Pleiotropy Can Be Effectively Estimated without Counting Phenotypes through the Rank of a Genotype-Phenotype Map

By Gu, Xun | Genetics, August 2014 | Go to article overview

Pleiotropy Can Be Effectively Estimated without Counting Phenotypes through the Rank of a Genotype-Phenotype Map


Gu, Xun, Genetics


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, P^sub min^), where P^sub min^ 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 (K^sub e^) estimated by the Gu-2007 method has the following meanings: (i) K^sub e^ is an estimate of K = min(r, P^sub min^), the rank of a genotype-phenotype map; (ii) K^sub e^ is an estimate for the minimum pleiotropy P^sub min^ only if P^sub min^ < 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 [arrow right] 19, one can estimate P^sub min^ between 1 and 19; and (v) K^sub e^ 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.

(ProQuest: ... denotes formulae omitted.)

PLEIOTROPY, or the capability of a gene to affect multiple phenotypes (Fisher 1930; Wright 1968), has played a cen- tral role in genetics, development, and evolution (e.g.,Lande 1980; Turelli 1985; Wagner 1989; Barton 1990; Keightley 1994; Hartl and Taubes 1996, 1998; Waxman and Peck 1998; Lynch et al. 1999; Bataillon 2000; Orr 2000; Poon and Otto 2000; Wagner 2000; Elena and Lenski 2003; Welch and Waxman 2003; Wingreen et al. 2003; Zhang and Hill 2003; MacLean et al. 2004; Otto 2004; Eyre-Walker et al. 2006; Pigliucci 2008; Wagner et al. 2008). Although func- tional genomics has brought high-throughput data to bear on the nature and extent of pleiotropy (Dudley et al. 2005; Ohya et al. 2005; Pal et al. 2006; Cooper et al. 2007), this issue remains highly controversial, largely because of the phenotypic complexity; see Wagner and Zhang (2011), Hill and Zhang (2012), and Paaby and Rockman (2013) for recent reviews and comments.

Meanwhile, a new research line has emerged in the past decade, aiming at the estimation of gene pleiotropy from genetics or sequence data, rather than the measurement of affected phenotypes (Martin and Lenormand 2006; Gu 2007a, b; Chevin et al. 2010; Su et al. 2010; Zeng and Gu 2010; Razeto-Barry et al. 2012; Chen et al. 2013). For instance, Gu (2007a) developed a statistical method to estimate the "effec- tive pleiotropy" (Ke) of a gene from the multiple-sequence align- ment (MSA) of protein sequences. Most genes have Ke in the range between 1 and 20 (Su et al. 2010), with the medium Ke = 6.5 of these estimates that is comparable to some empir- ical pleiotropy measures (Wagner and Zhang 2011; Paaby and Rockman 2013). However, we have to acknowledge that this approach is not very easy to be understood; that is, How can we know the amount of multifunctionality (pleiotropy) of a gene without biologically knowing each functional component?

In this article we try to answer the following questions: What quantity was actually estimated by the method proposed by Gu (2007a)? And under which condition can this estimate be interpreted as effective gene pleiotropy? To answer these questions, we introduce the concept of minimum pleiotropy (Pmin), which has an intrinsic relationship with the rank of the genotype-phenotype map. …

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