What is a mutation

1
What is a mutation?
Human Variome Project Hyderabad, India 27
September, 2008
Aravinda Chakravarti, PhD Center for Complex
Disease Genomics Johns Hopkins University School
of Medicine
2
Victor Almon McKusick (1921 - 2008)
3
(No Transcript)
4
(No Transcript)
5
What is a mutation?

• One does not need to ask this question of a
  geneticist!
• Mutation is a newly arisen genetic changecan be
  small or large but it does not segregatethe
  definition is temporal and the distinction from
  other variants is important since all variants
  arise from mutations

6
A database of what?

• All variants at a site/locus?
• dbSNP, HapMap, 1000 Genomes
• most do not have phenotypic effects
• All locus variants in a phenotype?
• mutation database (e.g., CF)
• some do not have phenotypic effects
• most not functionally tested
• many variants do not act alone

7
Variation data the preponderence of local rare
variantspurifying selection suggests many have
phenotypic effects
8
Mutation data the preponderence of rare variants
a mix of real and passenger mutations
R360W
Sjoblom et al. Science 314268-274, 2006 Wood et
al. Science 3181108-1113, 2007
9
Database of tested variants?

• We are becoming very good at assaying and
  cataloging sequence variation at most loci
  (HapMap, Structural Variation, 1000 Genomes
  Projects)
• We are still poor at assessing the meaning of a
  variant whether it is a mutation or a segregant
• functional tests of individual variants are
  difficult
• almost all disease variants are recognized by
  association
• population association (GWAS)
• association by frequency, conservation
  segregation
• disease and variant catalogs are contaminated
• We need catalogs with information on why each
  variant has the claimed effect.