an introduction to genetics for cat breeders kathryn robson mrc weatherall institute of molecular...
TRANSCRIPT
An introduction to genetics for cat breeders
Kathryn Robson
MRC Weatherall Institute of Molecular Medicine
University of Oxford
Genetics
• Just over 150 years old as a science• Gregor Mendel (1822-1884)• Coined the terms “recessive” and “dominant” in
reference to certain traits• Demonstrated that these traits were heritable• Proposed the existence of genes which he called
factors
Genes
• Most genes code for proteins• Humans have over 20,000 genes• Each chromosome contains many thousands of
genes• Chromosomes are made up of DNA and protein
Structure of a chromosome
There are almost 3 meters of DNA in a cell
Structure of a chromosome
• Workshop 1• 3m piece of string and cells
How many chromosomes?
• The diploid genome refers to the total number of chromosomes in a cell
• Chromosomes come in pairs apart from the sex chromosomes• One of each pair is inherited from each parent
Animal Diploid no. chromosomes
Human 46
Cat 38
Dog 78
Sheep 54
Cow 60
Individual chromosome paints identify specific chromosomes
Genes provide the instructions
• The DNA code comprises 4 building blocks• These are abbreviated to A, G, T and C• A codon is comprised of three of these building
blocks e.g. GAT or GGG• Each codon codes for an amino acid which is the
building block of protein
Proteins
• These can be structural e.g. the proteins that make up skin• These can be catalysts that speed up the chemical reactions
in the body• These can be the factory workers and part of a production
line• These can be the defense system e.g. antibodies• These can be part of the management team e.g. insulin
Congenital vs inherited disorders
• Congenital disorders – Quite often are developmental– Usually a one off– Manifest at birth or soon after
• Inherited disorders– Due to errors in the DNA, generally inherited from one or both
parents– May manifest at birth or much later in life
Mutations
• These are alterations in the DNA code • The come in different types
– Deletions– Insertions– Missense– Nonsense
• In some instances they change the instructions
Deletions and insertions
• The cat has a black mate.• The cat has a black mat.• The cart has a black mate.
Missense and nonsense mutations
• The cat has a black mate.• The rat has a black mate.• The hat has a black mate.• The cat has a bl.ck mate.
Mutations in genes give rise to inherited diseasesWhat do these genes have in common?
Myosin heavy chain Caveolin 3 Calreticulin 3
Myosin light chain kinase 2 Troponin T type 2 Actin cardiac muscle 1
Cardiac myosin binding protein 3
Tropomyosin 1 5’ AMP activated protein kinase subunit 2
Myosin light chain 3 Troponin I type 3 Cardiac LIM protein
Myosin light chain 2 Titin Vinculin
Myosin heavy chain 6 Troponin C type 1 Junctophilin 2
Myozenin Nexilin Phospholambin
Myopallidin
Mutations in genes give rise to inherited diseasesWhat do these gene have in common?
Mutations in the genes listed give rise to different forms of cardiomyopathy in humans
Many of them are muscle proteins uniquely found in heart muscle
The complexity of heart muscle
The order of the instructions is important
1.ONLY I hit him in the eye yesterday. (No one else did.)2.I ONLY hit him in the eye yesterday. (Did not slap him.)3.I hit ONLY him in the eye yesterday. (I did not hit others.)4.I hit him ONLY in the eye yesterday. (I did not hit outside the eye.)5.I hit him in ONLY the eye yesterday. (Not other organs.)6.I hit him in the ONLY eye yesterday. (He doesn't have another eye.)7.I hit him in the eye ONLY yesterday. (Not today.)8.I hit him in the eye yesterday ONLY. (Did not wait for today.)
Mitosis
• This is the term for cell division• With the exception of the cells that go on to
form the egg and sperms cells, all cells in the body undergo mitosis
• In this way they form identical copies of themselves
• This is for example a natural part of repair and growth
Mitosis
Meiosis
• This is the term for cell division that ends in the production of eggs and sperm
• In this form of division the number of chromosomes in each cell must be reduced from two copies of each chromosome down to one
• When the egg and sperm fuse the number of chromosomes goes back to two pairs of each, one from each parent
Cell division
• Workshop 2• Shuffling cards
Gametes
• These are the sperm and the egg cells• Each gamete has only one copy of each
chromosome• When the egg is fertilised by the sperm the
chromosomes exist as pairs, one of each pair coming from each parent
Dominant genes
• The black/seal gene is a dominant gene• The tabby gene is a dominant gene• You only need one copy of either of these genes to
see that these genes are present• If you have one copy of a gene you are a
heterozygote• These genes are found on the autosomes
Recessive genes
• The chocolate gene is a recessive gene• The dilute gene is a recessive gene• You need both copies of either of these genes for
their expression to be visible• You are therefore a homozygote for these genes• These genes are found on the autosomes
A genetic crossBoth parents are homozygous for different alleles at
the same locus
SSSS ssss
SsSs SsSs SsSs SsSs
The sire is homozygous for S and the dam homozygous for sEach of their gametes only contain S or s respectivelyEach kitten has inherited S from the sire and s from the damAll kittens regardless of gender are Ss, they are heterozygotes
F1 generation
A genetic crossBoth parents are heterozygotes for the two alleles at
the same locus
SsSs SsSs
S SS S S sS s s Ss S s ss s
The gametes from the sire are either S or sThe gametes from the dam are either S or s
Four possible combinations
A genetic crossImagine two parents heterozygous for the black gene
and the dilute gene
B bB b B
bB b
B BB B
B bB b
b Bb B
b bb b
Three kittens statistically should be seal and one blueTwo out of the three kittens are heterozygotes and carry the dilute gene
Seals and blues
Sex-linked genes genesred father
• The red gene is a sex-linked gene• This gene is present on the X-chromosome• Manifests itself in the F1 or first generation as a
tortoiseshell female if the X chromosome comes from the father
• The males in the F1 generation only inherit their X chromosome from their mother as they have inherited their Y chromosome from the father and therefore do not display or express the red gene
A genetic crossImagine two parents where the sire is red and the dam
is black
BB X YBB X Y
BBXXBBXX
B B X XB B X X
All male kittens are black because they inherit their mother’s X chromosome and their father’s Y chromosomeAll female kittens inherit an X chromosome from each parent, the one from their father carries the red geneThey are therefore all tortoiseshell
B BX Y B BX Y
B BX Y B BX Y
B B X XB B X X
Sex-linked genes genes 2red mother
• The red gene is a sex-linked gene• This gene is present on the X-chromosome• Manifests itself in the F1 or first generation as a
tortoiseshell female or red male if the X chromosome comes from a red mother
• The males in the F1 generation inherit their X chromosome from their mother as they have inherited their Y chromosome from the father and therefore are all red
A genetic crossImagine two parents where the dam is red and the sire
is black
BB X YBB X Y
BBXXBBXX
B B X XB B X X
All male kittens are red because they inherit their mother’s red X chromosome and their father’s Y chromosomeAll female kittens inherit an X chromosome from each parent, the one from their mother carries the red geneThey are therefore all tortoiseshell
B BX Y B BX Y
B BX Y B BX Y
B B X XB B X X
Sex-linked genes genes 3tortoiseshell mother
• The red gene is a sex-linked gene• This gene is present on the X-chromosome• Manifests itself in the F1 or first generation as a
tortoiseshell female or red male if the X chromosome comes from their tortoiseshell mother
• 50% of the kittens will not inherit the red X chromosome and so will not be red or tortoiseshell
A genetic crossImagine two parents where the dam is tortoieshell and
the sire is black
BB X YBB X Y
BBX XBBX X
B B X XB B X X
Half the male kittens are red because they inherit their mother’s red X chromosome and their father’s Y chromosomeHalf the female kittens inherit carry the red gene from their mother, half do notThose with the red gene are tortioiseshellThose kittens that do not inherit the X chromosome with the red gene are black (seal)
B BX Y B BX Y
B BX Y B BX Y
B B X XB B X X
Genes work together
• Lilacs and creams• To be lilac you need both two dilute genes and two
chocolate genes• To be cream you need two red genes if female and
two dilute genes• If male you need one red gene and two dilute genes
Chocolates and lilacs
X inactivation
• Males have one X and one Y chromosome• Females have two X chromosomes• One one X chromosome can be active in a cell• The partner X chromosome is inactive, it has been
silenced• X inactivation is random• Every tortoiseshell is unique
All four different colours of tortiesNote the different colour distribution on their heads
Reds and creams
A genetic crossBoth parents are homozygous for different alleles at the same locus and one parent is a dominant tabby
BBAABBAA
bbaabbaa
BAbaBAba
BAbaBAba
BAbaBAba
BAbaBAba
Sire is a dominant black (B) (seal) and dominant agouti (A) (tabby)Dam is homozygous for b and therefore dilute so is blueAll 4 kittens are heterozygous for the agouti gene (tabby)All 4 kittens are black and carry the dilute gene (heterozygotes)
F1 generation
A genetic crossImagine two parents heterozygous for the black gene
and the dilute gene and one parent is tabby
Bb AaBb Aa
BbaaBbaa
Ba BaBa Ba
Ba baBa ba
bA BabA Ba
ba Baba Ba
The eight different permutations are illustrated above4/8 kittens have inherited A and are so are tabby2/8 kittens have inherited bb and so are blue One of these kittens has inherited the Agouti gene and so is a blue tabby1/8 kittens is a dominant black1/8 kittens is a dominant black and is tabby
BA BaBA Ba
BA baBA ba
ba baba ba
bA babA ba
A genetic crossImagine two parents heterozygous for the black gene
and the dilute gene and one parent is tabby
Bb AaBb Aa
BbaaBbaa
Ba BaBa Ba
Ba baBa ba
bA BabA Ba
ba Baba Ba
BA BaBA Ba
BA baBA ba
ba baba ba
bA babA ba
Dominant Black tabby
Heterozygote Black tabby
Dominant Black
Black heterozygote
Heterozygote Black tabby
Blue tabby
Black heterozygote
Blue
A genetic crossImagine two parents heterozygous for the black gene
and the dilute gene and one parent is tabby
Bb AaBb Aa
BbaaBbaa
Ba BaBa Ba
Ba baBa ba
bA BabA Ba
ba Baba Ba
BA BaBA Ba
BA baBA ba
ba baba ba
bA babA ba
Dominant Black tabby
Heterozygote Black tabby
Dominant Black
Black heterozygote
Heterozygote Black tabby
Blue tabby
Black heterozygote
Blue
Tabby pointsNote that unlike the torties their masks are all very
similar
Tortie tabbies
Workshop 3
• Using the 2 gametes-red and blue pieces of paper work out the colour of the kitten you have
Next generation sequencing
Permits parallel sequencingCan sequence 16 genes at the same time e.g. CM genesReduces timeReduces costsOnce set up cost can be as little as£500 per patient/sample per panel run
Mutations in genes give rise to inherited diseasesWhat do these genes have in common?
Myosin heavy chain Caveolin 3 Calreticulin 3
Myosin light chain kinase 2 Troponin T type 2 Actin cardiac muscle 1
Cardiac myosin binding protein 3
Tropomyosin 1 5’ AMP activated protein kinase subunit 2
Myosin light chain 3 Troponin I type 3 Cardiac LIM protein
Myosin light chain 2 Titin Vinculin
Myosin heavy chain 6 Troponin C type 1 Junctophilin 2
Myozenin Nexilin Phospholambin
Myopallidin
Acknowledgements
• Photographs– Barrie Tackley– Robert Fox – Sue Allen– Veronica Buckle
