Journal
NATURE GENETICS
Volume 46, Issue 1, Pages 61-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2826
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Funding
- Wellcome Trust
- Wellcome Trust as part of WT Biomedical Informatics Hub
- BOLD grant (European Community's Seventh Framework Programme) [FP7-PEOPLE-ITN-2008]
- National Institute for Health
- Ministerio de Economia y Competitividad [SAF2011-27086, PLE2009-0162]
- National Institute for Health Research [NF-SI-0611-10219] Funding Source: researchfish
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The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized similar to 400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.
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