Their loss is our gain: regressive evolution in vertebrates provides genomic models for uncovering human disease loci

Abstract

Throughout Earth's history, evolution's numerous natural 'experiments' have resulted in a diverse range of phenotypes. Though de novo phenotypes receive widespread attention, degeneration of traits inherited from an ancestor is a very common, yet frequently neglected, evolutionary path. The latter phenomenon, known as regressive evolution, often results in vertebrates with phenotypes that mimic inherited disease states in humans. Regressive evolution of anatomical and/or physiological traits is typically accompanied by inactivating mutations underlying these traits, which frequently occur at loci identical to those implicated in human diseases. Here we discuss the potential utility of examining the genomes of vertebrates that have experienced regressive evolution to inform human medical genetics. This approach is low cost and high throughput, giving it the potential to rapidly improve knowledge of disease genetics. We discuss two well-described examples, rod monochromacy (congenital achromatopsia) and amelogenesis imperfecta, to demonstrate the utility of this approach, and then suggest methods to equip non-experts with the ability to corroborate candidate genes and uncover new disease loci.

Loss of critical developmental and human disease-causing genes in 58 mammals

“…In this work, we devised a novel approach to automate the survey of genomes for instances of coding gene sequence erosion. Knowledge of gene losses has far-reaching applications in studying the morphological and physiological adaptations of different species [10], in discovering alternative molecular pathways for critical genes [2], in medical genetics [13], and even in animal conservation programs [12]. We designed our approach for low false positive rates in order to be practically useful for the experimentalists tackling these research efforts.…”

“…Species with hiconfErosion that tolerate functional changes known to cause disease in humans provide intriguing potential for medical genetics [13]. Some of these "knockout experiments of nature" may tolerate and even derive selective advantage from gene loss(es) because of factors specific to their habitat niche.…”

“…For example, the enzyme gene GULO is inactivated in independent mammalian lineages that consequently lost the ability to synthesize Vitamin C, and must instead have a constant supply of it in their diet [3,4]; multiple visual system genes are no longer functional in subterranean mammals which live primarily in darkness [5,6]; taste receptor and other genes are lost in fully aquatic cetaceans [7][8][9]; renal transporter genes URAT1, GLUT9 and OAT1 are dead in fruit-eating bats, which could have facilitated their frugivorous diet [10]; the immune genes MX1 and MX2 are eroded in toothed whales, possibly making them more susceptible to certain viral pathogens [11]; and the loss of PON1 in several marine mammals may confer increased vulnerability to agricultural pesticide pollution [12]. Systematic annotation of gene losses across species may therefore not only reveal fascinating evolutionary events and genotype-phenotype relationships, but could also point us to "natural knockout" models for human pathologies that reveal compensating molecular pathways in species missing otherwise-indispensable genes [2,3,13].…”

Recapitulating evolutionary divergence in a singlecis-regulatory element is sufficient to cause expression changes of the lens geneTdrd7

“…Previous studies that investigated the genomes of subterranean mammals showed that many genes involved in eye development and function are diverged or lost in these species (9)(10)(11)(12)(13)(14). Naturallyoccurring or laboratory-induced gene-inactivating mutations in some of these genes in humans or mice cause malformation of eye structures and impaired vision (15)(16)(17)(18)(19), suggesting that the gene losses observed in subterranean mammals contributed to the evolution of degenerated eyes.…”

The dopamine receptor D5gene shows signs of independent erosion in Toothed and Baleen whales

“…Whole genome sequencing has greatly expanded our capacity to comprehend evolutionary history, the role of adaptation or the basis for phenotype differences across the tree of life. Multigenome comparisons have also been powerful to recognize the molecular basis of human diseases, a field named as phylomedicine [18–21]. Here we investigate the evolution of DRD 5 in mammalian species.…”