• Such mutations were originally thought to
cause severe diseases and/or be very
detrimental to the overall health of the
person
• Recent studies suggest that genomes in
healthy subjects can carry 200-800 loss of
function (LoF) protein-coding variants.
What is an LoF?
• “Genetic changes that are predicted to be
seriously disruptive to the function of proteincoding genes” (MacArthur, 2012; blog)
• Include insertion/deletion DNA reading
frameshifts, nonsense mutations (QuintanaMurci, 2012)
Experiment
• Genomes of 185 individuals analyzed; catalog of nearly
3,000 candidate LoF variants created
• The identified candidate LoF variants were put through
a series of filters and placed into several overlapping
categories:
- severe recessive disease alleles in
heterozygous state
- less deleterious alleles that have impact on
phenotype and disease risk
- benign LoF variation in redundant genes
- sequencing and annotation artifacts
(MacArthur, 2012; article)
Data/Results
• Out of catalog of candidate LoF variants:
- 25.0% eliminated as
sequencing/mapping errors
- 26.8% eliminated as annotation/
reference sequencing errors
- 11.1% eliminated as unlikely to
cause genuine loss of function
• 32.3% of remaining LoF variants found to be
partially deleterious, meaning a functional
protein could still be made (MacArthur, 2012;
article)
• 43.5% of original LoF candidates remained
after filtering tests
• These variants were found to:
- contain stop codons, disrupt splice-sites,
or result in insertions or deletions that change
DNA reading frame
- primarily be enriched in low-frequency
alleles; those present in higher frequencies are
either present in poorly evolutionary conserved
genes, multigene families, or have few proteinprotein interactions (MacArthur, 2012; article)
• Overall, the identified LoF variants are
extremely rare; majority of the identified
candidates are found in less than 2% of
population
• 26 known severe recessive disease-causing
mutations identified in LoF set
• 21 LoF variants identified in known novel
disease-causing mutations (MacArthur, 2012;
blog)
Discussion
• The low frequency of deleterious LoF variants
could be explained by purifying selection;
therefore variants associated with severe diseasecausing mutations are prevented from reaching
high frequencies (MacArthur, 2012; article)
• Contributes to the “less is less” hypothesis, which
states that LoF variants will be counter-selected
seeing as they cause disease (Quintana-Murci)
Take Home Message
• All human genomes carry around 100 LoF
variants. However, the majority of these do
not cause true loss of gene functioning and
the ones that do cause severe diseases are
extremely rare.
Literature Cited:
MacArthur, Daniel. "A Systematic Survey of Loss-of-Function Variants in
Human Protein-Coding Genes." Science Magazine: Sign In. The
American Association for the Advancement of Science, 11 Jan. 2012.
Web. 18 Nov. 2012.
<http://www.sciencemag.org/content/335/6070/823.full>.
Quintana-Murci, Lluis. "Perspective: Gene Losses in the Human
Genome." Science Magazine: Sign In. American Association of the
Advancement of Science, 17 Feb. 2012. Web. 18 Nov. 2012.
<http://www.sciencemag.org/content/335/6070/806.full.html>.
MacArthur, Daniel. "All Genomes Are Dysfunctional: Broken Genes in
Healthy Individuals." Web log post. Genomes Unzipped. WordPress,
02 June 2012. Web. 18 Nov. 2012.
<http://www.genomesunzipped.org/2012/02/all-genomes-aredysfunctional-broken-genes-in-healthy-individuals.php>.