1 Introduction

Snakes are a highly specialized branch of the lizard evolutionary branch, with remarkable ecological diversity and a wide distribution range. Snakes can be found in almost all terrestrial ecosystems in the world except the polar regions, and their habitats include forests, grasslands, deserts, wetlands and even oceans (Williams, 2020). Nearly 4 000 snake species have been recorded so far, accounting for about one-eighth of the diversity of all terrestrial vertebrates (Macrì et al., 2023). Snakes are highly differentiated in morphology and ecology: from blind snakes with a body length of less than 10 cm that live in burrows and feed on ants and termites, to giant pythons with a body length of several meters that prey on large mammals; from completely aquatic sea snakes to arboreal flying snakes and desert sidewind snakes, all of which reflect their amazing adaptability to different ecological niches. Snakes are also important medium-sized predators in many terrestrial ecosystems and play an irreplaceable role in maintaining the balance of the food web.

Snakes have undergone significant morphological and functional changes during their evolution, such as body elongation and limb degeneration, highly articulated skulls, and the production of venom glands and venom (Title et al., 2024). The emergence of these unique features enables snakes to take advantage of ecological opportunities that other reptiles cannot access, making them one of the most successful reptile groups on Earth. Studying the origin and early evolution of snakes can reveal the process and driving force of major evolutionary innovations such as limb degeneration and sensory organ reorganization (Macrì et al., 2023). At the same time, exploring the geographical diffusion history of snakes around the world will help us understand how plate geography and climate change affect biological evolution and biogeographic patterns (Klein et al., 2021). In addition, many ecological adaptations evolved by snakes during their long evolution (such as infrared perception at night, highly toxic saliva venom, and the ability to fast for a long time) provide excellent research examples for life sciences (Barua et al., 2020).

In recent years, new progress in the fields of paleontology, molecular systematics, and evolutionary developmental biology on snake evolution has improved our understanding of the evolutionary process of branches on the snake tree of life (Klein et al., 2021). For example, through the latest fossil discoveries and pedigree analysis, we have a newer and more accurate judgment on the earliest origin of snakes and the morphology of their ancestors. For example, with the help of high-throughput sequencing technology, scientists have constructed a large phylogenetic tree containing hundreds or even thousands of snakes, clarifying the relationship and differentiation time frame between the main groups (Barua et al., 2020; Title et al., 2024). On the other hand, the extreme evolution of snakes in morphology and function (such as loss of limbs, secretion of venom, efficient feeding and digestion, etc.) provides a classic case for the study of adaptive radiation and key trait evolution. In addition, as an important member of many ecosystems, understanding the evolution and adaptation of snakes is also of practical significance for protecting ecological diversity.

This study will summarize the research progress on the origin, spread and adaptive evolution of snakes, discuss the origin and early evolution of snakes, explain the global geographical spread of snakes, focus on the impact of key geological events on the evolution of snake distribution, analyze the adaptive evolution of snakes in different ecological environments, explore the molecular basis of these adaptive evolutions, and deepen the understanding of the ecological adaptive evolution of snakes through specific case studies, further look forward to future research directions and technical means, and propose possible developments in fossil discovery, emerging molecular technology and data analysis. This study helps to reveal how natural selection shapes the high degree of adaptation of snakes to the environment, and provides a comparative reference for the study of adaptive radiation of other biological groups.

2 The Origin and Early Evolution of Snakes

2.1 Time and place hypothesis of the origin of snakes

There have long been two hypotheses about the ecological habits of early snakes: "marine origin" and "terrestrial origin", but in recent years, many studies tend to favor the terrestrial burrowing origin model (Macrì et al., 2023). The reconstruction of the brain morphology and sensory ability of snakes provides new evidence: by comparing the 3D models of the brains of modern snakes and lizards, scientists speculate that the earliest crown snakes had a "burrowing + opportunistic foraging" lifestyle. Macrì et al. (2023) constructed a predictive model of the brain of snake ancestors and found that it was similar to the brain cavity morphology of some fossil snakes (such as the fossil snake Dinilysia in South America), and both showed sensory structural characteristics related to burrowing life (Figure 1). For example, ancestral snakes may have developed senses of smell and touch, but relatively degraded vision, adapted to low light or underground environments. This is consistent with the characteristics of many modern burrowing blind snakes, suggesting that the ancestors of snakes were probably small lizards that preyed on small invertebrates on the surface or in underground caves. This conclusion is also supported by morphological evidence: the inner ear structure of the Cretaceous snake Dinilysia is similar to that of modern burrowing snakes, indicating that the hearing and balance mechanisms are adapted to digging life.

Combining existing fossil and molecular evidence, the academic community generally believes that the direct ancestors of modern snakes may have appeared in the Late Cretaceous about 100 million years ago, with a slender trunk, reduced hind limbs and sensory structures adapted to digging life. These ancestors are close to the basal groups of modern snakes in evolutionary position (such as the ancestors of the blind snake superfamily Scolecophidia), laying the morphological and ecological foundation for the subsequent evolutionary radiation of snakes.

2.2 Fossil evidence

The origin of snakes has always been the focus of evolutionary biology and paleontology. Through fossil records and phylogenetic studies, scientists have gained important insights into the early evolutionary history of snakes in recent years (Klein et al., 2021; Macrì et al. 2023). Current evidence suggests that snakes originated from a lizard-like ancestor in the Mesozoic Era. As early as the turn of the Jurassic and Cretaceous periods, reptiles close to snakes appeared. For example, fossils such as Eophis from the Middle Jurassic found in Oxford, England, may represent early members of the snake evolutionary branch (although its snake-like attributes are still controversial).

The earliest confirmed snake fossil records come from the Cretaceous, such as the Najash fossils from the Late Cretaceous in Patagonia, Argentina (Garberoglio et al., 2019). Najash preserves the hind limb bones and is a genus of ancient snakes with two hind legs, reflecting the transitional characteristics of snakes from four-legged lizards to footless forms. The skull morphology of Najash and other fossils also shows that their skulls are between typical lizards and modern snakes, revealing the evolutionary starting point of key features of the skull of modern snakes (such as extremely flexible mandibles and skull base connections). These fossil evidences support that snakes originated from terrestrial lizards rather than marine monitors as traditionally believed: the skeletal morphology and sedimentary environment of Najash indicate that it lived in burrows on land rather than in water.

2.3 Molecular phylogenetic evidence

In addition to burrowing characteristics, the most striking evolutionary innovation of snakes is the elongation of the body and the disappearance of limbs. The body of snakes is composed of more than 200 vertebrae, far more than the number of ordinary lizards, and the front and rear limbs have degenerated and disappeared to varying degrees. The genetic developmental basis of limb degeneration is an important research topic. Molecular developmental biology studies have shown that key gene regulatory regions that control limb development have functional loss or mutations in snakes. For example, studies have shown that the regulatory elements of the Sonic hedgehog signaling pathway are lost in snake embryos, resulting in the cessation of embryonic limb bud development (Peng et al., 2023). Ovchinnikov et al. (2023) compared the genomes of snakes and limbless amphibians (caecilians) and found that both had convergent genetic changes in genes related to limb development. For example, the regulatory regions of the HOX gene cluster showed significant traces of selective pressure. These molecular evidences are consistent with the fossil record, indicating that snakes achieved extreme body lengthening and the disappearance of limbs through changes in regulatory genes in the early stages of evolution, allowing them to move freely in underground caves and narrow crevices.

3 Global Geographical Diffusion of Snakes

3.1 Methods for reconstructing the history of geographical diffusion

The geographical diffusion of snakes in geological history is closely related to continental drift and climate change. Modern snakes are distributed almost all over the tropical and temperate land in the world, and only polar regions, high-altitude cold regions and some oceanic islands lack native snakes. This global diffusion pattern is the result of multiple cross-continental migrations and dispersions of snakes during their evolution (Klein et al., 2021). Studies have shown that the main evolutionary lineages of snakes underwent a key radiation and diffusion at the turn of the Mesozoic and Cenozoic eras. In particular, the mass extinction event at the end of the Cretaceous (about 66 million years ago) had a profound impact on the geographical diffusion of snakes.

As Klein et al. (2021) proposed in a comprehensive analysis of fossil and molecular data, the few snake ancestors that survived the K-Pg extinction event quickly differentiated into multiple major lineages and expanded using the ecological space vacated by the extinction of dinosaurs. It is estimated that all living snakes can be traced back to less than five ancestral populations that survived at that time. These ancestors may have been distributed on the remnants of Gondwana in the southern hemisphere, especially in ancient South America or Africa (because fossil evidence such as Najash came from South America, and the current diversity of basal groups such as blind snakes is higher in Africa and South America). In the post-disaster environment, the surviving snakes survived the crisis by relying on their ability to hide for a long time and endure hunger. Subsequently, snakes entered a period of rapid radiation expansion: during the Paleocene-Eocene (about 65~50 million years ago), multiple branches of snakes appeared almost synchronously in different regions of the world and colonized new ecosystems.

3.2 Overview of the radiation history of snakes on various continents

A significant milestone in the geographical spread of snakes was the first colonization of the Asian continent. According to Klein et al. (2021), the ancestors of snakes originated in the Southern Hemisphere, but first spread into Asia in the early Paleogene. Asia experienced tropical climate expansion and island chain connection during the Paleocene-Eocene, providing corridors for snakes to migrate across the ocean. Once entering the Asian continent, snakes experienced a new round of diversification, especially the rapid rise of advanced snakes (Colubroidea) in Asia. Advanced snakes include Colubridae, Elapidae, Viperidae, etc., which are the most species-rich and widely distributed snake group today. Molecular clock research supports that advanced snakes may have originated in Asia in the Eocene and then spread to Eurasia and Africa. For example, some of the earliest fossil records of Elapidae and Viperidae are from Asian strata, suggesting that these highly venomous snakes appeared in Asia earlier than in other regions. Colubridae (Colubridae), the largest living snake family, has its diversity center in Southeast Asia. It is believed that it also originated and radiated mainly in the warm regions of Asia, and then some members entered Africa, Europe and America through land bridges.

Another important event in the history of snake dispersal was the global climate cooling and land bridge formation that occurred from the end of the Eocene to the Oligocene (about 40 million years ago). During the Oligocene, Africa and Eurasia were connected, and Asia and North America were connected through the Bering Land Bridge, creating conditions for the spread of snakes in the Northern Hemisphere. Some ancient groups, such as members of the Boidae family, may have spread through Eurasia to the Americas during this period. There is also evidence that the ancestors of the Viperidae family entered North America through the Northern Route during the Oligocene (fossil records support that the earliest vipers in North America can be traced back to the late Oligocene). In the Neogene, North and South America were connected after the formation of the Isthmus of Panama, and snakes also achieved two-way exchanges between the two Americas. For example, the American rattlesnakes and the East Asian pit vipers are closely related, which may reflect the exchanges through the Bering Road during the Miocene (Title et al., 2024). In contrast, some South American endemic groups, such as the Aniliidae family, have long been confined to the South American continent left by Gondwana, and have been deeply differentiated from the northern hemisphere groups.

3.3 Sea snakes and marine diffusion mechanisms

In addition to spreading through land bridges, the ocean also plays an important role as a channel for snakes to spread. Snakes have evolved marine lifestyles independently many times, and the Hydrophiinae is a branch that is fully adapted to the marine environment (Ludington et al., 2023). Molecular systematic studies show that sea snakes originated from terrestrial cobras near the coast of Australia around the middle Miocene (about 15 million years ago) (Simões et al., 2020). Since then, sea snakes have rapidly spread to the warm waters of the entire Indo-Pacific. Because sea snakes are viviparous and can stay away from land for their entire lives, they have successfully crossed the vast ocean and reached the waters near oceanic islands far away from the continent. This mode of diffusion makes sea snakes one of the most widely distributed reptile groups, and sea snakes are even found near isolated archipelagos in the Pacific Ocean. Similarly, some snakes that live in freshwater and coastal environments (such as the Homalopsidae in Southeast Asia) have also spread into new areas through rivers and coasts. It can be seen that waterway diffusion has made a certain contribution to the formation of the global distribution of snakes.

4 Ecological Adaptation Evolution of Snakes

4.1 Diversified evolution of body shape and movement modes

Snakes show diverse adaptability in movement and habitat. The fact that snakes can move efficiently despite completely losing their limbs is itself a great feat of adaptation. Different snakes have evolved diverse movement modes according to their habitats: for example, ground-dwelling species such as colubrids achieve rapid crawling by bending in an "S" shape; burrowing species such as blind snakes adapt to underground life by creeping and burrowing, with smooth bodies and wedge-shaped heads, which facilitate movement through the soil (Cabral et al., 2022). In desert environments, some species of the genus Crotalus (such as the horned rattlesnake) have evolved "sidewind" movement, where the body contacts the ground at a specific angle and slides rapidly sideways to avoid burns from the hot sand surface. This is a behavioral adaptation to soft, hot sand dunes.

Arboreal snakes require different movement abilities. For example, arboreal flying snakes (genus Chrysopelea) can flatten their bodies and glide from the tree canopy to the ground, making them one of the few snakes with gliding adaptations. Studies have shown that flying snakes continuously twist their bodies in a wave-like manner while gliding to increase aerodynamic stability (Gong et al., 2022). The aerodynamic model study by Jafari et al. (2017) showed that this "swimming in the air" of flying snakes can effectively prevent stalling and increase the gliding distance. It can be seen that although snakes have lost their limbs, they have successfully adapted to various ecological spaces from underground, ground to trees through the diversified evolution of body morphology and movement patterns.

4.2 Evolution of sensory systems and predation strategies

A core theme of the evolution of ecological adaptation of snakes is the evolution of predation and feeding methods. Compared with lizards, snakes have made major breakthroughs in feeding adaptation: the highly movable skull and mandibular joints enable them to swallow prey that is several times larger than their own diameter (Title et al., 2024). In addition, snakes have greatly expanded the limits of lizards in terms of hunting skills and prey spectrum because their limbless bodies can wrap around prey or enter small spaces (Ballell et al., 2024). For example, pythons and anacondas have evolved powerful wrapping forces to strangle large prey, while cobras, vipers, etc. have evolved fangs and venom to quickly subdue and digest prey. The evolution of these predatory adaptations is considered to be one of the important driving forces for the successful radiation of snakes (Barua and Mikheyev, 2020).

The sensory and communication functions of snakes have also undergone significant adaptive evolution to meet the needs of orientation, foraging and avoiding enemies in different environments. In terms of vision, most snakes have evolved a visual system that is sensitive to low light and high contrast to improve their ability to move at night, while sacrificing some color resolution capabilities (Katti et al., 2018). Interestingly, however, some aquatic or nocturnal snakes have increased their sensitivity to specific wavelengths. For example, studies have found that the visual proteins that sense blue and green light in the retina of sea snakes have undergone frequency shift mutations, allowing them to effectively identify prey and predators in the blue-dominated seawater light environment (Rossetto et al., 2023; Rossetto et al., 2024). On the other hand, some snakes have special infrared thermal imaging capabilities. For example, the rattlesnakes of the Viperidae family and the anacondas of the Python family have heat-sensing organs "cheek pits" in their snouts, which can detect tiny infrared radiation in the environment.

4.3 Habitat selection and niche evolution

In ecological adaptive evolution, snakes have also made changes in reproduction and life history in response to different environments. For example, many snakes living in high latitudes and high altitudes have evolved ovoviviparity or viviparity to adapt to cold climates. This transformation is believed to be beneficial for the embryo to obtain a more stable temperature development in the mother's body, thereby breaking the adverse effects of the cold environment on the incubation of eggs outside (Domínguez-Guerrero et al., 2024). In special environments such as tropical islands, some snakes have evolved parthenogenesis (reproduction without mating). A typical example is the flowerpot snake (Indotyphlops braminus), a triploid parthenogenetic species that has spread around the world through plant trade.

Snakes have also evolved some defensive adaptations in morphology, color, and behavior. For example, many non-venomous snakes confuse predators by imitating the body color patterns of venomous snakes (mimicry); some vibrate their tail scales to make sounds to simulate rattlesnakes to warn natural enemies. These adaptations increase their survival probability and are a model of the co-evolution of behavior and morphology under natural selection. In terms of color adaptation, new research has found that some snakes have ultraviolet reflective patterns that are invisible to the human eye, which may be related to ecological habits (Figure 2) (Crowell et al., 2024).

5 Molecular Basis of Adaptive Evolution

5.1 Progress in genome research

In recent years, with the release of high-quality snake reference genomes, scientists have been able to more fully understand the genetic basis of their adaptive evolution. For example, Peng et al. (2023) compared the whole genomes of 14 snake species from 12 families and revealed that multiple structural variations were directly related to limb degeneration. Specifically, key regulatory elements that control forelimb development (such as ZRS) mutate in snakes such as pythons, which cannot activate the Sonic hedgehog gene, resulting in stunted limb development. The relationship between this molecular mechanism and morphological characteristics provides a classic case for studying vertebrate evolution.

In addition, Ovchinnikov et al. (2023) compared the HOX gene regulatory regions of snakes and another type of limbless amphibian, caecilians, and found the presence of convergent evolutionary features. This molecular convergence emphasizes that similar genetic mechanisms can independently produce similar adaptive phenotypes in different lineages, which is strong evidence of convergent evolution at the genome level.

5.2 Functional exploration of adaptive genes

Snakes are particularly adaptable to extreme environments in their sensory, digestive and toxic systems. Taking the visual system as an example, many burrowing or nocturnal snakes have lost some cone cell function-related genes, thereby gaining stronger night vision (Simões et al., 2020). The LWS gene in sea snakes has undergone a wavelength shift mutation, making it more adaptable to the marine environment of blue-green light. The infrared sensing ability has evolved through the expression regulation of the TRPA1 gene. In snakes with infrared perception ability such as vipers and pythons, this gene has undergone changes such as enhanced temperature sensitivity and specific expression in the trigeminal nerve, becoming one of their predatory weapons.

In terms of the venom system, snake venom is composed of a variety of toxin proteins, most of which are derived from the replication and functional remodeling of non-toxic physiological genes. For example, protein families such as PLA2 and SVMP have expanded and mutated to form new toxic functions (Casewell et al., 2020). Barua and Mikheyev (2020) further found that these toxin genes have a "gear shift" phenomenon at the expression level, that is, rapid changes in expression magnitude and type in different lineages are one of the strategies to adapt to different prey types.

In addition, the metabolic system of snakes also shows amazing plasticity. The "metabolic storm" phenomenon in which the organs of Burmese pythons rapidly expand and the metabolic rate soars in a short period of time after feeding is the result of rapid response of gene expression. Castoe et al. (2013) found that its liver, small intestine and other tissues upregulated metabolism-related genes on a large scale within 24 hours after feeding, forming the molecular basis of extreme digestive adaptation.

5.3 Epigenetics and gene regulation mechanisms

In the adaptive evolution of snakes, gene expression regulation plays a core role. The expression variation of venom genes not only depends on the sequence changes of the coding region, but is also closely related to the variation of regulatory regions such as promoters and enhancers. Mason et al. (2022) pointed out in the transcriptome analysis of venom glands of 52 pit vipers that the expression profiles of toxin genes in different lineages were significantly different and closely related to their main prey species, reflecting that the venom system has achieved rapid evolution through epigenetic regulation in dietary adaptation.

In addition, snakes' responses to environmental pressures also show characteristics at the epigenetic level. For example, small populations of rattlesnakes have reduced functional genetic variation reserves due to decreased neutral genetic diversity, which may limit their ability to respond to environmental changes (Mathur et al., 2023). This reduction in variation is not only reflected at the SNP level, but may also affect the diversity of regulatory elements.

From a macro perspective, those snake lineages that survived and expanded rapidly during dramatic changes in geological history tend to have higher genetic diversity and regulatory resilience. Grundler and Rabosky (2021) pointed out that this genetic background helps them quickly evolve new adaptive traits in new niches, indicating that the plasticity of gene regulation may be the key to species adaptability.

6 Case Studies of Ecological Adaptive Evolution of Snakes

6.1 Evolutionary adaptation of snakes in the marine environment

The ocean was once considered a restricted area for reptiles, but the emergence of sea snakes broke this stereotype. Sea snakes (mainly members of the subfamily of the family Cobra) are fully adapted to marine life and have evolved a series of morphological and physiological characteristics to cope with marine ecology. For example, the body of sea snakes is flattened laterally and the tail is flat like a paddle, which is convenient for efficient swimming in the water; the nostrils have valves that can be closed to block water when diving; the skin can tolerate high salt and is permeable to a certain extent, allowing it to directly absorb rainwater through the skin for drinking in the sea where fresh water is scarce (Crowe-Riddell et al., 2019a). Even more peculiar is that some sea snakes have photoreceptors in the skin of their heads that can sense changes in light - studies have found that the tail skin of some rose sea snakes has behavioral responses to light stimulation, which is believed to help avoid being preyed on when the tail is exposed to the water (Figure 3) (Crowe-Riddell et al., 2019b).

In addition, sea snakes have changed from oviparous to viviparous to get rid of their dependence on landing to lay eggs, so that they can almost never leave the seawater environment throughout their lives. From a molecular perspective, as mentioned above, sea snakes have made adjustments to their vision and blood physiology to adapt to the ocean. Peng et al. (2020) provided a comprehensive perspective on the sea snake genome: the study sequenced the chromosome-level genome of the smooth short-tailed sea snake (Hydrophis curtus) and identified genetic adaptive changes related to marine life, such as genes that control skin ion permeability and metabolic genes required for long diving. Unique amino acid substitutions or expansions.

6.2 Snake adaptation in arid desert environments

Deserts and semi-deserts have extreme environments (high temperatures, lack of water, sparse shelters), but many snakes still thrive here and have evolved special adaptations to cope with challenges. Take desert vipers and rattlesnakes in North America and Africa as examples. They often use "sidewinding" to move on hot and soft sand. This movement mode allows the snake's body to touch the ground with the minimum contact surface, leaving two parallel sliding traces alternately, thereby effectively reducing the heat conduction between the body and the hot sand surface, while avoiding sinking into the sand (Cabral et al., 2022). Desert snakes also face the problem of extreme water shortage. Many desert snakes reduce water loss through behavioral adjustments (such as hiding in cool caves during the day and moving at night). At the same time, the waste produced by their metabolism is mainly crystalline uric acid rather than liquid urine, in order to save water to the maximum extent.

Another challenge in arid environments is the lack of hiding places. Snakes are often exposed on the vast surface and are easily targeted by natural enemies. In response, some desert snakes have evolved efficient camouflage and defense strategies. For example, the body color patterns of the African side-striped viper (Bitis caudalis) blend into the gravel background. Its habit is to quickly bury itself in the sand with only its eyes exposed to alert, which prevents water evaporation and avoids the sight of predators (Valkonen et al., 2020). In addition, many rattlesnakes have evolved distinctive black and white ringed tails in the desert. When they vibrate their tails to make a sound, the tail rings also form a visual warning, and the double signal deters predators. It is worth mentioning that snakes such as the North American king snake (Lampropeltis genus) have evolved anti-venom capabilities in desert-semi-desert areas, and can prey on venomous snakes without being affected by their venom (Harris and Fry, 2021).

6.3 Snake adaptation in the forest canopy environment

The canopy and understory of tropical rainforests provide arboreal snakes with diverse ecological opportunities and have also spawned a series of morphological and sensory evolutions. Arboreal snakes tend to have slender bodies, particularly long and muscular tails, so that they can wrap around branches to maintain balance (Cabral et al., 2022). For example, the Southeast Asian vine snake (Ahaetulla) has a body as thin as a vine and is extremely difficult to detect when it is motionless. Its tail can account for more than half of its total length, so it can wrap one end of its body tightly around a branch and stretch the other end freely to prey on lizards or frogs on the tree. The South Asian Chrysopelea can not only walk between branches, but also stretch its body flat and glide from a height of tens of meters (Yeaton et al., 2024).

The arboreal environment also affects the evolution of snake reproduction and color patterns. For example, many arboreal snakes have evolved to lay eggs in tree holes or plant leaf cups to take advantage of high humidity and safe hatching places. Some, such as arboreal pit vipers, have simply evolved to be viviparous, eliminating the trouble of protecting eggs in trees. In terms of color, arboreal snakes often have green protective colors to hide among branches and leaves, such as the green bamboo snake (Trimeresurus genus) with bright green body, perfectly blending into the background of leaves. These characteristics reflect the selection pressure of the arboreal environment: hiding from predators and ambushing prey. Recent studies on the evolution of snake color have further revealed the role of ultraviolet color in arboreal species. Crowell et al. (2024) found that the backs of arboreal snakes have stronger ultraviolet reflections, which may be used to maintain body temperature or communicate under the light filtered by the canopy, which is not obvious in ground-dwelling snakes.

7 Future Research Directions and Technology Outlook

7.1 Rich and accurate snake fossil records

Currently, known snake fossils are relatively rare and mostly scattered bones, which limits our understanding of the evolutionary path of snake morphology. In the future, it is necessary to find snake fossils in more regions and more strata around the world, especially in the critical period of the Cretaceous and early Paleogene. For example, the late Cretaceous blind snake fossils recently discovered in Brazil have pushed the snake fossil record forward by about 40 million years, filling a "fossil gap". At the same time, with the help of modern CT scanning and 3D reconstruction technology, the internal structure of existing fossils (such as Najash, Dinilysia, etc.) can be re-studied to extract information that was difficult to obtain in the past (such as brain cavity, inner ear, spinal cavity morphology). These works will finely depict the details of the transition of snakes from lizards to modern snakes, and answer some of the current controversies, such as the upper and lower jaw connection mechanism of the earliest snakes, the structure of vertebral joints, etc.

7.2 Large-scale genomic and developmental studies

At the molecular level, although the genomes of several snake species have been published, they are still insufficient compared with their species diversity (Peng et al., 2023; Xia et al., 2025). In the future, more representative snake genomes need to be sequenced, especially species covering different families and ecological types, to build a panoramic view of snake genome diversity. Combined with these genomic data, comparative genomics and population genomics methods can be used to deeply explore the genetic basis of adaptive traits in snakes. Furthermore, functional validation work can be carried out on model species - although it is still challenging to use snakes directly as experimental subjects due to the difficulty in breeding snakes, cells and model organisms can be used. In terms of developmental biology, embryonic materials at different developmental stages of snakes (some species that currently rely mainly on artificial breeding, such as pythons and colubrids), and single-cell sequencing, in situ hybridization and other technologies can be used to analyze how the developmental program of snakes is regulated during limb degeneration and body elongation.

7.3 Integrate macro-ecological and micro-genetic data

Snake adaptive evolution research is moving towards a comprehensive macro- and micro-direction. On the one hand, big data and modeling methods can be used to analyze the relationship between snake trait evolution and environmental factors at a macro scale. For example, a global snake trait database (body size, diet, reproductive mode, etc.) can be constructed, combined with climate and geological data, and scalable Bayesian models or machine learning methods can be applied to quantify the impact of environmental changes on the rate and direction of snake evolution (Grundler and Rabosky, 2021; Cabral et al., 2022). On the other hand, from a micro perspective, more genetic data at the level of wild populations are needed to understand the current status of snake adaptation. The affordable high-throughput sequencing allows the acquisition of genome/amplicon sequences of a large number of wild snake populations, and population genetics methods can be used to detect recent signs of natural selection. Such research will provide guidance for snake conservation, that is, identifying genetic bottlenecks that may limit their ability to adapt, as well as potential "gene rescue" targets.

7.4 Prospects in the field of bionics and medicine

The study of adaptive evolution of snakes also has interdisciplinary application potential. For example, snakes' limbless movement, infrared perception, and venom composition provide inspiration for bionic engineering and new drug development. Taking snake robots as an example, engineers imitated the muscle sequence contraction and scale-ground friction pattern of snakes to design rescue robots that can flexibly move through ruins and pipes. In-depth research on the dynamics of different snake movement modes can optimize the efficiency and stability of such robots. For example, snake venom is rich in active peptides and enzymes that have strong effects on specific physiological pathways, and is a "natural library" for drug development. For example, Casewell et al. (2020) pointed out in their review that different snake venoms show unique effects in antibacterial and analgesic aspects due to their adaptation to different prey, which provides an opportunity for the development of antibiotic substitutes and analgesics. In addition, the physiological characteristics of snakes that can fast for a long time and their digestive organs grow rapidly have also inspired the medical community to study metabolic regulation and organ regeneration mechanisms. In the future, scientists may be able to learn from the gene expression patterns of pythons and seek ways to promote rapid regeneration of human livers after injury.

Acknowledgments

We sincerely thank the two anonymous reviewers for their valuable opinions and suggestions.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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