Are My Genes Mutated? Analyzing Loss of Function Variants in the Human Genome - PowerPoint Presentation

Slide1

Are My Genes Mutated?Analyzing Loss of Function Variants in the Human Genome

Group A1

Caroline

Kissel

, Meg

Sabourin

,

Kaylee Isaacs, Alex MaederSlide2

IntroductionMutations that occur in DNA synthesis can result in a mutated gene that deters or completely denatures the protein it codes for

Loss of function in gene can severely alter the phenotype of the organism or lead to the development of a serious disease.Slide3

Such mutations were originally thought to cause severe diseases and/or be very detrimental to the overall health of the personRecent studies suggest that genomes in healthy subjects can carry 200-800 loss of function (LoF) protein-coding variants.Slide4

What is an LoF?“Genetic changes that are predicted to be seriously disruptive to the function of protein-coding genes” (MacArthur, 2012; blog)Include insertion/deletion DNA reading frameshifts, nonsense mutations (Quintana-Murci, 2012)Slide5

ExperimentGenomes of 185 individuals analyzed; catalog of nearly 3,000 candidate LoF variants createdThe 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)

Slide6

Data/ResultsOut 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 function32.3% of remaining

LoF

variants found to be partially deleterious, meaning a functional protein could still be made (MacArthur, 2012; article)Slide7

43.5% of original LoF candidates remained after filtering testsThese 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 protein-protein interactions (MacArthur, 2012; article)Slide8

Overall, the identified LoF variants are extremely rare; majority of the identified candidates are found in less than 2% of population26 known severe recessive disease-causing mutations identified in LoF set 21 LoF variants identified in known novel disease-causing mutations (MacArthur, 2012; blog)Slide9

DiscussionThe low frequency of deleterious LoF variants could be explained by purifying selection; therefore variants associated with severe disease-causing 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)Slide10

Take Home MessageAll 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.Slide11

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-are-dysfunctional-broken-genes-in-healthy-individuals.php>.