Pilot Program for Exome Sequence Based Gene Discovery in Rare Mendelian Diseases

The University of Michigan Initiative on Rare Disease Research and the Center for Genetics in Health and Medicine (CGHM), are pleased to announce a new initiative to support the rapid discovery of genetic variants for rare Mendelian disorders through exome sequencing and bioinformatic analysis.  U-M investigators with DNA samples from patients with rare diseases should submit a two-page proposal describing the disorder, the DNA samples available for sequencing, and existing genetic or functional knowledge of the disorder.  The proposals that are selected will receive support in the form of preparing DNA samples for exome capture and sequencing and bioinformatic analysis of the data, with the intention that the results will be published as a collaborative effort between the applicant’s group and the supporting investigators.


Preferential consideration will be given to projects with multiple types of relevant information to facilitate bioinformatic filtering of observed variants.  These may include:
- clear diagnostic criteria,
- information regarding mode of inheritance,
- evidence for limited genetic or phenotypic heterogeneity,
- presence of consanguinity and relatedness of subjects,
- prior linkage analysis results,
- array CGH or cytogenetic data,
- functional knowledge about the disease,
- accompanying gene expression data,
- available samples for validation through targeted sequencing or genotyping, or
- other information not listed above that may enhance the chance of success of the exome sequencing approach.

Data collection and analysis

Successful applications will be approved to submit DNA samples for sequencing and analysis by a team of UM investigators experienced in exome analysis.  The group will be led by Dr. Jun Li (Assistant Professor, Department Human Genetics), and will be advised by Dr. Cristen Willer (Assistant Professor, Department Human Genetics and lead analyst of a large-scale NHLBI-funded exome sequencing project), Dr. Robert Lyons (Director of U-M Sequencing Core) and James Cavalcoli (Director of Collaborative Computing & Data Unit Bioinformatics Core).  The working group will apply uniform experimental and analytical protocols for the entire series of samples.  Target capture will use the latest reagents for either the Nimblegen Whole-Exome SeqCap method or the Agilent SureSelect method (to be decided at the start of the program), followed by 72-108 base paired-end sequencing on the Illumina Genome Analyzer II at the UM DNA Sequencing Core.  The experimental pipeline is expected to generate 30-60X useful sequence coverage for 80-90% of known coding exons in the human genome.  The working group will analyze the sequence data to catalog DNA variants (single nucleotide and small indels) and return the results to the investigators, along with basic annotation regarding the novelty and predicted function of the variants.  Additional bioinformatics support may be provided as needed. 


The entire program will support sequencing and variant discovery for approximately 30 samples.  Awards will be made for six or fewer samples per investigator. 


The candidate will provide a completed form, and a biosketch in NIH format (4 page version with funded and recently completed grants). Both Documents should be submitted as a single PDF to CGHMSequencingPilot@umich.edu. Completed applications are due no later than January 3rd, 2011 at 5:00 p.m. EST.

Download the Application form in PDF format here.

Download the Application form in MS Word format here.


A panel of experts will be convened by CGHM to review the applications based on a combination of scientific merit and the amount of sequencing required for each project.  


The deadline for application is Monday, January 3rd, 2011 at 5:00p.m. EST.


This program is supported by funds from the offices of the Dean of the Medical School and the OVPR.