Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion

Acta Neuropathol. 2014 Mar;127(3):391-6. doi: 10.1007/s00401-014-1250-x. Epub 2014 Feb 5.

Abstract

Recent advances are uncovering more and more of the genetic architecture underlying amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative condition that affects ~6,000 Americans annually. Chief among these was the discovery that a large repeat expansion in the C9ORF72 gene is responsible for an unprecedented portion of familial and sporadic ALS cases. Much has been published on how this expansion disrupts neuronal homeostasis and how gene-based therapy might be an effective treatment in the future. Nevertheless, it is instructive to look back at the origins of this important mutation. In this opinion piece, we attempt to answer three key questions concerning C9ORF72. First, how many times did the expansion occur throughout human history? Second, how old is the expansion? And finally and perhaps most importantly, how did the expansion spread throughout Europe? We speculate that the expansion occurred only once in the past, that this event took place in the Finnish population and that the Vikings and their descendants were responsible for disseminating this mutation throughout the rest of the continent.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • C9orf72 Protein
  • DNA Repeat Expansion*
  • European Continental Ancestry Group / genetics
  • Evolution, Molecular*
  • Human Migration
  • Humans
  • Internationality
  • Proteins / genetics*
  • Time Factors

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins