Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed

Natural or artificial selection targets the genome in response to environmental pressures or stresses as shaping adaptation and evolution.

“The rationale is that natural or artificial selection targets the genome in response to environmental pressures or stresses as shaping adaptation and evolution.”

• cites Charlesworth, 2007 sourcePartly supported

  The main text (page not supplied) describes favourable mutations spreading through populations and changing genomic variability. It also gives malaria protection as an example and links hitchhiking to adaptation in bacterial genomes. It does not address artificial selection or establish the broader claim about environmental pressures or stresses generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Under positive selection, strong and long range linkage disequilibrium and unexpectedly high local haplotype homozygosity might occur in the genome.

“Under positive selection, strong and long range linkage disequilibrium (LD) and unexpectedly high local haplotype homozygosity might occur in the genome (Gautier and Vitalis, 2012; Bomba et al., 2015).”

• cites Gautier and Vitalis, 2012 sourceNot checked — no full text of the source
• cites Bomba et al., 2015 sourceSupported

If a new allele of a mutation is beneficial under certain environmental pressure or stress, then the frequency of these alleles will rapidly increase in the population.

“This implies that if the new allele of a mutation is beneficial (increases the fitness of their carriers) under certain environmental pressure or stress, then the frequency of these alleles will rapidly increase in the population (Charlesworth, 2007).”

• cites Charlesworth, 2007 sourcePartly supported

  In the main text (page unavailable), Charlesworth describes a favourable mutation spreading through a population and potentially reaching fixation. The paper does not establish that its frequency will increase rapidly under environmental pressure or stress; it also discusses favourable mutations that remain segregating rather than reaching fixation. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

K=2 highlights best the ancient divergence between indicine and taurine cattle.

“Consistent with the previous findings and the origins of the genetic backgrounds of the cattle breeds worldwide (Mbole-Kariuki et al., 2014; Bahbahani et al., 2018), K = 2 highlights best the ancient divergence between indicine and taurine cattle.”

• cites Mbole-Kariuki et al., 2014 sourceSupported
• cites Bahbahani et al., 2018 sourceSupported

Mutations in the ERN1 and CAPG genes are associated with neurological dysfunction.

“Therefore, mutations in the ERN1 and CAPG genes are associated with neurological dysfunction (Liao et al., 2009; Minchenko et al., 2015).”

• cites Liao et al., 2009 sourceNot checked — no full text of the source
• cites Minchenko et al., 2015 sourceCould not verify

  The Results and discussion section studies a dominant-negative ERN1 mutant in U87 glioma cells and its effects on gene expression. Our copy does not address CAPG or associate mutations in either gene with neurological dysfunction (searched: CAPG, mutations, neurological dysfunction). (LLM, conf=0.74)

  Experimental — accuracy not yet measured

The candidate signature gene RAET1G is one of the few genes that could encode a ligand recognized by NKG2D proteins in response to stress and infections.

“Remarkably, the candidate signature gene RAET1G is one of the few genes that could encode a ligand recognized by NKG2D proteins in response to stress and infections (Eagle and Trowsdale, 2007; Tomasec et al., 2007; Lanier, 2015).”

• cites Eagle and Trowsdale, 2007 sourceNot checked — no full text of the source
• cites Tomasec et al., 2007 sourceSupported
• cites Lanier, 2015 sourceSupported

The ERN1 and CAPG genes might also be involved in the innate immune response since hypoxia triggers innate immunity responses through the activation of HIF-1α.

“The ERN1 and CAPG genes might also be involved in the innate immune response since hypoxia triggers innate immunity responses through the activation of the hypoxia induced factor α1 (HIF-1α) (Oosthuyse et al., 2001; Rius et al., 2008; Singh et al., 2016).”

• cites Oosthuyse et al., 2001 sourceNot checked — no full text of the source
• cites Rius et al., 2008 sourcePartly supported

  In the main text (page unavailable), Rius et al. report that hypoxia promotes HIF-1α accumulation and that the hypoxic response supports macrophages and neutrophils in infected tissue. They also describe HIF-1α as *suggested* to promote inflammatory cytokine expression in stimulated macrophages. This supports a link between hypoxia, HIF-1α and innate immunity, but not the broader assertion that hypoxia itself triggers innate immune responses through HIF-1α. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Singh et al., 2016 sourceNot checked — no full text of the source

The ERN1 and CAPG genes are involved in the regulation of hypoxia.

“The endoplasmic reticulum to nucleus signaling 1 (ERN1) and capping protein gelsolin-like (CAPG) genes are involved in the regulation of hypoxia (a state of a cell with inadequate or reduced oxygen availability) (Leach and Treacher, 1998).”

• cites Leach and Treacher, 1998 sourceCould not verify

  The “When is a tissue hypoxic?” section discusses cellular responses to low oxygen, but does not identify ERN1 or CAPG as regulators. Searches for both gene names and their expanded names found no passage addressing their role in hypoxia. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Reduction of the hypoxic response element in the spinal cord results in the progressive degradation of the motor neuron.

“The reduction of the hypoxic response element in the spinal cord results in the progressive degradation of the motor neuron (Oosthuyse et al., 2001; Minchenko et al., 2015).”

• cites Oosthuyse et al., 2001 sourceNot checked — no full text of the source
• cites Minchenko et al., 2015 sourceCould not verify

  The Results and discussion (page unavailable) examine hypoxic regulation of gene expression in U87 glioma cells, not the spinal cord or motor neurons. Searches for a spinal-cord hypoxic response element and progressive motor-neuron degeneration found no passage addressing the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

The E2F network as well as the Cdk1 and Cdk2 related pathways are associated with anemia, the most prominent and consistent clinical sign of trypanosome infection.

“The E2F network as well as the Cdk1 and Cdk2 related pathways are also associated with anemia which is the most prominent and consistent clinical sign of trypanosome infection (Kaminski et al., 2001; Dimova and Dyson, 2005; Noyes et al., 2011, Hu and Sun, 2016).”

• cites Kaminski et al., 2001 sourceNot checked — no full text of the source
• cites Dimova and Dyson, 2005 sourceNot checked — no full text of the source
• cites Noyes et al., 2011 sourcePartly supported

  The paper’s introductory section states that anemia is the most prominent and consistent clinical sign of infection. It does not link the E2F network or Cdk1/Cdk2-related pathways to anemia; its pathway table instead identifies other pathways and cell-cycle genes associated with anemia-related QTL. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

Rsb is a powerful method to detect selection signature when the selected allele has reached fixation.

“in agreement with Rsb being a powerful method to detect selection signature when the selected allele has reached fixation (Tang et al., 2007; Oleksyk et al., 2010; Bahbahani et al., 2018).”

• cites Tang et al., 2007 sourceSupported
• cites Oleksyk et al., 2010 sourceCould not verify

  The Extended linkage disequilibrium segments section discusses haplotype-based tests for detecting selection, but does not identify Rsb or assess its power when an allele has reached fixation. Searches for “Rsb,” “fixation,” and fixed sweeps found no passage addressing that specific claim; the section instead describes LD tests as most useful for recent, incomplete sweeps. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites Bahbahani et al., 2018 sourcePartly supported

  The Methods section uses Rsb to detect signatures of positive selection, and the Discussion contrasts it with iHS, which the authors say is weak at detecting haplotypes approaching fixation. The paper does not establish that Rsb is powerful when a selected allele has reached fixation; it also notes that Rsb cannot detect selection when the same region is under selection in both populations compared. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

The PSMD7 gene plays a critical role in the development of adaptive immunity or tolerance.

“This gene plays a critical role in the development of adaptive immunity or tolerance (Doolan and Hoffman, 1999).”

• cites Doolan and Hoffman, 1999 sourceCould not verify

  The section “IL-12 is required for P. yoelii sporozoite-induced protective immunity” (page not provided) assigns a critical role in the adaptive response to IL-12, not PSMD7. Searches for PSMD7 and immune tolerance found no passage in our copy addressing a role for that gene. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

The PSMD7 gene is involved in the processes of presenting antigens by the major histocompatibility complex (MHC) class I proteins to CD8+ T-lymphocytes.

“This gene is involved in the processes of presenting antigens by the major histocompatibility complex (MHC) class I proteins to CD8+ T-lymphocytes (Morrot and Zavala, 2004; Goldszmid and Sher, 2010; Jordan and Hunter, 2010).”

• cites Morrot and Zavala, 2004 sourceNot checked — no full text of the source
• cites Goldszmid and Sher, 2010 sourcePartly supported

  The 'Antigen presentation on MHC class I' section describes parasite antigens entering the class I pathway and eliciting CD8 T-cell responses (page not provided). But our copy does not mention PSMD7 or establish that this gene participates in that process; a search for PSMD7 found no matching passage. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Jordan and Hunter, 2010 sourcePartly supported

  The “Antigen Presentation During Parasite Infection” section states that CD8+ T cells recognize antigen presented in the context of MHC class I. It does not identify PSMD7 or establish that this gene participates in the process, so the gene-specific part of the claim is unsupported. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

The AP1M1 gene is a member of the adapter protein complex which is involved in thyroid abnormalities.

“Most importantly, the AP1M1 gene is a member of the adapter protein complex which is involved in thyroid abnormalities (Johnson et al., 2016).”

• cites Johnson et al., 2016 sourceSupported

This could be controlled by suppressing the development of auto-reactive immune cells through ubiquitination which is a degradative tag to be recognized by a proteasome complex such as PSMD7.

“This could be controlled by suppressing the development of auto-reactive immune cells through ubiquitination which is a degradative tag to be recognized by a proteasome complex such as PSMD7 (Lodish et al., 2004; Zinngrebe et al., 2014).”

• cites Lodish et al., 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zinngrebe et al., 2014 sourcePartly supported

  The ‘Ubiquitin in autoimmunity and autoinflammation’ section says ubiquitination is implicated in suppressing the development of autoreactive immune cells. The ‘Ubiquitin and ubiquitination’ section says some ubiquitin chains mark proteins for degradation, but the passages do not identify PSMD7 as the proteasome component involved or establish that degradation is the mechanism of that suppression. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Sheko, Nganda, Ankole, and Nuer are positioned between the African taurine and the African indicine clusters.

“Moreover, the Sheko, Nganda, Ankole, and Nuer are positioned between the African taurine and the African indicine clusters.”

At K=2, the two ancestries taurine and indicine are revealed.

“At K = 2, the two ancestries taurine and indicine are revealed.”

At K=3, Ankole, Nuer and Sheko show genetic heterogeneity with a considerable level of taurine admixture.

“At K = 3, Ankole, Nuer and Sheko show genetic heterogeneity with a considerable level of taurine admixture.”

The admixture plots show two individuals of Sheko with a high level of taurine introgression.

“Moreover, the admixture plots show two individuals of Sheko with a high level of taurine introgression.”

99 genomic regions harboring 364 signature genes were identified in Sheko.

“We identify 99 genomic regions harboring 364 signature genes in Sheko.”

Sheko shows the highest level of African taurine genomic contribution for all values of K among East African breeds.

“In general, Sheko shows the highest level of African taurine genomic contribution for all values of K among East African breeds.”

One of these individuals with higher taurine introgression is also detected by the PCA.

“One of these individuals with higher taurine introgression is also detected by the PCA ( Figure 1B , upper left corner).”

At K=6 and K=7, the African taurine breeds N'Dama and Muturu show separate genetic backgrounds.

“Furthermore, at K = 6 and K = 7, the African taurine breeds N’Dama and Muturu show separate genetic backgrounds.”

With increment of K, Sheko and Nuer show a higher level of genetic heterogeneity than the other east African breeds.

“Moreover, with the increment of the value of K, Sheko and Nuer show a higher level of genetic heterogeneity than the other east African breeds.”

Sheko has an admixed genome composed of taurine and indicine ancestries.

“We find that Sheko has an admixed genome composed of taurine and indicine ancestries.”

Nganda reveals a high level of within breed genetic differentiation.

“EASZ, Karamojong, Serere, Benshangul, Fogera, and Gindeberet also show minor levels of taurine admixture whereas Nganda reveals a high level of within breed genetic differentiation.”

EASZ, Karamojong, Serere, Benshangul, Fogera, and Gindeberet show minor levels of taurine admixture.

“EASZ, Karamojong, Serere, Benshangul, Fogera, and Gindeberet also show minor levels of taurine admixture whereas Nganda reveals a high level of within breed genetic differentiation.”

The PCA result shows the highest level of genetic heterogeneity in the Nganda breed.

“The PCA result also shows the highest level of genetic heterogeneity in the Nganda breed which might be caused by ongoing crossbreeding of Nganda with exotic breeds to enhance their productivity (Mwai et al., 2015).”

13 overrepresented pathways and 10 master regulators were identified in Sheko using the TRANSPATH database in the geneXplain platform.

“We also identify 13 overrepresented pathways and 10 master regulators in Sheko using the TRANSPATH database in the geneXplain platform.”

Most of the overrepresented pathways are related with oxidative stress responses.

“Most of the pathways are related with oxidative stress responses indicating a possible selection response against the induction of oxidative stress following trypanosomiasis infection in Sheko.”

The genomes of Ankole, Nganda, Nuer, and Sheko are mainly of indicine origin but have substantial taurine admixture.

“The genomes of Ankole, Nganda, Nuer, and Sheko are mainly of indicine origin but have substantial taurine admixture, a result supporting our interpretation of the first PC of Figure 2A”

96, 323, and 463 intergenic variants were identified in gene desert regions by iHS, CLR, and Rsb analyses in all candidate regions, respectively.

“Moreover, 96, 323, and 463 intergenic variants were identified in gene desert regions by iHS, CLR, and Rsb analyses in all candidate regions, respectively ( Supplementary Tables 8 – 10 ).”

Among the 364 unique candidate signature genes identified by iHS, CLR, and Rsb analyses, 260 had enriched GO terms (α = 0.05).

“Among the 364 unique candidate signature genes identified by iHS, CLR, and Rsb analyses, 260 disposed of enriched GO terms (α = 0.05) ( Supplementary Tables 5 – 7 ).”

15 candidate signature genes (4 by iHS, 3 by CLR, 7 by Rsb, and 1 by both iHS and CLR) are associated with trypanotolerant attributes as reported in previous studies.

“Mainly focusing on the top 10 candidate signature genes of each of the three methods, we performed a literature survey and identified 15 (4 genes identified by iHS, 3 genes identified by CLR, 7 genes identified by Rsb, and 1 gene identified by both iHS and CLR) candidate signature genes that are associated with trypanotolerant attributes which have been reported in previous studies ( Table 1 ).”

The comparison of candidate signature genes identified by the iHS, CLR, and Rsb methods shows more overlaps between iHS and CLR than between Rsb and iHS or CLR analyses.

“Moreover, the comparison of candidate signature genes identified by the iHS, CLR, and Rsb methods show more overlaps between iHS and CLR than between Rsb and iHS or CLR analyses ( Figures 5A, B ), in agreement with Rsb being a powerful method to detect selection signature when the selected allele has reached fixation (Tang et al., 2007; Oleksyk et al., 2010; Bahbahani et al., 2018).”

Among the 15 identified candidate signature genes, the MIGA1, RAETG, and PPP1R1AC genes are not significantly functionally enriched (α = 0.05).

“Among the 15 identified candidate signature genes ( Table 1 ), the MIGA1, RAETG, and PPP1R1AC genes are not significantly functionally enriched (α = 0.05).”

Among these genes, the immunoproteasome PSMD7 gene is involved in most of the overrepresented pathways.

“Among these genes, the immunoproteasome PSMD7 gene is involved in most of the overrepresented pathways.”

Among the 55 trypanotolerant QTL identified by crossing trypanotolerant N'Dama and susceptible Boran, 6 regions were overlapping with trypanotolerant QTL in N'Dama.

“Among the 55 trypanotolerant QTL, which were identified by crossing trypanotolerant N’Dama and susceptible Boran, 6 regions were overlapping with trypanotolerant QTL in N’Dama ( Supplementary Table 12 ).”

Our findings show strong selective sweeps in the genomic regions around the selected signature genes of Table 1.

“Our findings show strong selective sweeps ( Figures 4A–C ) in the genomic regions around the selected signature genes of Table 1 ( Supplementary Table 11 ).”

The TRANSPATH pathway analysis identified 15 genes out of 260 functionally enriched genes that are involved in 13 overrepresented TRANSPATH pathways.

“The TRANSPATH pathway analysis identified 15 genes out of 260 functionally enriched genes that are involved in 13 overrepresented TRANSPATH pathways ( Table 2 ).”

Among the identified candidate signature genes in Table 1, the AP1M1 and GNAS genes are found in the overlapping regions.

“Interestingly, among the identified candidate signature genes in Table 1 , the AP1M1 and GNAS genes are found in these overlapping regions.”

Most of these terms are associated with cellular transport, metabolic processes and biological regulation.

“Most of these terms are associated with cellular transport, metabolic processes and biological regulation ( Figure 6 ).”

Most of the identified candidate signature genes, overrepresented pathways, and master regulator molecules were involved in immune tolerance, neurological dysfunction, and anemia.

“Most of the identified candidate signature genes, overrepresented pathways, and master regulator molecules were involved in immune tolerance, neurological dysfunction, and anemia.”

The study identified candidate causative genes, pathways, and master regulators associated with the adaptation of the Sheko breed to its natural environmental pressure.

“We have identified the candidate causative genes, pathways, and master regulators associated with the adaptation of the Sheko breed to its natural environmental pressure.”

• AssumptionRests on an assumption: The Sheko breed is trypanotolerant.

Master regulatory network analysis using TRANSPATH identified ten master regulators (Figure 7).

“Applying the maximum radius of 10 steps upstream in the regulatory hierarchy, we identified ten master regulators ( Figure 7 ).”

Candidate signature genes involved in the regulation of hypoxia (ERN1 and CAPG) are not identified in the overrepresented hypoxia related pathways.

“For instance, candidate signature genes involved in the regulation of hypoxia (ERN1 and CAPG) are not identified in the overrepresented hypoxia related pathways.”

None of the most significant candidate signature genes (Table 1) was contained in the overrepresented pathway gene list (Table 2).

“None of the most significant candidate signature genes ( Table 1 ) was contained in the overrepresented pathway gene list ( Table 2 ).”

The positioning of Sheko, Nganda, Ankole, and Nuer close to the indicine cluster supports admixture of more indicine than taurine type genomes in these breeds.

“These breeds are close to the indicine cluster and thereby support the admixture of more indicine than taurine type genomes in these breeds.”

The oxidative stress pathway enrichment indicates a possible selection response against the induction of oxidative stress following trypanosomiasis infection in Sheko.

“Most of the pathways are related with oxidative stress responses indicating a possible selection response against the induction of oxidative stress following trypanosomiasis infection in Sheko.”

The three optimal genetic clusters suggested by the minimal CV error reflect the common genetic background unique to East Africa besides taurine and indicine ancestral genetic admixture.

“However, the three optimal genetic clusters suggested by the minimal CV error ( Supplementary Figure 1 ) reflect the common genetic background unique to East Africa besides taurine and indicine ancestral genetic admixture.”

The master regulator Caspase is a key protease which plays a major role for the emergence of adaptive immunity in harmony with the other master regulators.

“Our finding shows that the master regulator Caspase is a key protease which plays a major role for the emergence of adaptive immunity in harmony with the other master regulators.”

The master regulatory analysis suggests potential candidate therapeutic targets for the development of new drugs for trypanosomiasis treatment.

“Moreover, the master regulatory analysis suggests potential candidate therapeutic targets for the development of new drugs for trypanosomiasis treatment.”

The Sheko breed shows better trypanotolerance than other breeds such as Abigar and Horro.

“However, the Sheko breed shows better trypanotolerance than other breeds.”

• Also stated in: § Introduction · plain

  “In Ethiopia, Sheko shows better trypanotolerance attributes than other breeds such as Abigar and Horro (Lemecha et al., 2006).”

• cites Lemecha et al., 2006 sourceNot checked — no full text of the source

Mutations in the POLR3B, MIGA1, TTC3, ERN1, CAPG, GNAS, and TTBK2 genes might be associated with the response to the presence of the parasite in the brain white matter, cerebral fluid, thyroid, and parathyroid glands.

“Therefore, mutations in the POLR3B, MIGA1, TTC3, ERN1, CAPG, GNAS, and TTBK2 genes might be associated with the response to the presence of the parasite in the brain white matter, cerebral fluid, thyroid, and parathyroid glands.”

The PPP1R14C gene could play an important role in the tolerance mechanisms of Sheko with PP1, a competitive inhibitor of ATP binding of Src tyrosine kinase family members.

“Interestingly, the PPP1R14C gene could play an important role in the tolerance mechanisms of Sheko with PP1, a competitive inhibitor of ATP binding of Src tyrosine kinase family members (Hanke et al., 1996; Liu et al., 2002).”

• cites Hanke et al., 1996 sourceNot checked — no full text of the source
• cites Liu et al., 2002 sourceNot checked — no full text of the source

Polymorphisms in or nearby the MIGA1, CDAN1, HSPA9, and PCSK6 genes in the genome of Sheko might be associated with the evolutionary response against anemia.

“Notably, polymorphisms in or nearby the MIGA1, CDAN1, HSPA9, and PCSK6 genes in the genome of Sheko might be associated with the evolutionary response against anemia.”

Mutation in the PPP1R14C gene is associated with three tolerance attributes: immune tolerance, neurological dysfunction, and anemia.

“Therefore, the mutation in the PPP1R14C gene is associated with three tolerance attributes (immune tolerance, neurological dysfunction, and anemia).”

The SPAG11B, RAET1G, PPP1R14C, and TTC3 genes are involved in immune tolerance in Sheko.

“In agreement with this, we identified the SPAG11B, RAET1G, PPP1R14C, and TTC3 genes which are involved in immune tolerance in Sheko.”

Mutations or differential expression of these genes are critical for the immune tolerance of Sheko to combat anemia and neurological dysfunction caused by trypanosome infection.

“Therefore, the mutations or the differential expression of these genes are critical for the immune tolerance of Sheko to combat anemia and neurological dysfunction caused by trypanosome infection.”

These peptides are involved in the recruitment of T- and dendritic cells to facilitate the adaptive immunity.

“They are also involved in the recruitment of T- and dendritic cells to facilitate the adaptive immunity (Yang et al., 1999).”

• cites Yang et al., 1999 sourceNot checked — no full text of the source

Trypanotolerant N'Dama do better control anemia, a process mediated by hematopoietic cell differentiation, than trypanosusceptible breeds.

“In agreement with our findings, it has been reported by several studies that trypanotolerant N’Dama do better control anemia, a process mediated by hematopoietic cells differentiation, than trypanosusceptible breeds (Berthier et al., 2016; Naessens, 2006).”

• cites Berthier et al., 2016 sourceNot checked — no full text of the source
• cites Naessens, 2006 sourceNot checked — no full text of the source

The overlapping regions and genes of Sheko and N'Dama might indicate occurrence of selection at the same genes in these two breeds against the same environmental pressures.

“The overlapping regions and genes of Sheko and N’Dama might indicate occurrence of selection at the same genes in these two breeds against the same environmental pressures.”

This process would induce auto-immunity against self-antigens.

“This process would induce auto-immunity against self-antigens.”

The lack of significant functional enrichment for MIGA1, RAETG, and PPP1R1AC might indicate that these candidate signature genes in Sheko could be specific to the environmental pressure in the region such as trypanosomiasis.

“This might indicate that these candidate signature genes in Sheko could be specific to the environmental pressure in the region such as trypanosomiasis.”

The PDGFB → STATs pathway is involved in anemia.

“In addition, knock-out mice for PDGF-B develop anemia (Kaminski et al., 2001) which indicates that the PDGFB –> STATs pathway is also involved in this disease.”

• cites Kaminski et al., 2001 sourceNot checked — no full text of the source

Sufficient induction of CD8+ during infection leads to pathogen elimination.

“Sufficient induction of CD8+ during infection leads to pathogen elimination.”

During trypanosome infection, the red blood cell membrane might be damaged by parasite enzymes such as proteases or phospholipases.

“Moreover, during trypanosome infection, the red blood cell membrane might be damaged by parasite enzymes such as proteases or phospholipases.”

Allam et al. (2011) reported a similar profile during trypanosome infection in cattle that could be associated with neurological dysfunction such as muscle spasm.

“Allam et al. (2011) reported a similar profile during trypanosome infection in cattle that could be associated with neurological dysfunction such as muscle spasm (Tuntasuvan et al., 1997; Bastepe, 2008; Giordani et al., 2016).”

• cites Allam et al., 2011 sourceNot checked — no full text of the source
• cites Tuntasuvan et al., 1997 sourceNot checked — no full text of the source
• cites Bastepe, 2008 sourceNot checked — no full text of the source

Expression of alternatively spliced MBP mRNAs is related with the immune system in response to trypanosome infection or presence of a pathogen in the central nervous system.

“This suggested that the expression of alternatively spliced MBP mRNAs is related with the immune system in response to trypansome infection or the presence of a pathogen in the central nervous system.”

Our study is the first to show the potential of a molecular mechanism for controlling auto-reactive immune cells caused by trypanosomiasis in cattle.

“To the best of our knowledge, our study is the first to show the potential of a molecular mechanism for controlling auto-reactive immune cells caused by trypanosomiasis in cattle.”

Adaptive immunity also plays a key role for the emergence of auto-immunity.

“However, adaptive immunity also plays a key role for the emergence of auto-immunity.”

The identified candidate signature genes in Table 1 might play a major role in the natural tolerance attributes of Sheko against trypanosomiasis.

“Therefore, the identified candidate signature genes in Table 1 might play a major role in the natural tolerance attributes of Sheko against trypanosomiasis.”

In stress associated pathways, MBP, RAF1, MEF2A, and STAT3 genes are involved in the immune and nervous systems.

“Especially, in stress associated pathways we find MBP, RAF1, MEF2A, and STAT3 genes that are involved in the immune and nervous systems.”

The strong selective sweeps might indicate that the mutations in these genes have reached fixation or are near fixation.

“This might indicate that the mutations in these genes have reached fixation or are near fixation.”

Other overrepresented pathways (E2F network, G2/M phase, S phase, Plk1 cell cycle regulation, Aurora-B cell cycle regulation) are involved in cell cycle processes.

“while others [E2F network, G2/M phase (cyclin B:Cdk1), S phase (Cdk2), Plk1 cell cycle regulation and Aurora-B cell cycle regulation] pathways are involved in cell cycle processes.”

The study provides a first report on the top master regulators for trypanotolerance of Sheko.

“In general, our study provides a first report on the top master regulators for trypanotolerance of Sheko and the overall analysis framework might be helpful to understand the underlying mechanisms of different cattle diseases in future works.”

• AssumptionRests on an assumption: The Sheko breed is trypanotolerant.

These candidate signature genes might be specific to oxidative stress tolerance attributes in Sheko.

“This might indicate that these candidate signature genes might be specific to oxidative stress tolerance attributes in Sheko.”

Candidate signature genes involved in anemia, neurological dysfunction, listlessness, and immune tolerance might be governed by the top master regulator Caspase in harmony with other regulatory molecules.

“We believe that the candidate signature genes involved in anemia, neurological dysfunction, listlessness, and immune tolerance might be governed by the top master regulator Caspase in harmony with other regulatory molecules.”

This study for the first time identifies the master regulators involved in the regulatory mechanisms of trypanotolerance in relation to signatures of selection not only for Sheko breed but also in the context of cattle genomics.

“Particularly, this study for the first time identifies the master regulators involved in the regulatory mechanisms of trypanotolerance in relation to signatures of selection not only for Sheko breed but also in the context of cattle genomics, which can be used for the development of effective new drugs.”

• AssumptionRests on an assumption: The Sheko breed is trypanotolerant.

The genome of Sheko was targeted by these environmental pressures which are associated with trypanosomiasis.

“This entails that the genome of Sheko was targeted by these environmental pressures which are associated with trypanosomiasis.”

• AssumptionRests on an assumption: African animal trypanosomiasis has been the major selection pressure in the region.
• AssumptionRests on an assumption: The Sheko breed is trypanotolerant.

Most of the overrepresented pathways are mainly associated with host defense mechanisms against pathogens and anemia.

“This implies that most of the overrepresented pathways are mainly associated with host defense mechanisms against pathogens and anemia.”

Candidate signature genes might be involved in the evolutionary gear particularly toward trypanotolerance in Sheko.

“This indicates that the candidate signature genes might be involved in the evolutionary gear particularly toward trypanotolerance in Sheko.”

Trypanotolerance of Sheko could be controlled by some major selected genes whose major effect is close to fixation in the breed and cohorts of genes with minor effects.

“Hence, trypanotolerance of Sheko could be controlled by some major selected genes whose major effect close to fixation in the breed (become breed characteristic) and cohorts of genes with minor effects.”

• AssumptionRests on an assumption: The Sheko breed is trypanotolerant.

The paper's findings of the search for signature genes appear to be well substantiated by the results of the overrepresented pathways analysis.

“In summary, our findings of the search for signature genes appear to be well substantiated by the results of the overrepresented pathways analysis.”