Measuring intolerance to mutation in human genetics

Fuller, Zachary L.; Berg, Jeremy J; Mostafavi, Hakhamanesh; Sella, Guy; Przeworski, Molly

doi:10.1038/s41588-019-0383-1

Cited by 121 publications

(127 citation statements)

References 56 publications

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“…The pLI score for a gene measures the probability of intolerance to (generally heterozygous) loss-of-function mutations in that gene, as inferred from patterns of variation in ultra-deep human exome sequencing data 58 . pLI scores can be used to differentiate between haploinsufficient and haplosufficient genes or, similarly, between dosage-sensitive and insensitive genes 58 (although, strictly speaking, the scores are directly informative only about the strength of selection acting on heterozygotes 62 ). By contrast, phastCons scores simply measure a reduction in fixed derived alleles, and do not effectively differentiate among various forms of negative selection.…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic modeling of regulatory element turnover based on epigenomic data

Dukler

Huang

Siepel

2019

Preprint

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Evolutionary changes in gene expression are often driven by gains and losses of cis-regulatory elements (CREs). The dynamics of CRE evolution can be examined using multi-species epigenomic data, but so far such analyses have generally been descriptive and model-free. Here, we introduce a probabilistic modeling framework for the evolution of CREs that operates directly on raw chromatin immunoprecipitation and sequencing (ChIP-seq) data and fully considers the phylogenetic relationships among species. Our framework includes a phylogenetic hidden Markov model, called epiPhyloHMM, for identifying the locations of multiply aligned CREs, and a combined phylogenetic and generalized linear model, called phyloGLM, for accounting for the influence of a rich set of genomic features in describing their evolutionary dynamics. We apply these methods to previously published ChIP-seq data for the H3K4me3 and H3K27ac histone modifications in liver tissue from nine mammals. We find that enhancers are gained and lost during mammalian evolution at about twice the rate of promoters, and that turnover rates are negatively correlated with DNA sequence conservation, expression level, and tissue breadth, and positively correlated with distance from the transcription start site, consistent with previous findings. In addition, we find that the predicted dosage sensitivity of target genes positively correlates with DNA sequence constraint in CREs but not with turnover rates, perhaps owing to differences in the effect sizes of the relevant mutations. Altogether, our probabilistic modeling framework enables a variety of powerful new analyses.

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Section: Resultsmentioning

confidence: 99%

Phylogenetic modeling of regulatory element turnover based on epigenomic data

Dukler

Huang

Siepel

2019

Preprint

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“…It became clear during this era that these diseases are highly variable even among members of the same family (Lejeune et al ., ). The exact numbers of HI genes and HI diseases in humans are unknown, partly due to the difficulty of systematically distinguishing HI from other forms of dominant inheritance (Fuller et al ., ). However, known HI genes are clearly diverse in function (Veitia, Caburet, & Birchler, ).…”

Section: Introduction: the Basics Of Genetic Dominancementioning

confidence: 97%

Causes and effects of haploinsufficiency

2019

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Haploinsufficiency is a form of genetic dominance and is the underlying mechanism of numerous human inherited conditions in which the causal genes are sensitive to altered dosage. This review examines the poorly understood relationships between haploinsufficiency, dosage sensitivity and genetic dominance, whose common theme is the existence of nonlinear relationships between genotype and phenotype. We present an up‐to‐date account of the bases of haploinsufficiency from the perspective of theoretical and experimental models. We also discuss human conditions caused by haploinsufficiency, including developmental syndromes and cancer. Connections between the understanding of these conditions' genetic mechanisms and advances in treatments are also described.

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“…A powerful way of gaining insight into a gene's contribution to organismal homeostasis is by studying the fitness effect exerted by loss-of-function (LoF) variants in that gene. Fully characterizing this effect is challenging, as it requires estimation of both the selection coefficient for individuals with biallelic LoF variants, as well as the dominance coefficient (Falconer, Mackay, 1996;Fuller et al, 2019). However, recent studies based on the joint processing and analysis of large numbers of exome sequences have developed metrics which serve as approximations to genic LoF-intolerance in humans (Petrovski et al, 2013;Lek et al, 2016;Karczewski et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Promoter CpG density predicts downstream gene loss-of-function intolerance

Boukas

Björnsson

Hansen

2020

Preprint

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The aggregation and joint analysis of large numbers of exome sequences has recently made it possible to derive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoFintolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich promoters (top 10% CpG density) have a 67.2% probability of being highly LoF-intolerant, using the LOEUF metric from gnomAD. This is in contrast to 7.4% of genes downstream of the most CpG-poor (bottom 10% CpG density) promoters. Combining promoter CpG density with exonic and promoter conservation explains 33.4% of the variation in LOEUF, and the contribution of CpG density exceeds the individual contributions of exonic and promoter conservation. We leverage this to train a simple and easily interpretable predictive model that outperforms other existing predictors and allows us to classify 1,760 genes -which currently lack reliable LOEUF estimates -as highly LoF-intolerant or not. These predictions have the potential to aid in the interpretation of novel patient variants. Moreover, our results reveal that high CpG density is not merely a generic feature of human promoters, but is preferentially encountered at the promoters of the most selectively constrained genes, calling into question the prevailing view that CpG islands are not subject to selection.

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Measuring intolerance to mutation in human genetics

Cited by 121 publications

References 56 publications

Phylogenetic modeling of regulatory element turnover based on epigenomic data

Phylogenetic modeling of regulatory element turnover based on epigenomic data

Causes and effects of haploinsufficiency

Promoter CpG density predicts downstream gene loss-of-function intolerance

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