After the mapping of the human genome in 2003 and researchers would identify a gene associated with a 44 % risk of breast cancer in women, for example, it seemed that protecting them might be as simple as deactivating that gene. But the promise of such personalized medicine has not fully materialized, say two McMaster University researchers, because the full sophistication of the genetic blueprint has a more complex and far-reaching influence on human health than scientists had first realized.

McMaster University researcher Bhagwati Gupta, a professor of Biology. Credit: JD Howell, McMaster University

In the hope of integrating genetics more closely with medical practice, McMaster evolutionary biologists Rama Singh, PhD, and Bhagwati Gupta, PhD, carried out an exhaustive and critical review of decades of research in their field. They lay out their conclusions in an article “Genes and genomes and unnecessary complexity in precision medicine” published in Genomic Medicine.

“The sequencing of the human genome heralded the new age of ‘genetic medicine’ and raised the hope of precision medicine facilitating prolonged and healthy lives. Recent studies have dampened this expectation, as the relationships among mutations (termed ‘risk factors’), biological processes, and diseases have emerged to be more complex than initially anticipated. In this review, we elaborate upon the nature of the relationship between genotype and phenotype, between chance-laden molecular complexity and the evolution of complex traits, and the relevance of this relationship to precision medicine. Molecular contingency, i.e., chance-driven molecular changes, in conjunction with the blind nature of evolutionary processes, creates genetic redundancy or multiple molecular pathways to the same phenotype; as time goes on, these pathways become more complex, interconnected, and hierarchically integrated,” write the investigators.

McMaster University researcher Rama Singh, a professor of Biology. Credit: Georgia Kirkos, McMaster University

“Based on the proposition that gene-gene interactions provide the major source of variation for evolutionary change, we present a theory of molecular complexity and posit that it consists of two parts, necessary and unnecessary complexity, both of which are inseparable and increase over time. We argue that, unlike necessary complexity, comprising all aspects of the organism’s genetic program, unnecessary complexity is evolutionary baggage: the result of molecular constraints, historical circumstances, and the blind nature of evolutionary forces.”

“In the short term, unnecessary complexity can give rise to similar risk factors with different genetic backgrounds; in the long term, genes become functionally interconnected and integrated, directly or indirectly, affecting multiple traits simultaneously. We reason that in addition to personal genomics and precision medicine, unnecessary complexity has consequences in evolutionary biology.”

The biochemical pathway that shapes evolution is dense with inherited redundancies, they explain. Genetic information from our ancestors trails along forever in an incremental physical record that interacts significantly with our own most recently evolved and internally complex genetic network, which in turn interacts with the environment, creating almost infinite combinations and potential health outcomes.

Individual genes do not determine sickness or health on their own, the authors say, but act in concert with groups of other genes—all in various stages of mutation—in ways that are just beginning to be understood.

“The idea has long been that individual genetic mutations could be classified as good, bad or neutral,” Singh says “Genes, though, do not work alone, and so no single gene can be considered to be good, bad or neutral in all contexts.”

The research paper explains that “unnecessary” complexity in the evolutionary pathway needs to be fully unpacked—down to the genomic variations between individual cells in the same person—before personalized medicine can be used effectively for improving human health.

“Our bodies have an immense ability to change and to cope with issues that arise. Context matters in our genome,” Gupta says. “Even a simple single mutation can have a profound effect on the body, when acting in combination with others.”

The scientists conclude that precision medicine is still critical to the future of medicine, but that the same technology that identified the “necessary” complexity of the genome also needs to be applied to the entire blueprint, including the “unnecessary” elements, creating a longer, more complicated road to the same destination.

“Any disease we see is a result of the interactions between necessary and unnecessary complexity,” says Gupta. “Nature does not go back in time. It goes forward, and as it encounters challenges, it comes up with solutions. Our genes carry the history of all the changes that have occurred over many generations. It may not be necessary to our function today, but it is embedded in our genes.”

“Complexity is not a curse. It’s a reflection of our evolutionary history, and it needs to be recognized as an important part of the body that medicine is trying to treat,” Singh says. “Beyond personalized medicine, complexity bears on the evolution of life itself.”

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