Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders.
Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole-genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing.
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Heather
H
Fairfield
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Anuj
A
Srivastava
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Guruprasad
G
Ananda
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA;
Rangjiao
R
Liu
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
Martin
M
Kircher
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA;
Anuradha
A
Lakshminarayana
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Belinda S
BS
Harris
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Son Yong
SY
Karst
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Louise A
LA
Dionne
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Coleen C
CC
Kane
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Michelle
M
Curtain
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Melissa L
ML
Berry
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Patricia F
PF
Ward-Bailey
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Ian
I
Greenstein
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Candice
C
Byers
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Anne
A
Czechanski
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Jocelyn
J
Sharp
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Kristina
K
Palmer
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Polyxeni
P
Gudis
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Whitney
W
Martin
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Abby
A
Tadenev
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Laurent
L
Bogdanik
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
C Herbert
CH
Pratt
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Bo
B
Chang
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
David G
DG
Schroeder
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Gregory A
GA
Cox
Department of Genetics, Washington University, St. Louis, Missouri 63130, USA;
Paul
P
Cliften
Department of Genetics, Washington University, St. Louis, Missouri 63130, USA;
Jeffrey
J
Milbrandt
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Stephen
S
Murray
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Robert
R
Burgess
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
David E
DE
Bergstrom
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Leah Rae
LR
Donahue
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland;
Hanan
H
Hamamy
Pediatric Department, The University of Jordan, Amman 11942, Jordan;
Amira
A
Masri
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland;
Federico A
FA
Santoni
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1211 Geneva 4, Switzerland.
Periklis
P
Makrythanasis
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1211 Geneva 4, Switzerland.
Stylianos E
SE
Antonarakis
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
Jay
J
Shendure
The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
Laura G
LG
Reinholdt
D000818:Animals; D059472:Exome; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics; D008040:Genetic Linkage; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D008297:Male; D051379:Mice; D009154:Mutation; D010641:Phenotype; D015203:Reproducibility of Results