For any human disease –– whether it’s “a Mendelian disorder” such as phenylketonuria (PKU) or “a complex disease” such as type-2 diabetes (T2D) –– each patient exhibits a different onset, severity and clinical course. For example, PKU can present itself and be diagnosed in the newborn nursery in some babies, whereas others will not become symptomatic for several years. T2D can appear in the patient at any time, but there are examples of identical twins in which one might be diagnosed at age 38 while the other is not symptomatic until age 55. The reasons for these differences (in onset, severity and clinical course) lie in MODIFIER GENES. The well-written, thorough review [attached] is highly recommended as an accurate update on modifier genes.
Functional annotation of the genome has progressed at a remarkable pace since the Human Genome Project was more or less completed in 2003 –– aided tremendously by continual advances in high-throughput DNA-sequencing technologies and computational capacity to analyze genome-scale datasets. With these resources, many contributing genes have been identified for specific diseases, and other phenotypes such as height, weight and body mass index (BMI). Presently, causative genes have been identified for >3,300 of the ~4,900 Mendelian disorders reported in humans. In parallel, systematic efforts to assign molecular function and phenotypic outcome to every gene in the genome, via targeted genetic engineering and high-throughput phenotyping infrastructures, have been undertaken in a variety of model organisms (e.g. mouse, zebrafish, fly). Similar strategies to characterize the impact of naturally occurring loss-of-function mutations in humans are being pursued.
However, as has been realized for the past 100 years, genes do not act in isolation. The ultimate phenotypic manifestation of most genetic variants depends on interactions with several additional genetic elements –– usually in the context of functional networks. Effects of such modifier genes can result from direct interaction with the target-gene product, mechanistic contribution to the same biological process, and/or functional compensation through alternative pathways.
All these traits (phenotypes) are rarely consistent across genetic backgrounds and environments, but instead vary in many ways, depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme case, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles remain nevertheless healthy, despite afflicted family members in the same environment (this is called “incomplete penetrance”).
These genetic-background effects often result from the action of so-called ‘‘modifier genes’’ that modulate the phenotypic manifestation of target genes in an epistatic manner (gene ´ gene interactions with one gene hierarchical over another gene). While complicating the prospects for gene discovery and feasibility of mechanistic studies –– such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Herein [attached] the authors review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. Authors propose that modifier-effects emerge from gene-interaction networks, whose structure and function vary with genetic background. Authors suggest that these effects can be exploited as safe and effective ways to prevent, stabilize, and possibly reverse the disease and/or dysfunction.
Am J Hum Genet Aug 2o17; 101: 177–191