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Pleiotropy can be effectively estimated without counting phenotypes through the rank of a genotype-phenotype map.

ABSTRACT: Although pleiotropy, the capability of a gene to affect multiple phenotypes, has been well known as one of the common gene properties, a quantitative estimation remains a great challenge, simply because of the phenotype complexity. Not surprisingly, it is hard for general readers to understand how, without counting phenotypes, gene pleiotropy can be effectively estimated from the genetics data. In this article we extensively discuss the Gu-2007 method that estimated pleiotropy from the protein sequence analysis. We show that this method is actually to estimate the rank (K) of genotype-phenotype mapping that can be concisely written as K = min(r, Pmin), where Pmin is the minimum pleiotropy among all legitimate measures including the fitness components, and r is the rank of mutational effects of an amino acid site. Together, the effective gene pleiotropy (Ke) estimated by the Gu-2007 method has the following meanings: (i) Ke is an estimate of K = min(r, Pmin), the rank of a genotype-phenotype map; (ii) Ke is an estimate for the minimum pleiotropy Pmin only if Pmin < r; (iii) the Gu-2007 method attempted to estimate the pleiotropy of amino acid sites, a conserved proxy to the true gene pleiotropy; (iv) with a sufficiently large phylogeny such that the rank of mutational effects at an amino acid site is r ? 19, one can estimate Pmin between 1 and 19; and (v) Ke is a conserved estimate of K because those slightly affected components in fitness have been effectively removed by the estimation procedure. In addition, we conclude that mutational pleiotropy (number of traits affected by a single mutation) cannot be estimated without knowing the phenotypes.

SUBMITTER: Gu X

PROVIDER: S-EPMC4125405 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Pleiotropy can be effectively estimated without counting phenotypes through the rank of a genotype-phenotype map.

Gu Xun X

Genetics 20140603 4

Although pleiotropy, the capability of a gene to affect multiple phenotypes, has been well known as one of the common gene properties, a quantitative estimation remains a great challenge, simply because of the phenotype complexity. Not surprisingly, it is hard for general readers to understand how, without counting phenotypes, gene pleiotropy can be effectively estimated from the genetics data. In this article we extensively discuss the Gu-2007 method that estimated pleiotropy from the protein s ...[more]

PMID: 24899162

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Project description:Understanding evolution requires detailed knowledge of genotype-phenotype maps; however, it can be a herculean task to measure every phenotype in a combinatorial map. We have developed a computational strategy to predict the missing phenotypes from an incomplete, combinatorial genotype-phenotype map. As a test case, we used an incomplete genotype-phenotype dataset previously generated for the malaria parasite's 'chloroquine resistance transporter' (PfCRT). Wild-type PfCRT (PfCRT3D7) lacks significant chloroquine (CQ) transport activity, but the introduction of the eight mutations present in the 'Dd2' isoform of PfCRT (PfCRTDd2) enables the protein to transport CQ away from its site of antimalarial action. This gain of a transport function imparts CQ resistance to the parasite. A combinatorial map between PfCRT3D7 and PfCRTDd2 consists of 256 genotypes, of which only 52 have had their CQ transport activities measured through expression in the Xenopus laevis oocyte. We trained a statistical model with these 52 measurements to infer the CQ transport activity for the remaining 204 combinatorial genotypes between PfCRT3D7 and PfCRTDd2. Our best-performing model incorporated a binary classifier, a nonlinear scale, and additive effects for each mutation. The addition of specific pairwise- and high-order-epistatic coefficients decreased the predictive power of the model. We evaluated our predictions by experimentally measuring the CQ transport activities of 24 additional PfCRT genotypes. The R2 value between our predicted and newly-measured phenotypes was 0.90. We then used the model to probe the accessibility of evolutionary trajectories through the map. Approximately 1% of the possible trajectories between PfCRT3D7 and PfCRTDd2 are accessible; however, none of the trajectories entailed eight successive increases in CQ transport activity. These results demonstrate that phenotypes can be inferred with known uncertainty from a partial genotype-phenotype dataset. We also validated our approach against a collection of previously published genotype-phenotype maps. The model therefore appears general and should be applicable to a large number of genotype-phenotype maps.

Dataset Information

Pleiotropy can be effectively estimated without counting phenotypes through the rank of a genotype-phenotype map.

Publications

Pleiotropy can be effectively estimated without counting phenotypes through the rank of a genotype-phenotype map.

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