Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders

Heather Fairfield, Anuj Srivastava, Guruprasad Ananda, Rangjiao Liu, Martin Kircher, Anuradha Lakshminarayana, Belinda S. Harris, Son Yong Karst, Louise A. Dionne, Coleen C. Kane, Michelle Curtain, Melissa L. Berry, Patricia F. Ward-Bailey, Ian Greenstein, Candice Byers, Anne Czechanski, Jocelyn Sharp, Kristina Palmer, Polyxeni Gudis, Whitney MartinAbby Tadenev, Laurent Bogdanik, C. Herbert Pratt, Bo Chang, David G. Schroeder, Gregory A. Cox, Paul Cliften, Jeffrey Milbrandt, Stephen Murray, Robert Burgess, David E. Bergstrom, Leah Rae Donahue, Hanan Hamamy, Amira Masri, Federico A. Santoni, Periklis Makrythanasis, Stylianos E. Antonarakis, Jay Shendure, Laura G. Reinholdt

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


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.

Original languageEnglish
Pages (from-to)948-957
Number of pages10
JournalGenome research
Issue number7
StatePublished - Jul 1 2015


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