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Study Explores Genetics of Sleeping Sickness Susceptibility in African Cattle

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Researchers have cobbled together clues about the genetic shifts that have left some African cattle breeds better equipped to deal with infection by the parasites that cause African sleeping sickness in humans and wasting disease in cattle.

In a paper set to appear online this week in the Proceedings of the National Academy of Sciences, an international team led by investigators in the UK and Kenya used a combination of gene expression profiling and transcriptome and targeted gene sequencing to characterize African cattle breeds that are sensitive or relatively resistant to Trypanosoma congolense infection. The search yielded two genes that appear to have undergone trypanosomiasis-related selective sweeps: TICAM1 and ARHGAP15.

"The two genes discovered in this research could provide a way for cattle breeders to identify the animals that are best at resisting disease when infected with the causative trypanosome parasites, which are transmitted to animals and people by the bite of infected tsetse flies," senior author Steve Kemp, a geneticist affiliated with the University of Liverpool and the International Livestock Research Institute in Nairobi, said in a statement.

Trypanosoma parasites such as T. brucei, T. vivax, and T. congolense spread from one animal to the next via tsetse flies. Some breeds of cattle in sub-Saharan Africa are more resistant to trypanosomiasis than others, researchers explained. But Trypanosoma parasites still have devastating effects on African agriculture, weakening or killing cattle that would otherwise be used to plow, transport cargo, or produce milk.

"Trypanotolerance is an economically important trait of great biological interest," the team wrote, "and an understanding of its mechanisms has the potential to transform cattle-keeping in tsetse-affected areas of Africa."

For the current study, researchers focused mainly on cattle from two breeds: the humpless West African Bos taurus breed N'Dama, which is relatively resistant to trypanosome infections, and the humped, zebu (Bos indicus) breed Boran, which was introduced to the region more recently. While Boran and other humped cattle tend to be larger, more docile, and produce more milk than N'Dama, researchers noted, they are also much more prone to trypanosomiasis.

Consequently, there is interest in identifying the genetic basis of N'Dama tolerance to trypanosomes so that this trypanotolerance can be introduced to Boran and other breeds.

"Development of breeds of trypanotolerant cattle that are better adapted to the diverse needs of African farmers could substantially improve productivity in the whole agricultural system," researchers explained.

In an effort to understand trypanotolerance, the team first sorted through sequence data generated on expressed sequence tag libraries made from liver, spleen, lymph node, and bone marrow samples from three N'Dama and three Boran animals infected with T. congolense.

By looking for non-synonymous variants in QTL regions previously identified through N'Dama and Boran breed crosses, they narrowed in on the Rho GTPase-activating protein 15 gene ARHGAP15, which contained a non-synonymous SNP as well as two synonymous variants.

The team then used Affymetrix Bovine Genome arrays to assess gene expression patterns in liver, spleen, and lymph node samples cattle from N'Dama and Boran cattle before T. congolense infection, 21 days after infection, and 35 days after infection, assessing 25 animals from each breed overall.

Among the genes that were up regulated in cattle exposed to trypanosomes were a slew of genes from immune system pathways — particularly the natural killer cell-mediated toxicity pathway. Genes in the MAP kinase signaling pathway, which tends to be active in natural killer cells, were also up-regulated in both breeds following infection, researchers reported.

Although the expression of genes in the MAP kinase pathway bumped up in both N'Dama and Boran cattle that were infected with T. congolense, genes in this pathway were also differentially expressed in lymph node samples from the two breeds.

That hints that the pathway may not only be important to infection response, but might also account for some of the susceptibility differences seen in humped and humpless cattle.

"The presence of the MAPK pathway in the list of pathways associated with differentially expressed genes as well as the pathways associated with responding genes emphasizes its potential importance," the authors wrote.

Signaling genes again turned up when the team looked for signals of selection in the African and other cattle. For instance, using data collected by the Bovine SNP consortium, the team found evidence for positive selection on ARHGAP15 in N'Dama cattle and cattle from an East African breed known as Sheko, which seems to share many alleles with humped cattle.

A second gene in the QTL region, the Toll-like receptor pathway gene TICAM1, did not show signals of selection in Sheko cattle. Nevertheless, when researchers did targeted sequencing of TICAM1 and nearby non-coding sequences in dozens of cattle from several African, European, and Indian breeds and in plains bison, as an outgroup, they found two distinct TICAM1 haplotypes, with African B. taurus cattle carrying more derived alleles that may reflect longer exposures to trypanosome parasites.

"[B]oth ARHGAP15 and TICAM1 appear to have functional polymorphisms that could affect the response to infection and are associated with signatures of selection," the team concluded. "This is persuasive evidence that these genes are QTL genes, but definitive proof of their role in determining trypanotolerance status must await either a transgenic approach or a breeding program, which exploits them and in the process identifies recombinants."

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