Over the past 100 million years, many mammals, such as moles or mole rats, for example, have evolved to live almost entirely underground. During their transition to adapt to life underground, many species have reduced or completely lost their sense of sight, and often have only a small remnant of an eye that can sometimes be completely covered by skin and fur.

In addition, the sections of the DNA that usually control how the eyes form have changed in these animals. Since there is less need for a working eye in dark environments, DNA related to the eye is no longer protected from damaging mutations in mammals that live underground. So, by comparing the DNA of mammals that live aboveground and underground, scientists can identify the parts of DNA that help form mammals’ eyes.

Previous studies have discovered many sections of DNA responsible for producing the proteins that make up the eye. However, scientists know less about which sections of DNA control when and where these proteins are made. To address this, Partha et al. have studied the DNA of four underground mammals: the star-nosed mole, the cape golden mole, the naked mole-rat and the blind mole-rat.

By comparing the DNA of these animals with that of mammals that live above ground, Partha et al. identified sections of DNA that contained an abnormally high number of changes in the blind underground mammals. Many of these sections are involved in forming the eye, including controlling when and where proteins are made. Overall, the findings show that comparing rates of evolution in different species can help uncover sections of DNA that guide and influence how organisms develop.

Understanding how the eye is formed is not only of interest to scientists studying evolution and biology; it also has wider applications in healthcare. Many people suffer from unexplained eye abnormalities, and insight into the sections of DNA that control the eye’s development could help medical professionals diagnose these cases and design new treatments.

The subterranean habitat has been colonized by numerous animal species for its shelter and unique sources of food (Andersen, 1987; Nevo, 1979). Obligate fossorial species in particular have adopted the underground as a dedicated home, yet the intense demands of life underground often require unique specializations. For one, the air present in tunnels is often low in oxygen (hypoxic) and high in carbon dioxide (hypercapnic) (Nevo, 1979). This dark environment also requires the development of enhanced senses to compensate for loss of vision. These and other subterranean specializations have been reported in many independent evolutionary lineages of insects, amphibians, reptiles, and mammals (Leys et al., 2003; Lacey et al., 2000; Albert et al., 2007; Wilkinson, 2012). Within mammals alone, there are several unrelated subterranean species, including the true moles (family Talpidae), the African golden moles (Chrysochloridae), and the marsupial moles (Notoryctidae). There are also at least three unrelated lineages of subterranean rodents: the naked mole-rat (Heterocephalus glaber), blind mole-rats (Spalacidae), and the pocket gophers (Geomyidae).

Fossorial mammals have evolved a number of morphological and physiological traits that are considered adaptations to subterranean life, affecting how they sense their environment, how they move through it, or how they deal with its physiological demands. For one, species that dig with their forelimbs, like the star-nosed mole, have enlarged forelimbs and claws that allow them to tunnel through substrate, whereas species that dig with their teeth, such as the naked mole-rat, have reduced limbs and continuously growing incisors (Dubost, 1968; Ellerman, 1956). In the absence of light, non-visual sensory systems have been elaborated. These include the sensitive vibrissae (i.e., sensory hairs) of the naked mole-rat and the large and elaborate snout of the star-nosed mole, which has become a remarkable ‘tactile eye’ (Eloff, 1951; Hill et al., 2009; Catania, 1999). Fossorial mammals have also evolved an ability to withstand hypoxic conditions that rivals that of species living at high altitude (Nevo, 1979; Ar et al., 1977). For example, some species have high erythrocyte counts and high skeletal-muscle myoglobin to facilitate oxygen exchange. Some of these adaptive strategies are shared by different fossorial lineages and as such represent prime examples of convergent evolution (Nevo, 1979). Yet, some of the most striking convergent transformations in subterranean mammals are the reductions and losses of traits shared among aboveground mammals, of which the most prominent example is the reduction of the eye (Dubost, 1968; Hill et al., 2009; Cei, 1946a, 1946b).

Vision in many subterranean mammals is limited, and the degree of limitation in each species is related to the extent of its underground habitation (Nemec et al., 2008; Quilliam, 2009; Sanyal et al., 1990). For example, star-nosed moles (Condylura cristata) that share their time aboveground and underground possess diminutive eyes with thick eyelids (Catania, 1999), whereas the naked mole-rat , which spends almost all of its time underground, has tiny eyes that are rarely opened (Hetling et al., 2005). Even more extreme are the completely subcutaneous eyes of the cape golden mole (Chrysochloris asiatica) and the blind mole-rat (genus Nannospalax), which are thought to reflect their strictly subterranean lifestyle (Sanyal et al., 1990; Sweet, 1909). While some degree of visual regression is shared between subterranean mammals, not all visual structures and genetic pathways have regressed to the same degree. For instance, the eyes of true moles and mole-rats show anatomical regression and always exhibit a small eye but retain ocular architecture, suggesting that the basic eye developmental programs must be largely intact in these animals (Carmona et al., 2008, 2010; Quilliam, 1966). The convergent loss of vision and visual structures in subterranean mammals allows us to ask which genetic regions – coding or non-coding – contributed to regression in these species and which were conserved.

The genetic causes of these malformations have been probed through studies of blind cavefish and evolutionary analysis of retinal genes in subterranean mammals (Jeffery, 2009; Emerling and Springer, 2014). Pioneering work by Hendriks et al. found the evolutionary rate of the lens and retina protein αA-crystallin to be markedly accelerated in the Middle Eastern blind mole-rat (Spalax ehrenbergi), as would be expected under relaxed constraint (Hendriks et al., 1987). Furthermore, Emerling and Springer (2014) revealed that regressive genetic changes in retinal proteins are unevenly distributed across different visual pathways and eye tissues. Previous studies have placed more emphasis on retinal components of vision and connections to the visual cortex because it is these components that sense light and transmit images to the brain for vision (Emerling and Springer, 2014; Cooper et al., 1993). Less emphasis has been placed on the genes contributing to other eye tissues, such as the cornea.

The genomes of four subterranean mammals have been sequenced and studied for changes that have occurred in response to their unique environment. The naked mole-rat genome revealed genetic changes in key genes involved in thermogenesis and circadian rhythm, as well as gene loss and deactivating mutations in core visual perception genes (Kim et al., 2011). The genome of the blind mole-rat (Nannospalax gailili) also yielded diverse insights into its subterranean adaptations, such as an impactful change to the P53 protein that allows cells to escape hypoxia-induced apoptosis, as well as the upregulation of specific pathways involved in the response to hypoxia and hypercapnia (Fang et al., 2014). Additionally, parallel evolution was seen in the deactivation of visual perception genes in the blind mole-rat and naked mole-rat. The convergence of such changes provides evidence that they have occurred in response to the subterranean environment rather than as a result of unrelated species-specific conditions or neutral processes, highlighting a potential strategy to discover additional genetic regions showing a similar response (Losos, 2011; Stern, 2013; Rosenblum et al., 2014).

Previous studies have used convergent evolution to reveal genetic changes that are related to environmental shifts without a priori expectations of which regions might respond. One strategy has been to search for convergent amino acid substitutions at specific protein sites (Foote et al., 2015; Liu et al., 2010; Dobler et al., 2012). A complementary strategy is to search for convergent changes in selective pressure on larger functional regions, such as genes or regulatory sequences, because evolution at different nucleotides within a gene could nevertheless lead to convergent phenotypic effects. In practice, convergent changes in selective pressure are inferred by studying evolutionary rates, because selective constraint slows evolution, whereas lack of constraint and adaptation speed it. Computational methods employing this strategy search for functional elements whose evolutionary rates changed on those branches exhibiting the convergent environmental change (Marcovitz et al., 2016; Hiller et al., 2012; Chikina et al., 2016; Lartillot and Poujol, 2011). One demonstration of this approach by our group identified genes that convergently responded when mammalian lineages shifted from a terrestrial to a marine environment (Chikina et al., 2016). Another recent study by Prudent et al.(2016) demonstrated that regions showing convergent rate acceleration in the subterranean environment were enriched in visual perception genes and also contained circadian rhythm genes. Together, these studies show the promise of convergent rates to reveal genes underlying major changes in morphology and physiology that are related to drastic environmental shifts.

To investigate the demands placed upon subterranean species by their extreme environment, we searched for genes exhibiting convergent rate changes in four subterranean mammals. We report a large set of genes showing marked relaxation of constraint in subterranean species, which were highly enriched for visual functions. This set also contained many genes of undetermined function, which could be unrecognized causative genes in eye-related diseases. Finally, we pinpointed the eye-specific transcriptional enhancers in the Pax6 gene region using a new variant of our method and demonstrated the potential to detect new eye-specific enhancers at key developmental genes.

The independent transitions of four mammals to a subterranean environment has been accompanied by convergent phenotypic changes that have arisen as a result of adaptation to new environmental stresses in the underground ecotope (Nevo, 1979; Leys et al., 2003; Lacey et al., 2000; Albert et al., 2007; Wilkinson, 2012). Here, we report a genome-wide effort encompassing both coding and regulatory regions to identify the changes in genotype that have accompanied this phenotypic adaptation by studying changes in their evolutionary rates. Our study reveals that genes showing convergent acceleration in subterranean species are highly enriched for function in visual pathways. The decreased selective pressure on visual pathways in the dim-light subterranean environment leads to a relaxation of constraint on genetic elements involved in various eye-related phenotypes, including eye morphology, photoreception and visual transduction. In addition to accelerated change in genes in visual pathways, we observe an accelerated rate of evolution of many genes involved in skin-related phenotypes in the subterranean mammals. Whereas we see accelerated change in visual genes primarily as a result of relaxation of constraint, we see that some skin-related genes also show accelerated change due to positive selection, perhaps as a result of selection of traits contributing to a fossorial lifestyle. Aside from these two phenotypes, we do not observe a comparably strong enrichment for genes involved in the other environmental challenges associated with a subterranean lifestyle, such as hypoxia, hypercapnia and high infectivity. It is possible that the subterranean mammals may show species-specific adaptations to these stresses, whereas our analysis from a convergent evolutionary perspective reflects changes common to all the species.

Closer examination of the accelerated genes that are enriched for vision-related pathways reveals that accelerated genes tend to be lens- or retina-specific. On the other hand, genes encoding specifically for the outer ocular structure, the cornea, do not show significant acceleration, indicating the preservation of developmental programs that are important for ocular architecture. In two of the four moles with non-subcutaneous eyes, the cornea can come into direct contact with the external environment, perhaps necessitating the proper development of the structure in the highly infective subterranean niche. Lens- and retina-specific genes that are involved with the processes of photoreception and phototransduction would be under greater relaxed constraint given the dim-light environment, accruing damaging mutations at a much higher rate. Our analyses also reveal that genes that are associated with congenital eye diseases are accelerated in the four subterranean mammals. For the lens, which is largely made up of crystallins, we find many crystallin genes (Crybb3, Cryba1, Crybb1, Crygc, Crygs, etc.) in our accelerated set of genes contributing to various forms of cataracts (Graw, 2009). Similarly, we find multiple genes involved in ciliopathies to be accelerated, including ‘deleted in primary ciliary dyskinesia’ (Dpcd), Iqcb1 (a component of primary cilia), and ciliary neurotrophic factor (Cntf). Further inspection of the accelerated list of genes could potentially reveal new candidate genes that are important for congenital eye diseases.

Genes that are involved in the embryonic development of eyes do not show significant global acceleration, potentially due to their pleiotropic nature: these developmental transcription factors tend to have important regulatory roles in non-eye-related pathways that are not under relaxed constraint. We successfully tested our hypothesis that eye-specific regulatory elements of such genes are under relaxed constraint in the moles, using a novel variant of our approach that calculates convergent rate acceleration at the non-coding level. Although the strong rate acceleration in the three eye-specific enhancers of PAX6 suggests relaxation of constraint in the subterranean mammals, in the absence of functional tests we cannot be sure that the eye-specific activity is truly lost. Furthermore, we found an enrichment of such convergently accelerated non-coding regions preferentially near eye developmental transcription factor genes, identifying potential enhancer elements driving the expression of these genes specifically in the eye. As a large-scale validation approach, we show that rate acceleration in subterranean mammals strongly overlaps regions identified as eye enhancers by the FANTOM5 consortium. These proof-of-principle analyses serve to illustrate the power of convergent-evolution-based tools for the identification of eye-specific regulatory elements. Despite the apparent rapid rate of enhancer evolution across mammals, our methods and those of colleagues showcase the utility of applying evolution-based approaches to conserved non-coding regions in identifying regulatory elements underlying important developmental functions (Marcovitz et al., 2016; Villar et al., 2015). These methods present a unique opportunity to perform genome-wide scans for eye- and other tissue-specific regulatory elements, and potentially serve as complementary approaches to genome-wide assays in the identification of active enhancer elements in the genome. As more genomes are sequenced, we expect these methods to become more powerful in revealing gene regulatory changes underlying convergent phenotypes.

Overall, our results suggest that genes and non-coding regions that are involved in vision pathways are accumulating deleterious mutations by neutral processes, given the relaxation of constraint on these pathways in the subterranean environment. However, this does not preclude the possibility that the initial inactivating mutations in these pathways were adaptive in nature. The initial shutdown of eye development may have been caused by positively selected changes, followed by continued regression of structural and physiological eye genes through neutral processes. Indeed, there is evidence of such a progression of events during eye regression in blind cavefish (Jeffery, 2005). Adaptive forces for reduced eyes may have been driven by the energetic costs of maintaining functioning eyes and the risk of pathogen entry through the eye (Moran et al., 2015). We note that our rate-based analysis detects signatures of sequence divergence that are based on what is observed at the end of these processes and does not shed light on the nature of the initial inactivating changes. In addition, our methods detect convergent changes in the rates of evolution of genes and hence are not designed to detect species-specific changes that might contribute to the subterranean adaptation.

Our results showcasing acceleration in the rates of convergent evolution of visual genes strongly supports previous reports of visual regression in the subterranean habitat. Emerling and Springer (2014) studied the regression of retinal genes in three of these four subterranean species and showed that a decrease in the amount of light entering the retina is associated with higher incidence of inactivating mutations in retinal genes. They found a significantly higher number of retinal pseudogenes in the moles compared to that in closely related subaerial species, an observation concordant with our results based on rate acceleration. Genome sequencing efforts for naked mole-rat and blind mole-rat also showed a strong enrichment of pseudogenes in visual pathways that are associated with the degradation of vision in these species (Cooper et al., 1993; Kim et al., 2011). A genome-wide study by Prudent et al. (2016) detected significant genomic differences in genes involved in vision-related pathways such as eye development and perception of light in two of these four subterranean mammals, namely cape golden mole and blind mole-rat. Using our rates-based framework, we performed a rigorous investigation of convergently evolving genes in a large set of four subterranean species, and elucidated the tissue-specificity and underlying reasons for their convergent rate changes. In a first-of-its-kind demonstration at the non-coding level, we applied our methods successfully to detect eye-specific enhancers showing accelerated evolution in subterranean mammals.

Visual regression is not limited to these four mole species, and mammals display specific types of regression and other general differences in visual capabilities. Our analysis of visual gene rates across other species revealed interesting patterns and trends, wherein some aboveground species with poor or remodeled visual systems showed mean rate acceleration comparable to subterranean mammals (Figure 8). This provides an opportunity to further probe specific differences in the development and function of visual systems in terms of the specific pathways that are relaxed or under constraint across species. In addition, integrating these other species into our rate-based framework can help in fine-tuning the predictive power of the evolutionary-based approaches. Deliberate selection of foreground branches based on specific combinations among these vision-impaired mammals might greatly improve the power of the methods in detecting convergent changes, especially at the non-coding level. In this regard, the availability of rich and diverse phenotypic annotations across mammals further lays the ground for the development of evolutionary-based approaches in functional and phenotypic annotation of non-coding regions (Marcovitz et al., 2016; O’Leary et al., 2011; O'Leary et al., 2013).

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Author details

1. Raghavendran Partha

   Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Visualization, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7900-4375

2. Bharesh K Chauhan

   1. UPMC Eye Center, Children’s Hospital of Pittsburgh, Pittsburgh, United States
   2. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, United States

   Contribution

   Data curation, Formal analysis, Funding acquisition, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6429-9190

3. Zelia Ferreira

   Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Visualization, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7619-7466

4. Joseph D Robinson

   Department of Molecular and Cell Biology, University of California, Berkeley, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Funding acquisition

   Competing interests

   No competing interests declared

5. Kira Lathrop

   1. UPMC Eye Center, Children’s Hospital of Pittsburgh, Pittsburgh, United States
   2. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, United States

   Contribution

   Visualization

   Competing interests

   No competing interests declared

6. Ken K Nischal

   1. UPMC Eye Center, Children’s Hospital of Pittsburgh, Pittsburgh, United States
   2. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, United States

   Contribution

   Funding acquisition, Writing—review and editing

   Competing interests

   No competing interests declared

7. Maria Chikina

   Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States

   Contribution

   Conceptualization, Software, Formal analysis, Funding acquisition, Writing—review and editing

   For correspondence

   mchikina@pitt.edu

   Competing interests

   No competing interests declared

8. Nathan L Clark

   Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States

   Contribution

   Conceptualization, Software, Formal analysis, Funding acquisition, Visualization, Writing—original draft, Writing—review and editing

   For correspondence

   nclark@pitt.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0006-8374

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