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Regions of the Canine Genome Associated with Osteosarcoma Identified by a Whole Genome Case-Control Association Study

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Regions of the Canine Genome Associated with Osteosarcoma Identified by a Whole Genome Case-Control Association Study Kenine E Comstock , Elinor Karlsson, Claire Wade, Evan T Keller, Eric Lander, Laurence Baker, Kerstin Lindblad-Toh

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slide1
Regions of the Canine Genome Associated

with Osteosarcoma Identified by a Whole Genome

Case-Control Association Study

Kenine E Comstock, Elinor Karlsson, Claire Wade, Evan T Keller, Eric Lander,

Laurence Baker, Kerstin Lindblad-Toh

University of Michigan, Ann Arbor & Broad Institute, Boston, USA

osteosarcoma in pet dogs and humans
Osteosarcoma in pet dogs and humans
  • Differences
  • Age of onset
  • Incidence in population
  • Common Features
  • Primary tumor occurs on weight bearing limbs
  • Tumor growth with an intact immune system
  • Similarities in histology
  • Location of metastases
  • Common environment
dogs and humans similarities in cancer genetics
Dogs and humans: Similarities in cancer genetics

The first example: Renal cancer syndrome

Canine Hereditary Multifocal Renal

Cystadenocarcinoma and Nodular Dermatofibrosis (RCND)

  • German Shepherds
  • Autosomal dominant
  • Similar in phenotype to human Birt-Hogg Dube syndrome.
  • We showed that mutations in the same gene in human and dogs were associated with both diseases.

RCND-affected

RCND-unaffected

Lingaas and Comstock, et al. Hum Mol Genet. 2003 12(23):3043-53

slide5
Advantages of canine models for mapping cancer genes
  • Large families, inbred, good genealogical records, relatively short generation times
  • Disease progression accelerated.
  • Genetic similarity within breeds: cancer is associated with fewer mutations than in the species as a whole.
methods for mapping genes
Methods for mapping genes

1. Linkage mapping using families

Best for rare, high penetrance diseases

2. Association mapping

For complex traits

Compares cases vs controls

No need for families

Markers: SNPs

100,000 SNPs or more for humans

Only ~30,000 SNPs in dogs!

Can narrow associated regions to kilobases

resources available for canine disease gene mapping
Resources available for Canine Disease Gene Mapping
  • 7x Canine Genome Sequence-released July 2005*
  • Comparative maps of human and dog chromosomes
  • SNP mapping set

*Lindblad-Toh et al. Nature (2005) 438:803-19

2 5 million snps discovered 1 snp kb
China gray wolf

Alaska gray wolf

India gray wolf

Spanish gray wolf

California Coyote

Boxer

Poodle

Alaskan Malamute

Bedlington Terrier

English Shepherd

German Shepherd

Labrador Retriever

Portuguese Waterdog

Rottweiler

Beagle

Italian Greyhound

2.5 million SNPs discovered (1 SNP/kb)
  • SNP discovery in 11 breeds
  • and 5 wild canids
dog snp chip for whole genome scans
Dog SNP Chip for whole genome scans

Designed and tested by Michigan/Broad group

in collaboration with Affymetrix

~26,500 optimized SNP Mapping Set

Now commercially available

Coverage

power analysis prediction of sample size needed
Power analysis: Prediction of sample size needed

*

*In humans, would need approx 800 + 800

can we map real traits using this snp marker set
Can we map real traits using this SNP marker set?

Yes! Power calculations appear correct

  • Predicted low sample numbers work
  • One significant associated region

*Elinor Karlsson and Claire Wade, Broad Institute

objectives
Objectives:
  • To identify genes involved with osteosarcoma susceptibility in dogs
  • To map a complex trait using the new SNP set.
large and giant breed dogs have a higher risk of osteosarcoma
Large and giant breed dogs have a higher risk of osteosarcoma

1) Mastiff-type breeds

2) Long-limbed breeds

Greyhound-5 to 10 X

Irish Wolfhound

Great Dane

Scottish Deerhound

Rhodesian Ridgeback

Great Pyrenees

Borzoi

Saint Bernard

Rottweiler-5 X increased risk

Labrador Retriever

Flat-coated Retriever

Golden Retriever

Mastiff

Bullmastiff

Newfoundland

slide14
Eligibility Criteria

Cases: Dogs diagnosed with osteosarcoma

Cases were confirmed by either radiography and/or by biopsy.

All cases are being confirmed by a single independent pathologist.

Controls: Healthy, cancer-free dogs

10 years and older for Greyhounds,

8 years and older for all other breeds.

Owners of control dogs are contacted regularly.

All dogs of a single breed in the study are unrelated

through the grandparents.

slide15
Study participants enrolled

Table 1: Samples collected as of May 1, 2006

relationship between haplotype size and breed
Relationship between haplotype size and breed

Haplotype  The series of alleles along a chromosome inherited by an individual from one parent.

Corgi

Irish wolfhound

stage 1 osa susceptibility gene mapping in each breed separately
1/2Mb-1Mb

x

x

x

x

Stage 1: OSA susceptibility gene mapping in each breed separately

We’ve started with Rottweilers:

Searched genome for 0.5-1 Mb disease-associated haplotypes

OSA+

OSA+

stage 2 fine mapping across dog breeds within a breed group
10-20kb

Stage 2: Fine mapping across dog breeds within a breed group

Add related breeds to narrow the region to a smaller, shared ancestral haplotype (~10-20kb). We are just getting started with this!

“OSA”

gene

{

{

Golden retriever

(OSA+)

Leonberger

(OSA+)

whole genome scan in rottweilers
Whole Genome Scan in Rottweilers:

Likelihood of an association

Location in the genome

regions associated with osteosarcoma in rottweilers
SNPs

SNPs grouped into 4 gamete “haplotype” blocks

Regions associated with osteosarcoma in Rottweilers

A

B

C

-log(10) of the p-value

  • Localized to three haplotype blocks
  • Association performed using Haploview
  • p< 0.01 with 100,000 permutations.
currently ongoing
Currently ongoing…
  • Screening for mutations
  • Genome scan in greyhounds
  • Fine mapping in related breeds
acknowledgements
Acknowledgements

Uppsala

Nicolette Hillbertz

Leif Andersson

Göran Andersson

Åke Hedhammar

Olle Kämpe

Henrik von Euler

Gerli Pielberg

Broad Institute

Elinor Karlsson

Claire Wade

Tara Biagi

Sara Fryc

Noriko Tonomura

Kerstin Lindblad-Toh

Michigan

Sarah Mandelbaum

Evan Keller

Larry Baker

Collaborators

Frode Lingaas (Oslo)

Guillermo Couto (Ohio)

Jaime Modiano (Denver)

Elaine Ostrander (NHGRI)

Bill Kisseberth (Ohio)

Cheryl London (Ohio)

Elizabeth McNiel (Minnesota)

Barbara Kitchell (Michigan State)

Karen Michalski (Serenity Animal Hosp)

Chieko Azuma (Tufts)

David Vail (Colorado)

Chand Khanna (NCI)

This study was funded in part by the Canine Health Foundation.

Dog photos were provided by Warren Photographic.

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