lecture 6 - multigenetic traits Flashcards
what is epistasis?
Multigenic diseasesresult from less severe mutations in more than one gene. Any of these mutations alone might not affect atrait, but together, they can lead to significant phenotypic differences.
Interactionamong the phenotypic effects of different genes, such asepistasis, thus adds another layer of complexity to the study of disease inheritance.
Epistasis is not restricted to the interactions of only two genes. Rather,epistasisoccurs in all of the following scenarios:
1. Whenever two or more loci interact to create new phenotypes
2. Whenever analleleat onelocusmasks the effects of alleles at one or more other loci
3. Whenever an allele at one locus modifies the effects of alleles at one or more other loci
Genes with epistatic relationships tend to code for proteins that work together in the same processes.
Let’s say workers A, B, and C carry out the steps for painting a design on a poster. Like genes,a,b, andcare the instructions.
Worker A puts paint into the tray;atells it how.worker B adds dye to the paint;btells it what colour.Worker C paints a design on the poster;ctells it what design.
The important aspect of epistasis is that it doesn’t just influence the phenotype, ithidesthe output of another gene or genes.
what are gene interactions and diseases?
-Epistasis/Modifier Genes
-Polygenic/Additive
-Copy number variation
-Multifactorial
what is Coat-Colour Inheritance in Labrador Retrievers?
there’s a golden and a black lab parent which produced a black fur offspring pup BbEe x BbEe
Colour is controlled by two genes
B = pigment production
E = incorporation into hair shaft
what is recessive epistasis?
A recessive mutation in one gene masks the phenotypic effects of another
appears when BbEe x BbEe which where the black from the previous example produce mixed colour offspring de to the masking of phenotypes
Gene B determines whether black (B) or brown (bb) pigment is produced.
Gene E determines if pigment is deposited in hair.
- Golden retrievers (ee) make
either black (B) or brown (bb)
pigment (look at noses)…..but
not in fur
The recessive allele (ee) is epistatic to the pigment gene when homozygous because it hides its output.
Hence recessive epistasis
what is the molecular explanation of recessive epistasis?
pigent production B and subsequent incorporation E into the hairshaft are controlled by 2 separate genes. to be black both genes must function. mutations in B (b) lead to brown and mutations in E (e) lead to no pigment
what is dominant epistasis?
The dominant allele (I) at the KIT locus, which confers white coat colour in the pig, is dominant over all of the alleles at the MC1R locus (E), which confer darker coat colours.
The effects of alleles at the E locus can only be observed in individuals with the recessive genotype ii at the I locus.
The I allele (white) is epistatic to E (darker). The dominant allele (I) is masking the action of either allele of the other gene.
Epistasis dramatically complicates the task of determining the genetic underpinnings of human traits
what is Redundancy: Duplicated Genes?
Petal colour in snapdragons
Two or more genes are performing the same function
Inactivation of one of these genes has little or no effect on the biological phenotype
whatever a dominant gene is present, the trait is expressed. one allele is sufficient to produce the pigment
what are modifier genes?
Modifier Genes: have a subtle, secondary effect which alters the phenotypes produced by the primary genes.
E.g. Tail length in mice. The mutant allele t causes a shortening of the tail. Not all tails are of the same length: another gene affects the
actual length
what is modifying environment?
Modifying Environment: The environment may influence the effect of a genotype on a phenotype.
E.g. Siamese cats: temperature dependent colour coat. Colour
shows up only in extremities, where the temp is lower (enzyme for pigment formation is active only at lower temp)
what is polygenic inheritance?
Single gene disorders are quite rare
Single gene disorders either give risk to a condition or they don’t
Most traits are Polygenic i.e. 1 trait coded by a number of altered and unaltered genes working together.
Alzheimer’s
Diabetes
Cancer
Eczema
how is polygenic inheritance skin colour?
Polygenic inheritance, alleles do not display dominance over others, rather, each contributing allele gives an additive effect rather than a masking effect. The additive effect means that each contributing allele produces one unit of colour.
3 genes control skin colour
64 possible allele combinations, 7 different coloured skin tones.
As the number of contributing alleles changes within the allele combinations, the units of melanin pigment increases and decreases.
The probability of the second lightest or darkest skin tones (1 or 5) is 6/64, the third lightest or darkest skin tones (2 or 4), is 15/64 and an entirely intermediate skin tone (3) is the most common at 20/64.
what are CNVs?
a tetrad is misfired at meiotic synapsis and the result after crossing over, is 2 unequal chromosomes, one with a duplication and one with a deletion
The globin genes evolved by gene duplication and mutation
Is this an isolated case or do many genes show gene copy number variation (CNV)?
The first large, systematic structural comparisons of the genomes of healthy humans were only carried out in 2004 to identify large numbers of CNVs that are present at significant frequency.
Further studies have revealed well over a thousand CNVs, which account for up to 5% of the human genome.
The Wellcome Trust Sanger Institute has developed a database of CNVs (called DECIPHER) associated with clinical conditions.
Mixture of beneficial and harmful effects depending on their genomic and environmental context (similar to the sickle-cell mutation in haemoglobin)
what are multifactorial traits?
inheritance controlled by many gene plus the effects of the environment
what are types of Congenital malformations?
Cleft lip/palateCongenital hip dislocation Congenital heart defectsNeural tube defectsPyloric stenosisTalipes
what are types of adult onset disorders
Diabetes mellitus Epilepsy Glaucoma Hypertension Ischaemic heart disease Manic depression Schizophrenia
what are The contributions of genetic and environmental factors to human diseases?
environmental =
CommongeneticscomplexMultifactorialLow recurrence rate
genetic= RareGenetics simpleUnifactorialHigh recurrence rate
what are multifactorial traits?
Examples include some cases of cleft lip and palate; neural tube defects; diabetes and hypertension
Caused by a combination of genetic predisposition and environmental influences. For example, certain drugs used to treat epilepsy are associated with an increased incidence of cleft lip
Pattern – more affected people in family than expected from incidence in population but doesn’t fit dominant, recessive or X-linked inheritance patterns
Human height is an extremely complex inheritance pattern as there are over 400 genes controlling for it, it is therefore extremely difficult to predict the height that an offspring will be. Continuous variation
Also affected by the environment. For example factors relating to general health of a growing child such as access to food and exposure to disease, could significantly affect the final height of a person.
Gene interactions and multifactorial traits really interfere with Mendel’s Laws!
what are CNVs like in the human genome?
The ~25,000 genes are usually present in two copies. Studies unveiled a new map of the genome by cataloguing genes variable in copy number across world-wide population
What types of genes are found to be copy number variable?
Genes that are involved in the immune system and in brain development and activity – two functions that have evolved rapidly in humans – tend to be enriched in CNVs.
Can CNVs cause disease?
Most CNVs are benign
However, CNVs that affect critical developmental genes do cause disease such as Parkinson’s and Alzheimer’s Disease.
what is the AMY1 gene copy number?
th most common human gene copy number variant reflects differing numbers of tandem repeats in the AMY1 gene
AMY1 maps to the short arm of chromosome 1
Cytogenetic localization of DNA sequences with fluorescence in situ hybridization (FISH).
AMY1 CNVs always map to single site, implying tandem duplications
why is there so much AMY1 variation?
sequence differences between the AMY1 gene is small so AMY1 CNVs is recent, maybe in the last 200,000 years
The proportion of individuals from the combined high-starch sample with at least six AMY1 copies (70%) was nearly two times greater than that for low-starch populations (37%).
Low Starch Diet
Low AMY1 Copy Number
High Starch Diet
High AMY1 Copy Number
what are Genes on Different ChromosomesDihybrid crosses
Genes on different chromosomes are inherited independently.
If we cross two individuals that are heterozygous (+/-) at two genes that are on different chromosomes (the F1 cross), then the wild-type and mutant alleles at the two genes segregate independently (at random).
The outcome, for the F2, is a 9:3:3:1 phenotypic ratio
what is population clustering of CNVs
clustering of CNVs from 2010 unrelated individuals shows clear discrimination between populations
if CNVs were population-specific they would appear at an apex. these must be adaptive
