Identification of population-informative markers from high-density genotyping data through combined feature selection and machine learning algorithms: Application to European autochthonous and cosmopolitan pig breeds.

Large genotyping datasets, obtained from high-density single nucleotide polymorphism (SNP) arrays, developed for different livestock species, can be used to describe and differentiate breeds or populations. To identify the most discriminating genetic markers among thousands of genotyped SNPs, a few statistical approaches have been proposed. In this study, we applied the Boruta algorithm, a wrapper of the machine learning random forest algorithm, on a database of 23 European pig breeds (20 autochthonous and three cosmopolitan breeds) genotyped with a 70k SNP chip, to pre-select informative SNPs. To identify different sets of SNPs, these pre-selected markers were then ranked with random forest based on their mean decrease accuracy and mean decrease gene indexes. We evaluated the efficiency of these subsets for breed classification and the usefulness of this approach to detect candidate genes affecting breed-specific phenotypes and relevant production traits that might differ among breeds. The lowest overall classification error (2.3%) was reached with a subpanel including only 398 SNPs (ranked based on their mean decrease accuracy), with no classification error in seven breeds using up to 49 SNPs. Several SNPs of these selected subpanels were in genomic regions in which previous studies had identified signatures of selection or genes associated with morphological or production traits that distinguish the analysed breeds. Therefore, even if these approaches have not been originally designed to identify signatures of selection, the obtained results showed that they could potentially be useful for this purpose.

Genome-wide association studies for diarrhoea outcomes identified genomic regions affecting resistance to a severe enteropathy in suckling rabbits.

Selection and breeding strategies to improve resistance to enteropathies are essential to reaching the sustainability of the rabbit production systems. However, disease heterogeneity (having only as major visible symptom diarrhoea) and low disease heritability are two barriers for the implementation of these strategies. Diarrhoea condition can affect rabbits at different life stages, starting from the suckling period, with large negative economic impacts. In this study, from a commercial population of suckling rabbits (derived from 133 litters) that experienced an outbreak of enteropathy, we first selected a few animals that died with severe symptoms of diarrhoea and characterized their microbiota, using 16S rRNA gene sequencing data. Clostridium genus was consistently present in all affected specimens. In addition, with the aim to identify genetic markers in the rabbit genome that could be used as selection tools, we performed genome-wide association studies for symptoms of diarrhoea in the same commercial rabbit population. These studies were also complemented with FST analyses between the same groups of rabbits. A total of 332 suckling rabbits (151 with severe symptoms of diarrhoea, 42 with mild symptoms and 129 without any symptoms till the weaning period), derived from 45 different litters (a subset of the 133 litters) were genotyped with the Affymetrix Axiom OrcunSNP Array. In both genomic approaches, rabbits within litters were paired to constitute two groups (susceptible and resistant, including the mildly affected in one or the other group) and run case and control genome-wide association analyses. Genomic heritability estimated in the designed experimental structure integrated in a commercial breeding scheme was 0.19-0.21 (s.e. 0.09-0.10). A total of eight genomic regions on rabbit chromosome 2 (OCU2), OCU3, OCU7, OCU12, OCU13, OCU16 and in an unassembled scaffold had significant single nucleotide polymorphisms (SNPs) and/or markers that trespassed the FST percentile distribution. Among these regions, three main peaks of SNPs were identified on OCU12, OCU13 and OCU16. The QTL region on OCU13 encompasses several genes that encode members of a family of immunoglobulin Fc receptors (FCER1G, FCRLA, FCRLB and FCGR2A) involved in the immune innate system, which might be important candidate genes for this pathogenic condition. The results obtained in this study demonstrated that resistance to an enteropathy occurring in suckling rabbits is in part genetically determined and can be dissected at the genomic level, providing DNA markers that could be used in breeding programmes to increase resistance to enteropathies in meat rabbits.

Upregulation of Notch Signaling and Cell-Differentiation Inhibitory Transcription Factors in Stable Chronic Obstructive Pulmonary Disease Patients.

Notch signaling is involved in the prevention of cell differentiation and cell fate in various organs, including the lungs. We aimed to determine the transcriptomic and protein expression of Notch receptors, their ligands, and related transcription factors in stable COPD. The expression and localization of Notch receptors, their ligands, and related transcription factors were measured in bronchial biopsies of individuals with stable mild/moderate (MCOPD) (n = 18) or severe/very severe (SCOPD) (n = 16) COPD, control smokers (CSs) (n = 13), and control nonsmokers (CNSs) (n = 11), and in the lung parenchyma of those with MCOPD (n = 13), CSs (n = 10), and CNSs (n = 10) using immunohistochemistry, ELISA tests, and transcriptome analyses. In the bronchial biopsies, Notch4 and HES7 significantly increased in the lamina propria of those with SCOPD compared to those with MCOPD, CSs, and CNSs. In the peripheral lung bronchiolar epithelium, Notch1 significantly increased in those with MCOPD and CSs compared to CNSs. ELISA tests of lung parenchyma homogenates showed significantly increased Notch2 in those with MCOPD compared to CSs and CNSs. Transcriptomic data in lung parenchyma showed increased DLL4 and HES1 mRNA levels in those with MCOPD and CSs compared to CNSs. These data show the increased expression of the Notch pathway in the lungs of those with stable COPD. These alterations may play a role in impairing the regenerative-reparative responses of diseased bronchioles and lung parenchyma.

Genome-wide landscape of runs of homozygosity and differentiation across Egyptian goat breeds.

Understanding the genomic features of livestock is essential for successful breeding programs and conservation. This information is scarce for local goat breeds in Egypt. In the current study, genomic regions with selection signatures were identified as well as runs of homozygosity (ROH), genomic inbreeding coefficients (FROH) and fixation index (FST) were detected in Egyptian Nubian, Damascus, Barki and Boer goat breeds. A total of 46,268 SNP markers and 337 animals were available for the genomic analyses. On average, 145.44, 42.02, 87.90 and 126.95 ROHs were detected per individual in the autosomal genome of the respective breeds. The mean accumulative ROH lengths ranged from 46.5 Mb in Damascus to 360 Mb in Egyptian Nubian. The short ROH segments (< 2 Mb) were most frequent in all breeds, while the longest ROH segments (> 16 Mb) were exclusively found in the Egyptian Nubian. The highest average FROH was observed in Egyptian Nubian (~ 0.12) followed by Boer (~ 0.11), while the lowest FROH was found in Damascus (~ 0.05) and Barki breed (~ 0.03). The estimated mean FST was 0.14 (Egyptian Nubian and Boer), 0.077 (Egyptian Nubian and Barki), 0.075 (Egyptian Nubian and Damascus), 0.071 (Barki and Boer), 0.064 (Damascus and Boer), and 0.015 (Damascus and Barki), for each pair of breeds. Interestingly, multiple SNPs that accounted for high FST values were observed on chromosome 6 in regions harboring ALPK1 and KCNIP4. Genomic regions overlapping both FST and ROH harbor genes related to immunity (IL4R, PHF23, GABARAP, GPS2, and CD68), reproduction (SPATA2L, TNFSF12, TMEM95, and RNF17), embryonic development (TCF25 and SOX15) and adaptation (MC1R, KDR, and KIT), suggesting potential genetic adaptations to local environmental conditions. Our results contribute to the understanding of the genetic architecture of different goat breeds and may provide valuable information for effective preservation and breeding programs of local goat breeds in Egypt.

Population genomic structures and signatures of selection define the genetic uniqueness of several fancy and meat rabbit breeds.

Following the recent domestication process of the European rabbit (Oryctolagus cuniculus), many different breeds and lines, distinguished primarily by exterior traits such as coat colour, fur structure and body size and shape, have been constituted. In this study, we genotyped, with a high-density single-nucleotide polymorphism panel, a total of 645 rabbits from 10 fancy breeds (Belgian Hare, Champagne d'Argent, Checkered Giant, Coloured Dwarf, Dwarf Lop, Ermine, Giant Grey, Giant White, Rex and Rhinelander) and three meat breeds (Italian White, Italian Spotted and Italian Silver). ADMIXTURE analysis indicated that breeds with similar phenotypic traits (e.g. coat colour and body size) shared common ancestries. Signatures of selection using two haplotype-based approaches (iHS and XP-EHH), combined with the results obtained with other methods previously reported that we applied to the same breeds, we identified a total of 5079 independent genomic regions with some signatures of selection, covering about 1777 Mb of the rabbit genome. These regions consistently encompassed many genes involved in pigmentation processes (ASIP, EDNRA, EDNRB, KIT, KITLG, MITF, OCA2, TYR and TYRP1), coat structure (LIPH) and body size, including two major genes (LCORL and HMGA2) among many others. This study revealed novel genomic regions under signatures of selection and further demonstrated that population structures and signatures of selection, left into the genome of these rabbit breeds, may contribute to understanding the genetic events that led to their constitution and the complex genetic mechanisms determining the broad phenotypic variability present in these untapped rabbit genetic resources.

Decreased humoral immune response in the bronchi of rapid decliners with chronic obstructive pulmonary disease.

BACKGROUND: Identification of COPD patients with a rapid decline in FEV1 is of particular interest for prognostic and therapeutic reasons. OBJECTIVE: To determine the expression of markers of inflammation in COPD patients with rapid functional decline in comparison to slow or no decliners. METHODS: In COPD patients monitored for at least 3 years (mean ± SD: 5.8 ± 3 years) for lung functional decline, the expression and localization of inflammatory markers was measured in bronchial biopsies of patients with no lung functional decline (FEV1% + 30 ± 43 ml/year, n = 21), slow (FEV1% ml/year, - 40 ± 19, n = 14) and rapid decline (FEV1% ml/year, - 112 ± 53, n = 15) using immunohistochemistry. ELISA test was used for polymeric immunoglobulin receptor (pIgR) quantitation "in vitro". RESULTS: The expression of secretory IgA was significantly reduced in bronchial epithelium (p = 0.011) and plasma cell numbers was significantly reduced in the bronchial lamina propria (p = 0.017) of rapid decliners compared to no decliners. Bronchial inflammatory cell infiltration, CD4, CD8, CD68, CD20, NK, neutrophils, eosinophils, mast cells, pIgR, was not changed in epithelium and lamina propria of rapid decliners compared to other groups. Plasma cells/mm2 correlated positively with scored total IgA in lamina propria of all patients. "In vitro" stimulation of 16HBE cells with LPS (10 µg/ml) and IL-8 (10 ng/ml) induced a significant increase while H2O2 (100 µM) significantly decreased pIgR epithelial expression. CONCLUSION: These data show an impaired humoral immune response in rapid decliners with COPD, marked by reduced epithelial secretory IgA and plasma cell numbers in the bronchial lamina propria. These findings may help in the prognostic stratification and treatment of COPD.

Alveolar Nitric Oxide and Peripheral Oxygen Saturation in Frequent Exacerbators with Asthma: A Pilot Study.

INTRODUCTION: Asthmatics can experience recurrent exacerbations (AEs), irrespectively of asthma severity. Airway inflammatory monitoring could be fundamental to optimize the asthma management. The present study evaluated whether exhaled NO concentrations in proximal and distal respiratory compartments are different in AE-prone patients in combination with T2 blood biomarkers and resting oxygen saturation (SpO2). METHODS: In this observational cross-sectional study, 91 mild-to-severe asthmatics were enrolled. Clinical characteristics, blood and lung function parameters including SpO2, and FENO were evaluated. On 50 randomly selected patients, CANO and JawNO were also analyzed. Then, patients were stratified in frequent exacerbators (FEs) or non-frequent exacerbators (nFEs), according to AE frequency in the previous year (phase I). Chart data were re-evaluated through a 12-month follow-up period post exhaled NO measurement to detect occurrence of novel AE (phase II). RESULTS: FE asthmatics had poorer asthma control and required higher therapeutic intensity (p < 0.05). FENO, CANO, and JawNO were similar between FE and nFE. FE exhibited higher total serum IgE levels and residual volume values but reduced SpO2 than nFE (p < 0.05); SpO2<96.5% characterized the FE patient (odds ratio = 2.94). In phase II, CANO was higher in the group with novel AE at 1-month post-NO measurement (p < 0.05), but not afterward. A higher prevalence of CANO >6 ppb was detected in asthmatics who developed AE within 1 month, suggesting its potential clinical use as biomarker in predicting near-future AE (RR = 11.20). CONCLUSION: AE-susceptible asthmatics are characterized by air trapping and distal airway inflammation in conjunction with lower oxygen saturation. CANO and SpO2 could exert specific roles, respectively, in predicting AE and monitoring FE asthmatics.

Predictors of Low and High Exhaled Nitric Oxide Values in Asthma: A Real-World Study.

BACKGROUND: In asthma, exhaled nitric oxide (FENO) is a clinically established biomarker of airway T2 inflammation and an indicator for anti-inflammatory therapy. OBJECTIVES: The aim of the study was to identify, in an observational real-world cross-sectional study, the main characteristics of patients with asthma as classified by their FENO level. METHOD: We stratified 398 patients with stable mild-to-severe asthma according to FENO level as low (≤25 ppb) versus elevated (>25 ppb), subdividing the latter into two subgroups: moderately elevated (26-50 ppb) versus very high FENO (>50 ppb). Clinical, functional, and blood parameters were extrapolated from patients' chart data and compared with the FENO stratification. Predictors of low and elevated FENO asthma were detected by logistic regression model. RESULTS: Low BMI, higher blood eosinophilia, allergen poly-sensitization, the severest airflow obstruction (FEV1/FVC), and anti-leukotriene use are predictors of elevated FENO values in asthma, as well as persistent rhinitis and chronic rhinosinusitis with or without nasal polyps. Beyond these, younger age, more than 2 asthma exacerbations/year, higher airflow reversibility (post-bronchodilator ∆FEV1), and oral corticosteroid dependence are predictors of very high FENO values. In contrast, obesity, obstructive sleep apnoea syndrome, gastroesophageal reflux disease, arterial hypertension, and myocardial infarction are predictors of low FENO asthma. In our population, FENO correlated with blood eosinophils, airflow obstruction, and reversibility and negatively correlated with age and BMI. CONCLUSIONS: Stratifying patients by FENO level can identify specific asthma phenotypes with distinct clinical features and predictors useful in clinical practice to tailor treatment and improve asthmatic patients' outcomes.

Signatures of selection are present in the genome of two close autochthonous cattle breeds raised in the North of Italy and mainly distinguished for their coat colours.

Autochthonous cattle breeds are genetic resources that, in many cases, have been fixed for inheritable exterior phenotypes useful to understand the genetic mechanisms affecting these breed-specific traits. Reggiana and Modenese are two closely related autochthonous cattle breeds mainly raised in the production area of the well-known Protected Designation of Origin Parmigiano-Reggiano cheese, in the North of Italy. These breeds can be mainly distinguished for their standard coat colour: solid red in Reggiana and solid white with pale shades of grey in Modenese. In this study we genotyped with the GeneSeek GGP Bovine 150k single nucleotide polymorphism (SNP) chip almost half of the extant cattle populations of Reggiana (n = 1109 and Modenese (n = 326) and used genome-wide information in comparative FST analyses to detect signatures of selection that diverge between these two autochthonous breeds. The two breeds could be clearly distinguished using multidimensional scaling plots and admixture analysis. Considering the top 0.0005% FST values, a total of 64 markers were detected in the single-marker analysis. The top FST value was detected for the melanocortin 1 receptor (MC1R) gene mutation, which determines the red coat colour of the Reggiana breed. Another coat colour gene, agouti signalling protein (ASIP), emerged amongst this list of top SNPs. These results were also confirmed with the window-based analyses, which included 0.5-Mb or 1-Mb genome regions. As variability affecting ASIP has been associated with white coat colour in sheep and goats, these results highlighted this gene as a strong candidate affecting coat colour in Modenese breed. This study demonstrates how population genomic approaches designed to take advantage from the diversity between local genetic resources could provide interesting hints to explain exterior traits not yet completely investigated in cattle.

Asthma in the Real-World: The Relevance of Gender.

BACKGROUND: The possible gender impact on asthma arouses current and outstanding interest, but few studies addressed this issue in the real-world setting. OBJECTIVE: This cross-sectional study tested the hypothesis of a potential difference between asthmatic males and females in a real-life setting, such as a third-level asthma clinic. METHODS: A total of 499 asthmatic outpatients (301 females and 198 males, mean age 58.25 years) were consecutively visited. The visit included history, asthma control, and severity grade, physical examination, lung function, fractional exhaled nitric oxide assessment, and blood sample for biomarkers. RESULTS: There were more females than males (about 3 of 5). Asthmatic females smoked less (p < 0.0001) than males and had higher FEV1 (p = 0.0022) and FVC (p = 0.0004) values than asthmatic males. CONCLUSIONS: Gender difference was associated with smoking and lung function impairment; thus, this issue should be carefully considered in asthmatic patients in daily clinical practice.

A real-world assessment of asthma with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) includes 2 main phenotypes: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). CRS has been reported to be a comorbidity of asthma. OBJECTIVE: This study aimed to investigate the role of CRS in outpatients with asthma visited in real-world setting. METHODS: This cross-sectional study enrolled 499 consecutive outpatients with asthma. Age, sex, body mass index, smoking status, lung function, Asthma Control Test, inflammatory type 2 biomarkers (including fractional exhaled nitric oxide, blood eosinophils, serum total immunoglobulin E, and allergy), treatment step according to the Global Initiative for Asthma, and comorbidities (obstructive sleep apnea syndrome, arterial hypertension, bronchiectasis, diabetes mellitus type 2, and osteoporosis) were evaluated. RESULTS: A total of 179 (35.87%) patients had CRS, in particular 93 (18.64%) had CRSsNP and 86 (17.23%) had CRSwNP. Type 2 inflammation (defined by at least 1 positive biomarker) was present in 81.44% of patients (fractional exhaled nitric oxide > 30 parts per billion in 46.9%, blood eosinophil count > 300 cell/µL in 39.67%, serum total immunoglobulin E >100 IU/mL in 51.54%, and allergy in 53.71%). By multivariate analysis, type 2 inflammation and blood eosinophils greater than 300 cell/µL were the main predictors (odds ratio [OR] 2.54 and 2.26, respectively) of CRS-asthma association. In particular, CRSwNP comorbidity was predicted by type 2 inflammation (OR 3.4) and blood eosinophils greater than 300 cell/µL (OR 3.0). Smoking had conflicting outcome. CONCLUSION: This study confirmed that CRS is a frequent asthma comorbidity because it affects more than one-third of outpatients with asthma. CRSwNP is associated with type 2 inflammation and blood eosinophilia. These outcomes underline that CRSwNP asthma phenotype deserves adequate attention for careful management and optimal identification of the best-tailored therapy.

Elevated serum IgE, oral corticosteroid dependence and IL-17/22 expression in highly neutrophilic asthma.

Information on the clinical traits associated with bronchial neutrophilia in asthma is scant, preventing its recognition and adequate treatment. We aimed to assess the clinical, functional and biological features of neutrophilic asthma and identify possible predictors of bronchial neutrophilia.The inflammatory phenotype of 70 mild-to-severe asthma patients was studied cross-sectionally based on the eosinophilic/neutrophilic counts in their bronchial lamina propria. Patients were classified as neutrophilic or non-neutrophilic. Neutrophilic asthma patients (neutrophil count cut-off: 47.17 neutrophils·mm-2; range: 47.17-198.11 neutrophils·mm-2; median: 94.34 neutrophils·mm-2) were further classified as high (≥94.34 neutrophils·mm-2) or intermediate (47.17- <94.34 neutrophils·mm-2). The effect of smoking ≥10 pack-years was also assessed.Neutrophilic asthma patients (n=38; 36 mixed eosinophilic/neutrophilic) had greater disease severity, functional residual capacity, inhaled corticosteroid (ICS) dose and exacerbations, and lower forced vital capacity (FVC) % pred and forced expiratory volume in 1 s (FEV1) reversibility than non-neutrophilic asthma patients (n=32; 28 eosinophilic and four paucigranulocytic). Neutrophilic asthma patients had similar eosinophil counts, increased bronchial CD8+, interleukin (IL)-17-F+ and IL-22+ cells, and decreased mast cells compared with non-neutrophilic asthma patients. FEV1 and FVC reversibility were independent predictors of bronchial neutrophilia in our cohort. High neutrophilic patients (n=21) had increased serum IgE levels, sensitivity to perennial allergens, exacerbation rate, oral corticosteroid dependence, and CD4+ and IL-17F+ cells in their bronchial mucosa. Excluding smokers revealed increased IL-17A+ and IL-22+ cells in highly neutrophilic patients.We provide new evidence linking the presence of high bronchial neutrophilia in asthma to an adaptive immune response associated with allergy (IgE) and IL-17/22 cytokine expression. High bronchial neutrophilia may discriminate a new endotype of asthma. Further research is warranted on the relationship between bronchoreversibility and bronchial neutrophilia.

A next generation sequencing approach for targeted Varroa destructor (Acari: Varroidae) mitochondrial DNA analysis based on honey derived environmental DNA.

Honey contains DNA from many different organisms that are part of hive micro-environmental niches and honey bee pathospheres. In this study, we recovered and sequenced mite mitochondrial DNA (mtDNA) from honey from different locations around the world (Europe, Asia, Africa, North and South America). DNA extracted from 17 honey samples was amplified with eight primer pairs targeting three mite mtDNA genes, obtaining 88 amplicons that were sequenced with an Ion Torrent sequencing platform. A bioinformatic pipeline compared produced reads with Varroa spp. mtDNA sequence entries available in GenBank and assigned them to different mitotypes. In all honey samples, the highest percentage of reads was attributed to the K1 lineage, including a few variants derived from it, in addition to J1 reads observed in the two South American samples and C1-1 reads obtained from the Chinese honey. This study opens new possibilities to analyse mite lineages and variants and monitor their geographical and temporal distribution, simplifying surveillance against this damaging honey bee parasite.

Genome-wide patterns of homozygosity provide clues about the population history and adaptation of goats.

BACKGROUND: Patterns of homozygosity can be influenced by several factors, such as demography, recombination, and selection. Using the goat SNP50 BeadChip, we genotyped 3171 goats belonging to 117 populations with a worldwide distribution. Our objectives were to characterize the number and length of runs of homozygosity (ROH) and to detect ROH hotspots in order to gain new insights into the consequences of neutral and selection processes on the genome-wide homozygosity patterns of goats. RESULTS: The proportion of the goat genome covered by ROH is, in general, less than 15% with an inverse relationship between ROH length and frequency i.e. short ROH (< 3 Mb) are the most frequent ones. Our data also indicate that ~ 60% of the breeds display low FROH coefficients (< 0.10), while ~ 30 and ~ 10% of the goat populations show moderate (0.10 < FROH < 0.20) or high (> 0.20) FROH values. For populations from Asia, the average number of ROH is smaller and their coverage is lower in goats from the Near East than in goats from Central Asia, which is consistent with the role of the Fertile Crescent as the primary centre of goat domestication. We also observed that local breeds with small population sizes tend to have a larger fraction of the genome covered by ROH compared to breeds with tens or hundreds of thousands of individuals. Five regions on three goat chromosomes i.e. 11, 12 and 18, contain ROH hotspots that overlap with signatures of selection. CONCLUSIONS: Patterns of homozygosity (average number of ROH of 77 and genome coverage of 248 Mb; FROH < 0.15) are similar in goats from different geographic areas. The increased homozygosity in local breeds is the consequence of their small population size and geographic isolation as well as of founder effects and recent inbreeding. The existence of three ROH hotspots that co-localize with signatures of selection demonstrates that selection has also played an important role in increasing the homozygosity of specific regions in the goat genome. Finally, most of the goat breeds analysed in this work display low levels of homozygosity, which is favourable for their genetic management and viability.

Patterns of homozygosity in insular and continental goat breeds.

BACKGROUND: Genetic isolation of breeds may result in a significant loss of diversity and have consequences on health and performance. In this study, we examined the effect of geographic isolation on caprine genetic diversity patterns by genotyping 480 individuals from 25 European and African breeds with the Goat SNP50 BeadChip and comparing patterns of homozygosity of insular and nearby continental breeds. RESULTS: Among the breeds analysed, number and total length of ROH varied considerably and depending on breeds, ROH could cover a substantial fraction of the genome (up to 1.6 Gb in Icelandic goats). When compared with their continental counterparts, goats from Iceland, Madagascar, La Palma and Ireland (Bilberry and Arran) displayed a significant increase in ROH coverage, ROH number and FROH values (P value < 0.05). Goats from Mediterranean islands represent a more complex case because certain populations displayed a significantly increased level of homozygosity (e.g. Girgentana) and others did not (e.g. Corse and Sarda). Correlations of number and total length of ROH for insular goat populations with the distance between islands and the nearest continental locations revealed an effect of extremely long distances on the patterns of homozygosity. CONCLUSIONS: These results indicate that the effects of insularization on the patterns of homozygosity are variable. Goats raised in Madagascar, Iceland, Ireland (Bilberry and Arran) and La Palma, show high levels of homozygosity, whereas those bred in Mediterranean islands display patterns of homozygosity that are similar to those found in continental populations. These results indicate that the diversity of insular goat populations is modulated by multiple factors such as geographic distribution, population size, demographic history, trading and breed management.

Signatures of selection and environmental adaptation across the goat genome post-domestication.

BACKGROUND: Since goat was domesticated 10,000 years ago, many factors have contributed to the differentiation of goat breeds and these are classified mainly into two types: (i) adaptation to different breeding systems and/or purposes and (ii) adaptation to different environments. As a result, approximately 600 goat breeds have developed worldwide; they differ considerably from one another in terms of phenotypic characteristics and are adapted to a wide range of climatic conditions. In this work, we analyzed the AdaptMap goat dataset, which is composed of data from more than 3000 animals collected worldwide and genotyped with the CaprineSNP50 BeadChip. These animals were partitioned into groups based on geographical area, production uses, available records on solid coat color and environmental variables including the sampling geographical coordinates, to investigate the role of natural and/or artificial selection in shaping the genome of goat breeds. RESULTS: Several signatures of selection on different chromosomal regions were detected across the different breeds, sub-geographical clusters, phenotypic and climatic groups. These regions contain genes that are involved in important biological processes, such as milk-, meat- or fiber-related production, coat color, glucose pathway, oxidative stress response, size, and circadian clock differences. Our results confirm previous findings in other species on adaptation to extreme environments and human purposes and provide new genes that could explain some of the differences between goat breeds according to their geographical distribution and adaptation to different environments. CONCLUSIONS: These analyses of signatures of selection provide a comprehensive first picture of the global domestication process and adaptation of goat breeds and highlight possible genes that may have contributed to the differentiation of this species worldwide.

Genome-wide SNP profiling of worldwide goat populations reveals strong partitioning of diversity and highlights post-domestication migration routes.

BACKGROUND: Goat populations that are characterized within the AdaptMap project cover a large part of the worldwide distribution of this species and provide the opportunity to assess their diversity at a global scale. We analysed genome-wide 50 K single nucleotide polymorphism (SNP) data from 144 populations to describe the global patterns of molecular variation, compare them to those observed in other livestock species, and identify the drivers that led to the current distribution of goats. RESULTS: A high degree of genetic variability exists among the goat populations studied. Our results highlight a strong partitioning of molecular diversity between and within continents. Three major gene pools correspond to goats from Europe, Africa and West Asia. Dissection of sub-structures disclosed regional gene pools, which reflect the main post-domestication migration routes. We also identified several exchanges, mainly in African populations, and which often involve admixed and cosmopolitan breeds. Extensive gene flow has taken place within specific areas (e.g., south Europe, Morocco and Mali-Burkina Faso-Nigeria), whereas elsewhere isolation due to geographical barriers (e.g., seas or mountains) or human management has decreased local gene flows. CONCLUSIONS: After domestication in the Fertile Crescent in the early Neolithic era (ca. 12,000 YBP), domestic goats that already carried differentiated gene pools spread to Europe, Africa and Asia. The spread of these populations determined the major genomic background of the continental populations, which currently have a more marked subdivision than that observed in other ruminant livestock species. Subsequently, further diversification occurred at the regional level due to geographical and reproductive isolation, which was accompanied by additional migrations and/or importations, the traces of which are still detectable today. The effects of breed formation were clearly detected, particularly in Central and North Europe. Overall, our results highlight a remarkable diversity that occurs at the global scale and is locally partitioned and often affected by introgression from cosmopolitan breeds. These findings support the importance of long-term preservation of goat diversity, and provide a useful framework for investigating adaptive introgression, directing genetic improvement and choosing breeding targets.

Genomic Analysis Suggests KITLG is Responsible for a Roan Pattern in two Pakistani Goat Breeds.

The roan coat color pattern is described as the presence of white hairs intermixed with pigmented hairs. This kind of pigmentation pattern has been observed in many domestic species, including the goat. The molecular mechanisms and inheritance that underlie this pattern are known for some species and the KITLG gene has been shown associated with this phenotype. To date, no research effort has been carried out to find the gene(s) that control(s) roan coat color pattern in goats. In the present study, after genotyping with the GoatSNP50 BeadChip, 35 goats that showed a roan pattern and that belonged to two Pakistan breeds (Group A) were analyzed and then compared to 740 goats of 39 Italian and Pakistan goat breeds that did not have the same coat color pattern (Group B). Runs of homozygosity-based and XP-EHH analyses were used to identify unique genomic regions potentially associated with the roan pattern. A total of 3 regions on chromosomes 5, 6, and 12 were considered unique among the group A versus group B comparisons. The A region > 1.7 Mb on chromosome 5 was the most divergent between the two groups. This region contains six genes, including the KITLG gene. Our findings support the hypothesis that the KITLG gene may be associated with the roan phenotype in goats.

The Valdostana goat: a genome-wide investigation of the distinctiveness of its selective sweep regions.

The Valdostana goat is an alpine breed, raised only in the northern Italian region of the Aosta Valley. This breed's main purpose is to produce milk and meat, but is peculiar for its involvement in the "Batailles de Chèvres," a recent tradition of non-cruel fight tournaments. At both the genetic and genomic levels, only a very limited number of studies have been performed with this breed and there are no studies about the genomic signatures left by selection. In this work, 24 unrelated Valdostana animals were screened for runs of homozygosity to identify highly homozygous regions. Then, six different approaches (ROH comparison, Fst single SNPs and windows based, Bayesian, Rsb, and XP-EHH) were applied comparing the Valdostana dataset with 14 other Italian goat breeds to confirm regions that were different among the comparisons. A total of three regions of selection that were also unique among the Valdostana were identified and located on chromosomes 1, 7, and 12 and contained 144 genes. Enrichment analyses detected genes such as cytokines and lymphocyte/leukocyte proliferation genes involved in the regulation of the immune system. A genetic link between an aggressive challenge, cytokines, and immunity has been hypothesized in many studies both in humans and in other species. Possible hypotheses associated with the signals of selection detected could be therefore related to immune-related factors as well as with the peculiar battle competition, or other breed-specific traits, and provided insights for further investigation of these unique regions, for the understanding and safeguard of the Valdostana breed.

Evidence of selection signatures that shape the Persian cat breed.

The Persian cat is mainly characterized by an extremely brachycephalic face as part of the standard body conformation. Despite the popularity, world-wide distribution, and economic importance of the Persian cat as a fancy breed, little is known about the genetics of their hallmark morphology, brachycephaly. Over 800 cats from different breeds including Persian, non-Persian breeds (Abyssinian, Cornish Rex, Bengal, La Perm, Norwegian Forest, Maine Coon, Manx, Oriental, and Siamese), and Persian-derived breeds (British Shorthair, Scottish Fold, Selkirk Rex) were genotyped with the Illumina 63 K feline DNA array. The experimental strategy was composed of three main steps: (i) the Persian dataset was screened for runs of homozygosity to find and select highly homozygous regions; (ii) selected Persian homozygous regions were evaluated for the difference of homozygosity between Persians and those considered non-Persian breeds, and, (iii) the Persian homozygous regions most divergent from the non-Persian breeds were investigated by haplotype analysis in the Persian-derived breeds. Four regions with high homozygosity (H > 0.7) were detected, each with an average length of 1 Mb. Three regions can be considered unique to the Persian breed, with a less conservative haplotype pattern in the Persian-derived breeds. Moreover, two genes, CHL1 and CNTN6 known to determine face shape modification in humans, reside in one of the identified regions and therefore are positional candidates for the brachycephalic face in Persians. In total, the homozygous regions contained several neuronal genes that could be involved in the Persian cat behavior and can provide new insights into cat domestication.