenotypes do not.
One assumption of Classic Mendelian genetics is that mutations are stably transmitted, unchanged, from generation to the next.
Anticipation – Phenotype gets more severe in each successive generation.
Somatic Mosaicism – Once repeat counts reach an approximate threshold these sequences become highly unstable. As a result, a single individual may have cells and tissues that differ in repeat count.
Penetrance – The proportion of persons with a repeat expansion for DM who will actually develop symptoms of the condition. In some cases, a person’s symptoms can be so mild (such as cataracts in late middle age or frontal balding) that they are never diagnosed with DM.
what is the Haemoglobin (Hb) Mutation?
Single amino acid change can lead to Sickle cell anaemia.
Glutamic acid is hydrophilic so interacts with water molecules helping to make the haemoglobin molecule soluble.
Valine is hydrophobic, it does not interact with water thus making the molecule less soluble.
These amino acids are the outside of the Hb molecule when it takes up its tertiary and quaternary structures.
how is sickle cell anaemia caused?
Normally, the majority of adult hemoglobin (HbA) is composed of four protein chains, two α and two β globin chains arranged into a heterotetramer. Mutation causes production of abnormal red blood cells (In sickle-cell disease, the mutation is specific to β globin).
The haemoglobin molecules of HbS/HbS homozygotes undergo a change in shape that distorts the morphology of the red blood cells and causes sickle-cell anaemia.
Heterozygotes, HbA/HbS, have a much less severe form of anaemia called sickle-cell trait.
Because the disease phenotype of HbA/HbS heterozygotes is more like, but not identical to, the HbA/HbA homozygote, the HbA allele is said to be haplo-insufficient to the HbS allele.
how does Dominance relations vary with the phenotype under consideration?
Haemoglobin itself, there isco-dominance.
Blood-cell shape, however, there isincomplete dominance.
Susceptibility to malaria – HbS is dominant
Finally, presence or absence of anaemia, the HbA alleleis dominant at sea level.
Do variations on dominance relations negate Mendel’s law of segregation?
Dominance relations affect phenotype and have no bearing on the random segregation of alleles
Mendel’s law of segregation still applies
Gene products control expression of phenotypes differently
Interpretation of phenotype/genotype relation is more complex.
Alleles can interact in complex ways
- incomplete dominance
- codominance
- pleiotrophy
Sickle-cell anaemia illustrates that the termsdominance,incomplete dominance,andcodominanceare somewhat arbitrary. The type of dominance inferred depends on the phenotypic level at which the observations are being made
what is X-linked inheritance recessive examples?
Haemophilia
Duchenne muscular dystrophy (DMD) (Becker BMD)
Fabry disease
Retinitis pigmentosa
Alport syndrome
Hunter syndrome
Ocular albinism
Adrenoleucodystrophy
what is X-linked inheritance dominant examples?
Vitamin D resistant rickets:
Rett syndrome
Incontinentia pigmenti
Fragile X syndrome
what are X-linked recessive diseases?
Disease is typically passed from an affected grandfather through carrier daughters to half of his grandsons.
Males are much more likely to be affected due to male hemizygosity (no backup copy of the gene on the second X chromosome).
Females are mosaics for mutant and normal X chromosomes.
Normally show an intermediate phenotype which is clinically unaffected or mildly affected but biochemically abnormal.
Females can be severely affected when there is heavily skewed X-inactivation, i.e. inactivation of most of the normal X chromosomes.
what are X-linked dominant disorders?
These disorders have the following characteristics:
1. Affected males pass the condition to all their daughters but to none of their sons.
2. Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters.
There are few examples of X-linked dominant phenotypes in humans. One example is hypophosphatemia, a type of vitamin D-resistant rickets (bones become bent and distorted).
Male Lethality is very common for X-linked dominant disorders
All daughters of an affected male and normal female are affected
One X chromosome has to come from the father
All sons of an affected male and normal female are unaffected
Father contributes the Y chromosome
50% of the offspring of an affected female and unaffected male will be affected
In the general population females are more likely to be affected than males (2:1).
Females have 2X chromosomes either of which could carry the mutant allele.
Females can be severely affected if most of the normal X chromosomes are inactivated.
Altering Mendel’s Ratios
what is rett syndrome?
First described in 1966
Discovered by Austrian Andreas Rett
Complex neurological disorder
Mainly affects girls
1 in 10,000 girls affected
Characteristics: Very variable, Development stalls after first year, Poor speech, Repetitive hand movements, Poor posture
X-linked ‘dominant’ condition
Caused by mutation in MeCP2 Gene
MECP2 is transcriptional repressor
Why such a variable phenotype?
Rett’s girls have unaffected parents:
all rett females are heterozygous for the MecP2 mutation. Variability caused by relative X inactivation in the brain
90% normal X-chromosome inactivated
Severe Rett’s, semi-lethal
50% normal X-chromosome inactivated
Typical Rett’s
10% normal X-chromosome inactivated
Essentially OK: these are Rett mothers
what is the Lyon hypothesis?
One X chromosome is genetically active in the body cells; the second is inactive and tightly coiled (Barr Body).
Either the maternal or paternal chromosome can be inactivated
Inactivation of the second X equalises the activity of X linked genes in males and females.
why do females have Barr bodies?
In females the inactivated X-chromosome is condensed and appears as a darkly staining body attached to the edge of the nuclear membrane. Barr Body Testing introduced for the 1968 Olympic Games.
what is the Molecular Mechanism of X-inactivation - XIC and XIST?
The X chromosome contains an X inactivation centre (XIC) which is located on the long arm of X.
XIC contains and unusual gene called inactive X(Xi)-specific transcript (XIST)
XIST expresses a noncoding functional 17kb RNA molecule.
XIST is expressed only when more than one X chromosome is found in the same cell.
The existence of XIC was first suggested by Mary Lyon in 1961. “Lyon Hypothesis”
It is thought that there is an autosomally-encoded ‘blocking factor’ which binds to the XIC of one X chromosome and prevents its inactivation.
What is X-inactivation?
XIST is transcribed but not translated. XIST appears to act as RNAi.
Current thinking is that it binds to the X Chromosome and is involved in it’s translocation to the nuclear periphery.
XIST appears to initiate X inactivation and it is the methylation of the inactive X genes that maintains inactivity.
RNA interference (RNAi) is a biological process in which RNA molecules inhibit gene expression, typically by causing the destruction of specific mRNA molecules
what id XIST RNA
XIST RNA is only expressed in cells containing at least two Xs and is not normally expressed in male cells.
Higher XIST expression can be seen in cells with more X chromosomes, as a counting mechanism dictates that only one X per cell can remain active. In such cells, XIST is expressed from all supernumerary Xs.
What are Tortoiseshell (Calico) Cats?
This female cat is heterozygous at its X-linked ‘orange’ gene
The orange gene has two alleles: + (orange) and - (black)
Tortoiseshell orange and black fur patterns due to random X inactivation
why is mendels laws not perfect?
People began to notice that not all traits are “Mendelian”
– This means, they do NOT follow Mendel’s
laws
– Was he just plain wrong?
Truth is, his laws are correct and did explain how genetics works
– Real life is just more complicated than peas!
