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Measuring Intolerance to Mutation in Human Genetics

View ORCID ProfileZachary L. Fuller, View ORCID ProfileJeremy J. Berg, View ORCID ProfileHakhamanesh Mostafavi, Guy Sella, View ORCID ProfileMolly Przeworski
doi: https://doi.org/10.1101/382481
Zachary L. Fuller
1Department of Biological Sciences, Columbia University
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  • For correspondence: zlf2101@columbia.edu
Jeremy J. Berg
1Department of Biological Sciences, Columbia University
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Hakhamanesh Mostafavi
1Department of Biological Sciences, Columbia University
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Guy Sella
1Department of Biological Sciences, Columbia University
2Department of Systems Biology, Columbia University
3Program for Mathematical Genomics, Columbia University
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Molly Przeworski
1Department of Biological Sciences, Columbia University
2Department of Systems Biology, Columbia University
3Program for Mathematical Genomics, Columbia University
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  • For correspondence: mp3284@columbia.edu
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Abstract

In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, it is useful to know whether a single disrupting mutation in a gene is likely to be deleterious1–4. With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large numbers of healthy individuals—genes that appear intolerant to mutation3,5–9. One measure in particular, pLI, has been widely adopted7. By contrasting the observed versus expected numbers of PTVs, it aims to classify genes into three categories, labelled null, recessive and haploinsufficient7. Here we discuss how pLI and similar measures relate to population genetic parameters and why they reflect the strength of selection acting on heterozygotes, rather than dominance or haploinsufficiency.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 01, 2018.
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Measuring Intolerance to Mutation in Human Genetics
Zachary L. Fuller, Jeremy J. Berg, Hakhamanesh Mostafavi, Guy Sella, Molly Przeworski
bioRxiv 382481; doi: https://doi.org/10.1101/382481
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Measuring Intolerance to Mutation in Human Genetics
Zachary L. Fuller, Jeremy J. Berg, Hakhamanesh Mostafavi, Guy Sella, Molly Przeworski
bioRxiv 382481; doi: https://doi.org/10.1101/382481

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