Lecture 3: Inheritance Flashcards
How many genes in the human genome
20 000 - 25 000
Number of chromosomes
- 22 pairs of autosomal
- 1 pair of sex chromosomes
each chromosome has one version of each gene so we have two alleles of each gene (sometimes can be same, sometimes different)
Qualitative vs quantitative trait
qual - have phenotypes you can put into discrete categories (blood type) aka can describe the quaaaality of the trait
quant - phenotypes that fall into a continuous range (skin colour)
Qualitative trait
- phenotype
- genes
- disorders
- inheritance pattern
- role of environment
- discrete variables ex. blood type
- single gene
- HD, CF, PKU (phenylketonuria), sickle cell anemia
- simple mendelian inheritance
- small role of env
Quantitative trait
- phenotype
- genes
- disorders
- inheritance pattern
- role of environment
- distributed over a continuous range ex. hair colour, intelligence
- multiple genes (polygenic)
- ASD, AD, MDD, CVD
- complex inheritance
- high role of env (stress, diet, etc)
Mendelian inheritance
each physical trait falls in a discrete category, likely due to a single gene, little role of the environment
- each physical trait is decided by a single gene with two alleles
Gamete production from a heterozygote
Meiosis of a heterozygous cell (two diff alleles) produces four gametes two with one allele and two with the other type of allele
Law of segregation
two parent alleles are randomly segregated into gametes, with only one allele being present in each gamete and any gamete has an equal chance (around 50%) of getting either allele
Pedigree trends
- if 50% of children have disease it’s dominant (vertical inheritence)
- recessive diseases show horizontal inheritance
- if the trait is sex-linked dominant, every son of a diseased mother will have it and half the daughters will have it
- if trait is recessive, two unaffected parents could have an affected child
Sex-linked disorders show what on a pedigree
disparity between the sexes in terms of inheritance patterns
Law of independent assortment
inheritance and expression of one trait does not affect that of another trait (example is that colour of the pea does not affect the shape of the pea)
Law of segregation vs Law of independent assortment
- alleles of the same gene segregate randomly into gametes in meiosis, and in humans each gamete gets one allele of each gene
- the alleles of different genes segregate independently
Exceptions to Mendel’s Laws
- gene linkage
- gene conversion and translocation
- genetic imprinting
- inheritance of mitochondrial DNA
gene linkage
genes close together are unlikely to be separated in meiotic recombination therefore genes for blue eyes and blonde hair are likely to have a low genetic distance which is why they are often seen together
CentiMorgan
1 cM is equal to the percentage of times the two genes (alleles) are separated in gametes. Approx equal to a million base pairs
- low recombination frequency = linked, high recombination frequency = unlinked
How can we use recombination frequency to map the genome
we can use certain genes as landmark genes
- find a genetic marker of a KNOWN location that is more frequently present in individuals with the disease
Gene conversion
DNA sequence is one chromosome is transferred to another - often homologous - chromosome which remains unchanged
- distinct from recombination!!! which is swapping (here one allele replaces another)
Translocation
exchange of genetic material between non-homologous chromosomes
- xchange can be balanced (reciprocal) or unbalanced (not reciprocal)
- some translocations are major risk factors for disease
Can you get down’s syndrome from translocation?
yes, if you translocate enough of chromosome 21 that you have essentially the equivalent of three gene products from there then you can get a down’s like syndrome
- some translocations associated with infertility (13 to 14)
DISC1
Disrupted in Schizophrenia gene
- variants thought to have arisen by translocation
Genetic imprinting
expression of gene is affected by the parental origin
- male and female parents have different patterns of DNA methylation (epigenetic) thus making different regions inaccessible to transcription machinery.
Angelman vs Prader Willi SYndrome
Both angelman and prader willi synrome are associated with a loss of a region of chromosome 15, however maternal inheritance of the deficit causes angelman syndrome while paternal inheritance of the deficit causes prader willi
- in angelman, the mothers mutated copy is not compensated by the father (methylated)
- in prader willi, the fathers mutated copy is not compensated for by the mother (methylated)
Inheritance of mitochondrial DNA
Mitochondria are self-replicating and have their own DNA
- maternal mitochondria from egg is inherited but paternal mitochondrial DNA (sperm) is not (can’t fit in the cytoplasm)
- can prevent mitochondrial diseases (which have high heritability) by replacing unhealthy mitochondria in the embryo with mitochondria from a donor.
Leber’s Hereditary Optic Neuropathy
- mitochondrial DNA disorder
- causes blindness
- in a pedigree, affected females always have affected children and affected males never have affected children
Oligogenic/Polygenic
traits that are controlled by more than gene
Quantitative traits
- moderate phenotypes are common
- distribution looks like a bell curve (normal distribution), and the more genes that contribute to the trait the more likely it is that the trait is normally distributed
Heritability of BPD, SZ, MDD, GAD
0.9, 0.7, 0.4, and 0.4
Example of diseases that are polygenic but do not have normal distribution
BPD, SZ, MDD, GAD
- all are heritable (first two extremely so) but not monogenic and also not normally distributed
Liability threshold model
proposes that the risk for the disorder increases the more genes we have (risk genes).
- Do you have enough genes to overcome the risk threshold? for ex. if 300 genes contribute to BPD and the threshold is 150, if you have over 150 then you have BPD.
GWAS and Polygenic mechanisms
Purely polygenic disorders should give GWAs hits and identify common SNPs that cause the disorder but that isn’t the case. GWAS studies have only shown a handful of genes of weak effect.
Amount of variance explained through common SNPs by PGS and GCTA
Less than 10%
Monogenic, oligogenic, polygenic, complex
- one gene, ultra rare, highly penetrant
- few genes (out of 100s), rare, strong effects each
- many gene variants, common, weak effects each
- many common variants modifying the effects of rare or ultra rare variants
Complex genetic architecture
small gene variants (polygenic causes) amplifying the already strong effects of rare inherited variants and de novo mutations (oligogenic)
QTL
a site on the chromosome containing multiple genes that contribute to a quantitative trait
- not sure which gene of the bunch contributes to the trait or if all do, but you know that loci is related to the trait bc it always appears.
QTL procedure
- Inbreed animals for 7-30 generations to create maximum phenotypes (two phenotypes at opposite ends of the spectrum)
- Identify genetic markers that distinguish between the red and the blue strains
- cross the strains to create an F1 (theoretically you will have mice now that will be heterozygous for all traits including the trait of interest)
- Now cross the heterozygote F1 generation to create an F2 gen. Because of recombination during meiosis the F2 will have shuffled genes
- now in F2 looking for the strain-specific markers (and match the genotype with phenotype. Do you always get one extreme phenotype when the organisms have this certain marker?)
- now graph the marker-trait relationship and see which ones are above the significance threshold
If a particular genetic marker is important for a trait, changing the allele at that loci will…
change the trait in question
