- In this research, we focused on identifying genomic regions affected by different selection pressures, mainly highlighting the recent positive selection, as well as understanding the candidate genes and functional pathways associated with the signatures of selection in the Mangalarga Marchador genome. - Conclusions: Our findings revealed evidence of signatures of selection in the MM breed that encompass genes acting on athletic performance, limb development, and energy to muscle activity, with the particular involvement of the HOX family genes. - The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. - If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. - The main difference between batida and picada gaits is how the movement is executed, being the diagonal support more frequent than the triple support in the batida gait. - In the picada gait, the lateral and triple supports overlap, providing a softer execution to the movement. - [4] described the influence of DMRT3 gene and transcription factors, involved in the coordin- ation of limb movement, in gaitedness across horse breeds. - Although DMRT3 appears to be important for gaits in certain breeds, other genes are certainly involved in the expression of this trait.. - Current studies bring the concept of selec- tion signatures, which are particular patterns of DNA identified in genomic regions with mutation and/or which have been under natural/artificial selection pressures in the population [7–9]. - The exploitation of selection signa- tures aids in identifying regions in the genome under se- lective pressure that may harbor genes and variants that modulate important phenotypes in horses [10, 11].. - Over the past few years, the interest in the detection of selection signatures in horses and other species has resulted in the increased number of publications on this topic, being the selection signatures described as results of domestication and selection processes that aimed to increase herd performance and productivity [12, 13].. - In this study, we used three different ap- proaches to search for signatures of selection in the gen- ome of MM: Tajima’s D (TD) [20], the integrated haplotype score (iHS) [22], and runs of homozygosity (ROH) [21]. - Therefore, we used stand- ard within-population approaches to scan for signatures of selection in the MM breed, especially to detect recent signatures. - In addition, a detailed discussion on signa- tures of selection that overlap with candidate genes and gene pathways previously described in the literature were provided, focusing more on candidates related to traits of importance in this breed, especially those re- lated to the type and quality of gait, temperament, con- formation, and locomotor system (muscular and skeletal structure).. - Prior information related to the gait groups of each indi- vidual, batida and picada, was considered in the PCA analysis to investigate whether individuals who belong to the same group would cluster together. - Only one cluster persisted in the dataset, meaning that all the individuals are genetically related when genomic information is considered. - The dispersion of the dataset and segregations (substruc- tures) was attributed to the importance of sires from dif- ferent families in the breed formation when the most significant number of clusters was assessed. - Therefore, one population, including all animals in the dataset, was taken into consideration for genomic scans of selection signatures.. - [24], which were possibly attrib- uted to the different approaches used in the studies, as well as the reduction in the number of animals. - In total, 147 genomic regions with negative and posi- tive tails were identified as significant selection signals in the TD test (P <. - In total, 292 genomic regions were observed as signatures of selection in the iHS test (Additional file 2:. - In total, 251 genomic regions were consistent in the iHS positive tail, representing the ancestral allele state, while 41 regions were consistent in the negative tail,. - Due to the large number of significant signals found in the iHS test, we did not follow the commonly used method of choosing to display only the top regions.. - We consider three parameters to prioritize candidate genes in our list: (I) genes within highlighted genomic regions based on the extremes iHS and piHS values, (II) genes related to locomotion, athletic performance, growth, fertility, conformation, pigmentation, and me- tabolism, and (III) genes that were also found in the Tajima’s D and ROH approaches. - Table 1 Candidate genes identified by Tajima ’ s D test under evidence of positive signature of selection in the Brazilian Mangalarga Marchador horses. - In the ROH analysis, 340 SNPs were observed within ROH island regions (mean hotspot) that were regions with frequencies ≥0.5 in the population (Additional file 2: Data S3). - The longest shared homozygous segment was detected in the ECA7, with length above 16 Mb.. - Most of the ROH segments found in the MM gen- ome corresponded to short segments with lengths around 1–2 Mb (Fig. - 3 Genome-wide distribution of selection signatures in the equine autosomal chromosomes. - Table 2 Candidate genes identified by integrated haplotype score (iHS) test under the evidence of signature of selection in the Brazilian Mangalarga Marchador horses. - To the best of our knowledge, this is the first study to provide a whole scan for signatures of selection in the MM genome. - Our findings shed light on the possible candidate genes/gene groups involved in the regions undergoing selection in this breed. - The allele A of the DMRT3 gene is only related to the picada gait in the MM, with two genotypes AA and CA, while the geno- type CC is related to batida gait [28]. - Selection in the MM breed is based exclusively on competitions where gaited performance records are eval- uated relative to that of competitors, often being an em- pirical selection. - In this regard, it is essential to understand which genes in the MM population are most relevant to accomplish such goals. - We next focused on exploring the signa- tures of positive recent selection found in the MM population and understanding the genes and pathways associated with these regions. - 4 Shared homozygosity interval for the most representative chromosomes in the ROH approach. - Based on footprints, one can observe regions shared between individuals in the population. - Due to the density of the genotyping panel used and the Table 3 Candidate genes identified by runs of homozygosity (ROH) test under evidence of positive signature of selection in the Brazilian Mangalarga Marchador horses. - Each method presents specific features implying that non-overlapping regions of signa- tures of selection between different methods should be treated as complementary information to better under- stand the different patterns of variation in the MM genome.. - however, many hitch- hiking effects were highlighted in the statistics based on the extended haplotype homozygosity and footprints on homozygous regions. - The pronounced balancing status in the studied population supported by the TD results was an interesting consequence, possibly explained by the nonexistence of any breeding program in the breed during the past years.. - breed compared to most modern breeds having origi- nated in the mid-eighteenth century. - In the present study, we found only one long ROH segment (>. - The number of short segments was more abundant, possibly due to events of recombination that occurred in the past and caused its reduction [19, 36], or due to the limita- tion of using genotyping data, thereby overestimating the number of short ROH [37]. - Evidence for this long ROH segment on ECA7 has already been described in the literature [34]. - Thus, we speculate that this candi- date region of signature of selection in ECA7 is possibly a consequence of a previous bottleneck and not recent positive selection because of the similarity in the results found in distinct breeds. - [34] for an intense bottleneck, but pointing to a common mo- ment in the evolutionary process for some breeds.. - One region on ECA1 encompassed the gene RASGRP1, which was found in common between ROH and iHS and played a key role in the development of T and B cells [41]. - In general, the genetic signals for the three statistics were most enriched in ontologies corresponding to “bio- logical regulation,” “metabolic process,” and “cellular process.” In the Panther results for iHS and ROH candi- date genes, the ontology “localization” was also very rep- resentative. - Exploring this information, we found that GLI3 is Table 4 Significant Gene Ontology (GO) terms identified in the. - FOXO1 and CCL19 “ response to bronchodilator ” (GO:0097366) CCL19 and WASHC1 “ regulation of lipid kinase activity ” (GO:0043550) The ELOVL5 “ energy production from fatty acids ” (GO:1901570, GO:. - GLI3 has been described in the literature as an embryonic patterning of human limbs and other struc- tures [47]. - The relationship between the HOX genes and limb musculoskeletal development has been well de- scribed in the literature. - Wellik [46] sug- gested that the integration of the musculoskeletal system is regulated in part by HOX function in the stromal con- nective tissue and plays critical roles in skeletal pattern- ing throughout the axial and appendicular skeleton.. - high significance levels were reached for the GO terms “anterior/posterior pattern specification” (GO embryonic skeletal system morphogenesis” (GO:0048704), and “sequence-specific DNA binding” (GO:0043565), mainly based upon the HOXB-cluster in the breeds Gidran, Lipizzan, Posavina, and Noriker.. - Other significant signals in the present study were found for the CCL19 and MAP3K6 genes enriched for the activation of JUN kinase (JNK) activity. - Exercise causes selective changes over gene expression, leading to differentiation in skeletal muscle structure and function, which provides strong evidence that this regulation may be associated with gait type seg- regation in the skeletal muscle on limbs. - The effect of activity during exercise in c-jun mRNA expression is via the phosphorylation of two serine residues through the JNKs in the c-Jun transactivation domain, leading to in- creased transcriptional activity [49].. - It is well known in the modern horse that athletic per- formance has been the target of selection in recent years for many breeds. - However, these genes/functions do not act alone in the MM perform- ance. - As observed in the network analysis, gene func- tions are dependent, with the major part of them being regulated in sets.. - Under these conditions, any two nodes in the graph are usually connected by just a few steps [50].. - Overall, the application of classical and recent tech- niques in genomics has successfully permitted the iden- tification of several putative selection signatures in the MM population. - This method could then be compared to the regions found within the breed and would clarify whether these signatures are unique to the breed (or the gait) rather than being general signatures of selection in horses or if they could potentially detect new genetic bases of gait in the MM. - Among the bio- logical processes, genes of biological interest such as the HOX gene family were enriched in the ontology corre- sponding to “anterior/posterior pattern specification.”. - Sample collection, gait patterns, and DNA extraction Blood sample were collected from competing horses during the 36th Brazilian National Exhibition of the Mangalarga Marchador breed, and also from horses raised in stud-farms located in the States of São Paulo and Minas Gerais. - SNP in the same position were removed. - with a total of 422,656 SNP available in the dataset for TD and iHS analyses (MAF <. - 0.01), and 444,929 SNP available in the dataset used in ROH ana- lysis (MAF <. - Genotype phas- ing was performed in Beagle v.5.0, which provides faster and accurate algorithms [53], and the phased data was used in the TD and iHS analyses.. - Before computing PCAs in the R software, close related individuals were excluded based on the high-values for pairwise PI_HAT statistic sum.. - Genome-wide scan for signals of positive selection We used three distinct approaches to capture the evolu- tionary aspects of the selection in the MM. - Sliding windows of 20 kb across all autosomal regions were used in the TD analysis. - The analysis was per- formed in the VCFtools (http://vcftools.sourceforge.net/. - The R package rehh v was used in the iHS analysis. - However, an ideal value for iHS or piHS (p-value for iHS) is not well defined in the literature. - The signatures of selection for ROH, i.e., ROH islands, were defined as ROH regions (mean hot- spot) with frequencies ≥0.5 in the population.. - The window size was defined based on LD in- formation and approximate values described in the literature. - S2 Final density of 545,219 SNP in the Mangalarga Marchador horse genome after Axiom ™ Analysis Suite pruning. - Worldwide frequency distribution of the “ gait keeper ” mutation in the DMRT3 gene. - Recent and ongoing selection in the human genome. - https://doi.org/10.1038/nrg2187.. - Signatures of natural selection in the human genome. - Mapping signatures of positive selection in the genome of livestock. - https://doi.org/10.1016/j.. - Detecting recent positive selection in the human genome from haplotype structure. - https://doi.org . - https://doi.org/10.1101/. - https://doi.org/10.1093/. - Fine- scale estimation of inbreeding rates, runs of homozygosity and genome-wide heterozygosity levels in the Mangalarga Marchador horse breed. - https://doi.. - A genome-wide association study reveals differences in the genetic mechanism of control of the two gait patterns of the Brazilian Mangalarga Marchador breed. - Allelic and genotypic frequencies of the DMRT3 gene in the Brazilian horse breed Mangalarga Marchador and their association with types of gait. - Signatures of selection in the genome of Swedish warmblood horses selected for sport performance. - https://doi.org/10.1186/s . - https://doi.org/10.1007/s . - Hedgehog-regulated processing of Gli3 produces an anterior/ posterior repressor gradient in the developing vertebrate limb. - https://doi.org/10.1016/S . - https://doi.org/10.1534/g
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