SRLV Project Development Background
Small ruminant lentiviruses (SRLVs) are a group of viruses that infect sheep and goats, leading to chronic, lifelong diseases affecting multiple organ systems. These infections primarily spread through vertical transmission from mother to offspring via colostrum or milk, though horizontal transmission can also occur through close contact, respiratory secretions, or shared equipment—particularly in crowded conditions.
SRLVs comprise viruses initially thought to be separate species. Ovine maedi-visna virus (OMVV) was first isolated from sheep in Iceland in the 1950s. In 1974, a virus closely related to OMVV was isolated from a dairy goat in North America and named caprine arthritis-encephalitis virus (CAEV). It has since become clear that both viruses occur in both sheep and goats, and they are now considered two distinct genotypes (A and B, respectively) of a single virus species (SRLV).
SRLVs target cells of the immune system, particularly macrophages and dendritic cells, resulting in persistent viral replication and progressive tissue damage. Clinical signs often include pneumonia, wasting, polyarthritis, mastitis, and in severe cases, paralysis or organ failure, though many infected animals remain asymptomatic for years, with signs typically emerging after long incubation periods. Genetic factors contribute to variations in disease susceptibility and symptom severity among species and breeds.
Given the complexity and chronic nature of SRLV infections, molecular sequence analysis has become essential in understanding viral diversity, tracking transmission patterns, and informing control measures. Genomic studies enable the identification of viral strains and mutations, providing insight into how the virus adapts to host immune responses and persists within populations. Without a vaccine or effective treatment, control relies heavily on preventive strategies, including test-and-cull programs, managing colostrum sources, and enhancing biosecurity practices to limit transmission. The integration of molecular diagnostics, such as PCR, with traditional serological tests has improved the accuracy of detection, enabling more targeted efforts to contain outbreaks. These genomic approaches not only support research into SRLV origins and evolution but also aid in developing tailored genotyping tools that can refine herd management strategies, thereby mitigating economic losses associated with SRLV infections and improving animal health outcomes.
The SRLV extension layer of Lentivirus-GLUE was developed in the Gifford Lab as part of a study investigating the emergence and origins of SRLVs. Initial analysis of published SRLV sequence data led to the hypothesis that the two major SRLV genotypes (A and B) evolved in parallel with distinct small ruminant breeds and subpopulations across the Eastern and Western hemispheres. Specifically, it was proposed that A-like SRLV lineages evolved in Asia, while B-like lineages emerged in Europe.
Interestingly, SRLV-C, which is found only in primitive sheep breeds in Northwestern Europe, is B-like yet groups basally relative to other B-like lineages in molecular phylogenies. This observation suggests that SRLV-C may represent descendants of ancestral strains introduced to Europe during the early spread of agropastoralism.
The earliest domesticated sheep and goat breeds were primarily raised for meat rather than wool or milk. Remnant populations of these ancient breeds persist along Europe’s northwestern periphery, particularly in more isolated places such as Scotland's Outer Hebrides (top left). Primitive sheep breeds include the Spælsau, or Old Norwegian Short Tail Landrace (bottom left), the Soay sheep from the St Kilda archipelago (bottom right), and Orkney's Rothesay sheep, known for their unique seaweed diet (top right). Notably, populations of primitive small ruminants in Norway carry a distinctive lineage of SRLV, called SRLV-C, which may originate from strains that were introduced during the initial wave of Neolithic agropastoralism, along with primitive breeds.
The overall relationship between SRLV diversity and geographic regions is complex, having likely been shaped by recent as well as historical factors. For example, one clade B subtype, SRLV-B3, appears to be prevalent in parts of the Middle East, and may reflect secondary radiation of B-like lineages into Asia. Notably, subtype B1 occurs in China, but this seems likely to reflect recent livestock trade. Taking these nuances into account, the global distribution and diversity of SRLVs can be seen as consistent with an ancient A-B split, possibly corresponding to the divergence of 'fat-tailed' and 'thin-tailed' sheep breeds in Eurasia. This hypothesis has implications for the origins of SRLV-A in Europe, Africa, and North America because it is well documented that the emergence of SRLV-A associated disease in these areas occured after (and sometimes in direct association with) the introduction of 'fat-tailed' sheep breeds.
Karakul sheep are a fat-tailed breed indigenous to Central Asia, with archaeological evidence indicating they have been continuously raised in Uzbekistan (left) for over 3,000 years. In the early 20th century, there were limited exports of karakul sheep to Europe, Southern Africa, and North America, driven by demand for their pelts, prized for their unique, tightly curled and glossy texture (middle right). President Theodore Roosevelt personally intervened to enable imports to the United States, establishing a North American herd (bottom right). In Europe, a German karakul herd was founded in the late 19th century from animals imported from Uzbekistan, and individuals from this population were later exported to South West Africa by European colonists, where they became the foundation of a thriving pelt industry (middle left - the karakul statue in Keetmanshoop, Namibia). In the 1950s, the emergence of 'maedi-visna' in Icelandic sheep (top right) was linked to the import of OMVV-infected karakul rams from Germany, two decades earlier. Similar diseases, now understood to be caused by SRLVs, emerged concurrently in other region where, a few decades earlier, karakul had been introduced, including mainland Europe, South Africa and North America.
In 2012, the Gifford Lab sampled SRLV diversity in the Lebanon, revealing a high diversity of SRLV strains in the Levant region. While this study provided valuable insights, it was inconclusive regarding the ancient origins of SRLV genotypes. The presence of basal SRLV-A lineages across the Levant (established by our study and others), and the grouping of these strains with isolates from China, are all consistent with a Western Eurasian origin for SRLV-A. Presently, however, alternative explanations remain plausible. A more comprehensive sampling of SRLV diversity - particularly in Central Asia will likely be required to elucidate the relationship between small ruminant breed dispersal and SRLV diversity. Such research could clarify whether the ancestral distribution of SRLV genotypes in Eurasia reflects an ancient East-West division, thereby enabling assessment of the hypothesis that the mid-20th-century export of Central Asian karakul sheep contributed to the emergence of SRLV-associated diseases among East Eurasian breeds.
Sampling SRLV diversity in Lebanon, 2012. The aim was investigate SRLV diversity in the regions where small ruminant domestication is thought to have originally occurred.
The SRLV extension of Lentivirus-GLUE represents an open, innovative approach to investigating viral origins and emergence, in which the diverse datasets crucial for these analyses are integrated into an extensible framework. As with all GLUE resources, the SRLV extension combines sequence data, annotations, metadata, alignments, and phylogenies to create a platform for comprehensive, reproducible analyses. In cases where competing hypotheses about origin and emergence exist, this platform supports transparent hypothesis testing, facilitated by version-controlled, documented workflows. By adhering to data-oriented principles that safeguard original data integrity, GLUE projects support both independent analysis outside the platform and collaborative investigations using GLUE’s integrated tools. Hosting on GitHub (or similar version control systems) further enhances transparency and facilitates collaborative research management. This adaptable model can be applied to other viruses with unresolved origins, offering a standardized yet flexible approach for evaluating competing hypotheses and fostering collective scientific insight.
In SRLV research, robust genotyping tools are essential for tracking viral evolution, understanding geographic and host-specific distribution, and supporting disease control efforts. Accurate genotyping enables researchers and veterinarians to classify SRLVs into distinct lineages, facilitating monitoring of specific strains within and between populations. Such tools are critical for assessing how SRLV genotypes relate to disease severity, transmission dynamics, and host adaptations.
To address this need, the GLUE framework facilitated the development of a genotyping tool based on Maximum Likelihood Clade Assignment (MLCA). This method efficiently assigns SRLV sequences to predefined genotypes using evolutionary placement. MLCA employs the Evolutionary Placement Algorithm (EPA) within RAxML to place new sequences onto a reference phylogenetic tree, enabling accurate clade assignments without recalculating the entire tree. This approach allows for rapid classification of SRLV sequences into established genotypes, enhancing the study of viral diversity and lineage tracking across regions and host populations.
Please note that genotype assignments are currently limited to SRLV genotypes and subtypes represented by at least one genome-length sequence and that form robust, monophyletic clades in phylogenies reconstructed from genome-length alignments. These lineages include:
- Genotype A: A0, A1, A3, A4, A8, A18
- Genotype B: B1, B2, B3
- Genotype C (Regarded as a subtype of genotype B)
- Genotype E: E1, E2
The SRLV genotyping tool was developed by repurposing an SRLV sequence dataset initially collected to investigate viral origins and emergence (see above). This reflects GLUE's foundational premise: genomics datasets can be shared and reused across distinct analytical contexts, maximizing the utility of genomics data and supporting comprehensive investigations into SRLV diversity and evolution.