Genetic Modifiers and Oligogenic Traits
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Downloaded from http://perspectivesinmedicine.cshlp.org/ at UNIV OF CO LIBRARIES on March 14, 2018 - Published by Cold Spring Harbor Laboratory Press Genetic Modifiers and Oligogenic Inheritance Maria Kousi and Nicholas Katsanis Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710 Correspondence: [email protected] Despite remarkable progress in the identification of mutations that drive genetic disorders, progress in understanding the effect of genetic background on the penetrance and expres- sivity of causal alleles has been modest, in part because of the methodological challenges in identifying genetic modifiers. Nonetheless, the progressive discovery of modifier alleles has improved both our interpretative ability and our analytical tools to dissect such phenomena. In this review, we analyze the genetic properties and behaviors of modifiers as derived from studies in patient populations and model organisms and we highlight conceptual and tech- nological tools used to overcome some of the challenges inherent in modifier mapping and cloning. Finally, we discuss how the identification of these modifiers has facilitated the elucidation of biological pathways and holds the potential to improve the clinical predictive value of primary causal mutations and to develop novel drug targets. ince the mapping of the first locus for auto- aspects of disease expressivity, such as age-of- Ssomal dominant retinitis pigmentosa (RP) onset, rate of progression, severity, and manifes- on the long arm of chromosome 3 (McWilliam tation of other comorbidities. Numerous re- et al. 1989) and the subsequent identification ports exist in the literature in which patients of rhodopsin (RHO) as the causal transcript with the same primary mutation show stark dif- (Dryja et al. 1990), the genetic dissection of dis- ferences in phenotypic expressivity, with the orders inwhich retinal degeneration comprises a more striking examples coming from noniden- core phenotypic component has accelerated tical twin studies in which patients that grow rapidly, leading to the report of more than 250 under a shared environment and carry the www.perspectivesinmedicine.org loci and genes cataloged in RetNet (as of May same primary mutation display distinct pheno- 2014; see https://sph.uth.edu/retnet/disease types, most likely because of genetic determi- .htm). These advances have had a clear contri- nants that act as modifiers (Walia et al. 2008). bution to both our understanding of photore- The example above is not an isolated oddity. ceptor biology and in providing genetic diag- Accumulating clinical and genetic evidence noses to families. At the same time, however, now suggests that, even for classically monogen- post hoc knowledge of disease-causing genes ic disorders, the view that the expressivity of the and mutations had a modest impact on the pre- phenotype is exclusively the property of domi- dictive ability of prognosis with regard to key nant or recessive mutations at a single locus Editors: Eric A. Pierce, Richard H. Masland, and Joan W. Miller Additional Perspectives on Retinal Disorders: Genetic Approaches to Diagnosis and Treatment available at www.perspectivesinmedicine.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a017145 Cite this article as Cold Spring Harb Perspect Med 2015;5:a017145 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ at UNIV OF CO LIBRARIES on March 14, 2018 - Published by Cold Spring Harbor Laboratory Press M. Kousi and N. Katsanis might be an oversimplification of the biological secting modifier phenomena, four major pa- phenomena (Dipple and McCabe 2000; Badano rameters play a prominent role: and Katsanis 2002; Scha¨ffer 2013). 1. Allelic heterogeneity. Phenotypic variability The concept of modifier genes and alleles can stem from mutations in different genes is not new (Haldane 1941). Nonetheless, the that contribute to disease endophenotypes. field of retinal degeneration disorders has been However, simpler models of genetic hetero- in a unique position to lead the efforts to un- geneity and their influence on phenotypic derstand genetic architecture, causality, and expressivity should first be considered. Locus variable expressivity. This is in part because and allelic heterogeneity are highlighted in of (1) large and well-phenotyped multiethnic Lebercongenitalamaurosis(LCA),adisorder cohorts; (2) a substantial (and growing) muta- for which at least 11 causative genes have been tional target of almost 300 genes, each known to reported under a recessive paradigm (re- be necessary for retinal biogenesis, homeostasis, viewed in Davis and Katsanis 2012). In addi- and/or function; and (3) the availability of in tion to genetic heterogeneity, LCA is also an vitro and in vivo tools to model genetic inter- example of allelic heterogeneity. For exam- action phenomena. Here we will discuss the ple, nonsense and frameshift, as well as mis- concepts of modifier genes and alleles, includ- sense mutations in CEP290 drive disorders ing their evolving terminology; we will high- ranging between nonsyndromic LCA to Jou- light examples that illustrate the still episodic, bert syndrome (JBTS) to the more severe yet significant, advances in dissecting the genet- Meckel Gruber syndrome (MKS) phenotype. ic basis of modification of penetrance and ex- These observations have reasonably suggest- pressivity; and we will discuss possible avenues ed that modifier genetic factors account toward improving our interpretative ability of for this marked variance in clinical presenta- such events. tion (den Hollanderet al. 2006, 2008; Sayeret al. 2006; Valente et al. 2006; Baala et al. 2007; PROPERTIES OF GENETIC MODIFIERS Frank et al. 2007; Perrault et al. 2007). How- ever, a discrete intronic mutation (c.2991þ A critical step in understanding genetic modi- 1655A.G) in CEP290 that creates a strong fication phenomena consists of providing a splice-donor site and inserts a cryptic exon clear definition for the term itself. Phenomena in the CEP290 mRNA resulting in an aber- described by terms such as epistasis, oligogenic rantly spliced transcript, appears to be suffi- inheritance, or genetic interaction/modifica- cient to cause LCA (den Hollanderet al. 2006, tion, are all effective synonyms of the same pro- www.perspectivesinmedicine.org 2008; Sayer et al. 2006; Valente et al. 2006; cess, namely, the effect of one gene/allele on Baala et al. 2007; Frank et al. 2007; Perrault the phenotypic outcome of a second gene/lo- et al. 2007). These data argue that, at least in cus. A distinction that can aid better defining some instances, this mutational event alone these genetic phenomena consists in establish- is sufficient to explain the disease without ing whether the primary locus is both necessary necessarily evoking the action of additional and sufficient to cause disease. If yes, then the alleles. In this example, recurrence of the spe- presence of allele(s) at a second locus/gene ex- cific mutation has facilitated that argument. erts purely a modifying role on the severity of However, typically bereft of such data, dis- the phenotype as defined by the rate of disease secting phenotype–genotype correlations progression; the severity of the phenotype with within a primary causal locus from modifier regard to its pleiotropy; or in the manifestation effects can be challenging, especially because of endophenotypes that necessitate genetic in- most such correlations are made on the basis teractions; if not, then the requirement of an of a few mutations. allele in a second gene to manifest pathology defines a case of digenic or oligogenic inheri- 2. Multiple interactions and gene/allele-specific tance (Fig. 1). In general, in the context of dis- interactions. The effect of genetic modifiers 2 Cite this article as Cold Spring Harb Perspect Med 2015;5:a017145 Downloaded from http://perspectivesinmedicine.cshlp.org/ at UNIV OF CO LIBRARIES on March 14, 2018 - Published by Cold Spring Harbor Laboratory Press Genetic Modifiers and Oligogenic Inheritance Primary disease locus mutation(s) Cone Rod Outer nuclear Retina layer Modifiers of expressivity Potentiator of Modifier of penetrance Phenotype exascerbating Phenotype ameliorating endophenotypes 3y 12y + Advanced retinal Mild retinal Normal clinical Advanced retinal degeneration degeneration Retinal degeneration + presentation degeneration + renal dysfunction neuronal abnormalities Figure 1. Schematic of the effects of modifiers on causal mutations. A genetic modifier can exert its effect on the phenotype established by mutation(s) at the primary locus in a number of ways. Depending on the nature of the www.perspectivesinmedicine.org modifier, this interaction can result in reduced penetrance of specific endophenotype(s) and/or disorders; in variable expressivity with the modifying locus resulting in either exacerbated phenotypes (i.e., earlier age of onset and faster progression of the disease); in a milder clinical presentation (i.e., later age of onset, attenuated disease progression, and absence/protection from specific endophenotypes); and modifiers that potentiate the manifestation of specific endophenotypes resulting in what is described as novel forms of disease. This figure was prepared using Servier Medical Art (http://www.servier.com/Powerpoint-image-bank). on penetrance and/or expressivity can vary type caused by the primary locus is challeng- from a “monogenic” model of modification, ing,dueprimarily tolackofgeneticpower.An in which one modifier can account