Transcript Managing Broken Genes in the Age of Genomics

Jared E. Decker
State Beef Genetics Specialist
[email protected]
http://web.missouri.edu/~deckerje/extension
http://steakgenomics.blogspot.com/
https://www.facebook.com/SteakGenomics
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
~100 genes where
one copy is
functional and the
other is broken

~20 genes where
the broken copy is
a lethal mutation

Called Loss of
Function
mutations
Science Vol. 335 no. 6070 pp. 823-828 DOI: 10.1126/science.1215040
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Inconvenient Genetic Truth
 Everybody has genetic defects!!!
Even the
most
beautiful
people in the
world
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Inconvenient Genetic Truth
 Everybody has genetic defects!!!
Even the
most
caring
people in
the world
4
5
What happens when a broken gene is
inherited from the father and the mother?

Genetic abnormality

Spontaneous abortion
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Causal mutations identified at Mizzou by whole
genome sequencing
Dog Breed
Basenji
Chinese Crested
Kerry Blue Terrier
Jack Russell Terrier
Basenji
Standard Schnauzer
Australian Shepherd
Soft Coated Wheaten
Tibetan Terrier
Chinese Crested
Canine Disease
Renal Fanconi Syndrome
Multiple Systems Degeneration
Multiple Systems Degeneration
Spinocerebellar Ataxia
Progressive Retinal Atrophy
Dilated Cardiomyopathy
Neuronal ceroid lipofuscinosis
Paroxysmal dyskinesia
Progressive retinal atrophy
Neuronal ceroid lipofuscinosis
Gene
FAN1
SERAC1
SERAC1
KCNJ10
SAG
RBM20
CLN8
PIGN
FAM161A
MSFD8
A documented human disease corresponds to each of
the canine diseases caused by mutations identified by
whole genome sequencing
Dog Breed
Basenji
Chinese Crested
Kerry Blue Terrier
Jack Russell Terrier
Basenji
Standard Schnauzer
Australian Shepherd
Tibetan Terrier
Soft Coated Wheaten
Chinese Crested
Gene
FAN1
SERAC1
SERAC1
KCNJ10
SAG
RBM20
CLN8
FAM161A
PIGN
MSFD8
Human Disease
Karyomegalic interstitial nephritis
MEGDEL syndrome†
MEGDEL syndrome†
SeSAME syndrome‡
Oguchi disease 1
Dilated cardiomyopathy 1DD
NCL8/Northern epilepsy
Retinitis pigmentosa 28
MCAHS syndrome 1≠
Neuronal ceroid lipofuscinosis 7
Mutations found by Lyons Cat Genetics lab
TRAIT
BREED
GENE
Vitamin-D dependent ricketts
DSH
CYP27B1
Chediak-Higashi syndrome
Persian
LYST
Atrichia
Sphynx
KRT71
Hypotrichia
Devon Rex
KRT71
Melanocyte migration
Birman
KIT
Hypotrichia
Cornish Rex
P2RY5
Hypotrichia
Selkirk Rex
KRT71
Craniofacial defect
Burmese
CART1
Hypokalemia
Burmese
WNK4
Gangliosidosis 1 and 2
Korat / Burmese
GBL1 / HEXB
PRA
Abyssinian
CRX / CEP290
PKD
Persian
PKD1
Pyruvate kinase deficiency
Several
PKLR
Hypertrophic cardiomyopathy
Maine Coon / Ragdoll
MYBPC
Lipoprotein lipase deficiency
Several
LPL
Spinal muscular atrophy
Maine Coon
LIX1-LNPEP

Full genome sequence 99
cats
 Centralized and publically
available
 Any breed or population of cat
worldwide
▪
▪
▪
▪
▪
Interesting trait or health issue
12 cats races
24 major breeds
Rare breeds
Other felids
What happens when a broken gene is
inherited from the sire and the dam?

Genetic abnormality

Spontaneous abortion
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

Some we know about
Some we don’t
KNOWN
Even the
most
beautiful
cattle in the
world
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
DNA tests can now be developed in a few
months

With DNA tests available, frequency of the
known genetic defect rapidly decreases

Now we can manage genetic defects

There are more than 35 genetic defects in
cattle with a DNA test
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
Documented in 1950’s

Became prevalent in 2000’s due to
heterozygotes having straight hind
limbs and long shaggy hair

Present in Galloway, Shorthorn,
%Maine-Anjou, %Chianina, and
other breeds with open herd
books

Single autosomal recessive
Beever, Jonathan Edward, and Brandy Michele Marron. "Screening for the genetic defect causing tibial hemimelia
in bovines." U.S. Patent 8,158,356, issued April 17, 2012.
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

Due to ~46,000 bp deletion in ALX
homeobox 4 (ALX4) gene,
a transcription factor expressed in
developing bones, limbs, hair,
teeth, and mammary tissue.
“Note the twisted hind limbs and
the large abdominal hernia. The
calf also had a meningocele and
cryptorchidism.” (Whitlock, Kaiser,
and Maxwell, 2008)
Beever, Jonathan Edward, and Brandy Michele Marron. "Screening for the genetic defect causing tibial hemimelia
in bovines." U.S. Patent 8,158,356, issued April 17, 2012.
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
Present in Maine-Anjou,
%Chianina, and Shorthorn

Lethal autosomal recessive

“Note the severe anasarca.”
(Whitlock, Kaiser, and
Maxwell, 2008)
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
Also known as “curly calf”

Recognized by American
Angus Association as a genetic
defect on September 16, 2008.

Recessive mutation

Twisted spin, contracted legs,
light muscled
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Recognized by American Angus
Association as a genetic defect on
June 12, 2009.
 Recessive mutation
 Calves carried to near term
 Weigh 25 to 35 lbs
 Head is severely enlarged
 Bones of skull are malformed
 No brain tissue is present and
skull is filled with fluid

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
In Hereford cattle

Autosomal recessive

Calves experience seizures,
especially during stress such
as temperature or handling
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
Also known as “Marble Bone
Disease”

In Red Angus

Cattle are typically born dead or
die in first 24 hours

Bones are extremely brittle and
lower jaw is short

~2721 bp deletion in the SLC4A2
gene affecting exons 2 and 3
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
In Hereford cattle

Autosomal recessive

8 base pair deletion
mutation in first exon of the
keratin 71 (KRT71) gene

Complete or partial loss of
hair
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
Also known as “Fawn Calf”

Nonlethal recessive genetic
abnormality

Upper limb joints have a
reduced range of motion
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

Polymelia
Most die as embryos
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The Truth: Every Living Thing Is A
Genetic Defect Carrier
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Seedstock:

Test at-risk breeding stock for genetic
defects
 Do we know the pedigree of the animals?
 Are there carriers in the pedigree?
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Commercial:

Crossbred

Outcross
 Avoid using the same bloodlines

Test at-risk breeding stock for genetic
defects
 Do we know the pedigree of the animals?
 Are there carriers in the pedigree?
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
Create a documented record of what
happened

Take a picture or video of affected calves

Freeze the entire animal if possible,
otherwise preserve the abnormal body
part

Obtain 40 hair bulbs from the calf, dam,
and sire
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
Breeders should contact their breed
association and local veterinarian

Need intensive description of phenotype

The majority of abnormalities are caused
by the environment, not genetics
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What happens when a broken gene is
inherited from the sire and the dam?

Genetic abnormality

Spontaneous abortion
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 Sequence the genomes of 165 registered
bulls



We will discover hundreds of broken genes
Most embryonic lethals
Breeds co-sponsoring sequencing:


Sequencing completed for all 165 of the
animals
Currently running data thru analysis
pipeline

We have already analyzed the genomes of
11 bulls
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
We have already analyzed the genomes of
11 bulls

Identified 176 possibly lethal alleles
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
Predictions are sums of marker effects

For lethal mutations
 Homozygous normal: effect is 0
 Heterozygous lethal: effect is -qif

Allows publication of a fertility EPD
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
Avoid mating carriers of the same lethal
mutation

Will also manage
 Genetic merit
 Genetic diversity

Built upon economic selection indexes
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
See abnormal calf

Bury calf
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
Report abnormal calves

Collect data

Create a test

Manage the defect
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
Sequence influential AI sires

Create tests for LOF mutations

Manage the mutations while accounting
for overall genetic merit
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Thank
You!
Questions?
http://web.missouri.edu/~deckerje/extension
http://steakgenomics.blogspot.com/
https://www.facebook.com/SteakGenomics
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