Non-Coding Loss-of-Function Variation in Human Genomes

Hum Hered. 2016;81(2):78-87. doi: 10.1159/000447453. Epub 2017 Jan 12.


Whole-genome and exome sequencing in human populations has revealed the tolerance of each gene for loss-of-function variation. By understanding this tolerance, it has become increasingly possible to identify genes that would make safe therapeutic targets and to identify rare genetic risk factors and phenotypes at the scale of individual genomes. To date, the vast majority of surveyed loss-of-function variants are in protein-coding regions of the genome mainly due to the focus on these regions by exome-based sequencing projects and their relative ease of interpretability. As whole-genome sequencing becomes more prevalent, new strategies will be required to uncover impactful variation in non-coding regions of the genome where the architecture of genome function is more complex. In this review, we investigate recent studies of loss-of-function variation and emerging approaches for interpreting whole-genome sequencing data to identify rare and impactful non-coding loss-of-function variants.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • DNA, Intergenic / genetics*
  • Exome / genetics
  • Genetic Variation*
  • Genetics, Population
  • Genome, Human*
  • Genomics
  • Humans


  • DNA, Intergenic