RT Journal Article
SR Electronic
T1 The human functional genome defined by genetic diversity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 082362
DO 10.1101/082362
A1 Julia di Iulio
A1 Istvan Bartha
A1 Emily H.M. Wong
A1 Hung-Chun Yu
A1 Michael Hicks
A1 Naisha Shah
A1 Victor Lavrenko
A1 Ewen F. Kirkness
A1 Martin M. Fabani
A1 Dongchan Yang
A1 Inkyung Jung
A1 William H. Biggs
A1 Bing Ren
A1 J. Craig Venter
A1 Amalio Telenti
YR 2016
UL http://biorxiv.org/content/early/2016/10/21/082362.abstract
AB Large scale efforts to sequence whole human genomes provide extensive data on the non-coding portion of the genome. We used variation information from 11,257 human genomes to describe the spectrum of sequence conservation in the population. We established the genome-wide variability for each nucleotide in the context of the surrounding sequence in order to identify departure from expectation at the population level (context-dependent conservation). We characterized the population diversity for functional elements in the genome and identified the coordination of conserved sequences of distal and cis enhancers, chromatin marks, promoters, coding and intronic regions. The most context-dependent conserved regions of the genome are associated with unique functional annotations and a genomic organization that spreads up to one megabase. Importantly, these regions are enriched by over 100-fold of non-coding pathogenic variants. This analysis of human genetic diversity thus provides a detailed view of sequence conservation, functional constraint and genomic organization of the human genome. Specifically, it identifies highly conserved non-coding sequences that are not captured by analysis of interspecies conservation and are greatly enriched in disease variants.