Most rare missense alleles are deleterious in humans: implications for complex disease and association studies.

By G. Kryukov, Len A. Pennacchio, Shamil R. Sunyaev. American Journal of Human Genetics, 2007

634 citations recorded by the source corpus.

View Paper: https://www.semanticscholar.org/paper/1beab3d0f0fd013b13202fde73c26d7ed87a9c09

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

Citations in the corpus

The Human Gene Mutation Database: 2008 update (2009, neutral): “HGMD data have also been used by researchers in several other studies, including the newly reported sequencing of diploid genomes from individual humans [24,25] and recent mutation [26] and evolutionary [27] studies.”
Exome sequencing identifies the cause of a Mendelian disorder (2009, positive): “Third, a large fraction of rare nonsynonymous variants in the human genome are predicted to be deleterious 6 .”
Exome sequencing as a tool for Mendelian disease gene discovery (2011, positive): “Third, a large fraction of rare, protein-altering variants, such as missense or nonsense single-base substitutions or small insertion– deletions (that is, indels), are predicted to have functional consequences and/or to be deleterious 14 .”
Prediction of Missense Mutation Functionality Depends on both the Algorithm and Sequence Alignment Employed (2011, background): “Because sequence alignments influence sequence-based methods that ultimately generate measures of pathogenicity [Kryukov et al., 2007], it is important to determine which types of sequence alignments will lead to better in silico assessments [Tavtigian et al., 2008].”
Optimal tests for rare variant effects in sequencing association studies. (2012, background): “This is because standard evolutionary principles and population genetics models indicate that majority of rare missense mutations are moderately deleterious [5].”
A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic (2009, background): “It has been reported that about 70% of all rare missense mutations are deleterious [4], but since not all deleterious mutations necessarily contribute to disease-risk, we simulate 50% D-variants as the baseline, but investigate other levels also (see Results).”
Natural selection on genes that underlie human disease susceptibility. (2008, background): “, if the selection coefficients acting on homozygotes are often in the range 28 < Nes < 0, where Ne is the effective population size) [7, 11], genes in which mutations cause recessive disorders should have higher Dn/Ds values than do those in which mutations lead to dominant disorders (e.”
Searching for missing heritability: Designing rare variant association studies (2014, background): “Hypomorphic alleles will typically be common rather than rare owing to weaker selection (s estimated in the range of 1010) (13, 29, 59) and rare hypomorphic alleles will increase detection power only modestly, owing to their smaller effect size (SI Appendix, Section 5.”
Patterns and rates of exonic de novo mutations in autism spectrum disorders (2012, methodology): “We examined the missense mutations as such variation can cause loss of function 11 using PolyPhen2 scores 12 to measure mutation severity.”