The Expanding Landscape of Alternative Splicing Variation in Human Populations

Am J Hum Genet. 2018 Jan 4;102(1):11-26. doi: 10.1016/j.ajhg.2017.11.002.


Alternative splicing is a tightly regulated biological process by which the number of gene products for any given gene can be greatly expanded. Genomic variants in splicing regulatory sequences can disrupt splicing and cause disease. Recent developments in sequencing technologies and computational biology have allowed researchers to investigate alternative splicing at an unprecedented scale and resolution. Population-scale transcriptome studies have revealed many naturally occurring genetic variants that modulate alternative splicing and consequently influence phenotypic variability and disease susceptibility in human populations. Innovations in experimental and computational tools such as massively parallel reporter assays and deep learning have enabled the rapid screening of genomic variants for their causal impacts on splicing. In this review, we describe technological advances that have greatly increased the speed and scale at which discoveries are made about the genetic variation of alternative splicing. We summarize major findings from population transcriptomic studies of alternative splicing and discuss the implications of these findings for human genetics and medicine.

Publication types

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

MeSH terms

  • Alternative Splicing / genetics*
  • Disease / genetics
  • Genetic Association Studies
  • Genetic Variation*
  • Genetics, Population*
  • Humans
  • Machine Learning
  • Phenotype
  • Quantitative Trait Loci / genetics
  • Sequence Analysis, RNA
  • Transcriptome / genetics