Genome-wide identification of signatures of positive selection in African admixed zebu cattle

The small East African shorthorn zebu (EASZ) is an indigenous stable zebu x taurine admixed cattle population highly adapted to the local African environment, i.e. disease resistance, thermotolerance, sustain themselves on poor feed quality, in comparison to the exotic productive cattle. Understanding the genetic control of their adaptations will help sustainable breeding improvement programs, both within populations and through crossbreeding. In this thesis, genome-wide SNP data, from two commercially available SNP arrays; the Illumina BovineSNP50 BeadChip v.1 and the Illumina BovineHD BeadChip, and full genome sequence of 10 pooled EASZ samples were used to define candidate regions with signatures of positive selection in the genome of EASZ. In chapter 2, the low-density SNP chip has defined 24 candidate regions (21 in the autosomes and three in the sex chromosome X (BTA X) by two Extended Haplotype Homozygosity (EHH)-based (intra-population iHS and inter-population Rsb) analyses and an inter-population FST approach. Characterising the EASZ genome with high-density genome-wide SNP analyses (meta-SS, Rsb, iHS and ΔAF) and pooled heterozygosity (Hp) sequence analysis, in chapters 3 and 4, identified a total of 266 autosomal and 20 BTA X candidate regions. Analysing genome-wide SNP data of zebu cattle populations from Uganda and Nigeria classified some of these regions as East African zebu-sharing and East and West African zebu-sharing candidate regions. Genes and quantitative trait loci (QTL) associated with adaptive traits (e.g., reproduction, immunity and heat stress) were found within the identified candidate regions. Moreover, Nine non-synonymous variants were found in five candidate genes and considered as possible causative mutations under selection. Finally, the mitochondrial DNA (mtDNA) of 13 EASZ were investigated and affiliated to T1a, T1b and T1b1 sub-haplogroups. No selective advantage was found to be associated with taurine mtDNA over the zebu type. Although purifying selection is the main selective factor influencing African cattle mtDNA, in Cox-2 gene of the T1b/ T1b1 sub-haplogroups a non-synonymous mutation may confer a selective advantage. The results of this thesis are just the first milestone to define the valuable genetic material in EASZ, which should be conserved in future composite cattle upon informed selective crossbreeding and/or the recently introduced gene modification techniques (TALEN and CRISPER/Cas9)

Genomic signatures of adaptive introgression and environmental adaptation in the Sheko cattle of southwest Ethiopia

<div><p>Although classified as an African taurine breed, the genomes of Sheko cattle are an admixture of Asian zebu and African taurine ancestries. They populate the humid Bench Maji zone in Sheko and Bench districts in the south-western part of Ethiopia and are considered as a trypanotolerant breed with high potential for dairy production. Here, we investigate the genome of Sheko cattle for candidate signatures of adaptive introgression and positive selection using medium density genome-wide SNP data. Following locus-ancestry deviation analysis, 15 and 72 genome regions show substantial excess and deficiency in Asian zebu ancestry, respectively. Nine and 23 regions show candidate signatures of positive selection following extended haplotype homozygosity (EHH)-based analyses (<i>iHS</i> and <i>Rsb)</i>, respectively. The results support natural selection before admixture for one <i>iHS</i>, one <i>Rsb</i> and three zebu ancestry-deficient regions. Genes and/or QTL associated with bovine immunity, fertility, heat tolerance, trypanotolerance and lactation are present within candidate selected regions. The identification of candidate regions under selection in Sheko cattle warrants further investigation of a larger sample size using full genome sequence data to better characterise the underlying haplotypes. The results can then support informative genomic breeding programmes to sustainably enhance livestock productivity in East African trypanosomosis infested areas.</p></div

Genome-wide identification of signatures of positive selection in African admixed zebu cattle

The small East African shorthorn zebu (EASZ) is an indigenous stable zebu x taurine admixed cattle population highly adapted to the local African environment, i.e. disease resistance, thermotolerance, sustain themselves on poor feed quality, in comparison to the exotic productive cattle. Understanding the genetic control of their adaptations will help sustainable breeding improvement programs, both within populations and through crossbreeding. In this thesis, genome-wide SNP data, from two commercially available SNP arrays; the Illumina BovineSNP50 BeadChip v.1 and the Illumina BovineHD BeadChip, and full genome sequence of 10 pooled EASZ samples were used to define candidate regions with signatures of positive selection in the genome of EASZ. In chapter 2, the low-density SNP chip has defined 24 candidate regions (21 in the autosomes and three in the sex chromosome X (BTA X) by two Extended Haplotype Homozygosity (EHH)-based (intra-population iHS and inter-population Rsb) analyses and an inter-population FST approach. Characterising the EASZ genome with high-density genome-wide SNP analyses (meta-SS, Rsb, iHS and ΔAF) and pooled heterozygosity (Hp) sequence analysis, in chapters 3 and 4, identified a total of 266 autosomal and 20 BTA X candidate regions. Analysing genome-wide SNP data of zebu cattle populations from Uganda and Nigeria classified some of these regions as East African zebu-sharing and East and West African zebu-sharing candidate regions. Genes and quantitative trait loci (QTL) associated with adaptive traits (e.g., reproduction, immunity and heat stress) were found within the identified candidate regions. Moreover, Nine non-synonymous variants were found in five candidate genes and considered as possible causative mutations under selection. Finally, the mitochondrial DNA (mtDNA) of 13 EASZ were investigated and affiliated to T1a, T1b and T1b1 sub-haplogroups. No selective advantage was found to be associated with taurine mtDNA over the zebu type. Although purifying selection is the main selective factor influencing African cattle mtDNA, in Cox-2 gene of the T1b/ T1b1 sub-haplogroups a non-synonymous mutation may confer a selective advantage. The results of this thesis are just the first milestone to define the valuable genetic material in EASZ, which should be conserved in future composite cattle upon informed selective crossbreeding and/or the recently introduced gene modification techniques (TALEN and CRISPER/Cas9)

Assessing genetic diversity and defining signatures of positive selection on the genome of dromedary camels from the southeast of the Arabian Peninsula

Dromedary camels (Camelus dromedarius) are members of the Camelini tribe within the Camelidae family. They are distributed throughout North Africa, the Arabian Peninsula and Southeast Asia. This domestic species is characterized by its superior adaptability to the harsh desert environment. In this study, whole autosomal data of 29 dromedary samples from the Southeast Arabian Peninsula in Oman; 10 from Muscat, 14 from Al-Batinah, and 5 from Al-Sharqiya, were investigated to assess their genetic relationship and to define candidate signatures of positive selection. A minimal genetic distinction that separates Muscat dromedaries from the other two populations was observed, with a degree of genetic admixture between them. Using the de-correlated composite of multiple signals (DCMS) approach, a total of 47 candidate regions within the autosomes of these dromedary populations were defined with signatures of positive selection. These candidate regions harbor a total of 154 genes that are mainly associated with functional categories related to immune response, lipid metabolism and energy expenditure, optical and auditory functions, and long-term memory. Different functional genomic variants were called on the candidate regions and respective genes that warrant further investigation to find possible association with the different favorable phenotypes in dromedaries. The output of this study paves the way for further research efforts aimed at defining markers for use in genomic breeding programs, with the goal of conserving the genetic diversity of the species and enhancing its productivity

Accessibility to biologics and its impact on disease activity and quality of life in patients with rheumatoid arthritis in Kuwait

Objective: Biologics are indicated in rheumatoid arthritis (RA) in case of persistent high disease activity despite conventional disease-modifying anti-rheumatic drugs (cDMARDs) or patients with contraindications to cDMARDs or poor prognostic factors. The purpose of this study was to compare the prescription rates of biologics in Kuwaiti and non-Kuwaiti patients and to assess whether this had an impact on disease activity and quality of life in RA patients. Methods: Data were extracted from the Kuwait Registry for Rheumatic Diseases. Adult patients who satisfied the ACR classification criteria for RA from four major hospitals in Kuwait were evaluated from February 2013 through May 2018. The treatment agents, disease activity, and quality of life of Kuwaiti patients were compared with non-Kuwaiti patients. Results: A total of 1651 RA patients were included; 806 (48.8%) were Kuwaiti patients. Among Kuwaiti patients, 62.5% were on biologic drugs in comparison with 14% of non-Kuwaiti patients. In comparison with non-Kuwaiti patients, Kuwaiti patients had significantly lower numbers of swollen joints (p < 0.001) and disease activity score-28 scores (p = 0.02) and less steroid use (p < 0.001) yet a significantly higher health assessment questionnaire-disability index (p < 0.001). Regression analysis showed that DAS-28 scores were significantly associated with the treatment type (p < 0.001) and that nationality was significantly predictive of the treatment type (p < 0.001). Conclusion: In the setting of easy accessibility to treatment for Kuwaiti patients, biologics were prescribed by rheumatologists at a higher rate than for non-Kuwaitis. This may explain the lower disease activity and the lower rate of steroid use in Kuwaiti patients than non-Kuwaitis. Key points: • Significant discrepancies in the rates of prescribing biologic therapies between KP and NKP in Kuwait were observed. • Several treatment outcomes were significantly better in the KP group than in the NKP group even after adjustment of confounding factors. • The poor access to biologic therapies was suggested to limit the effectiveness of RA treatments in the NKP group

Genome-Wide Variation, Candidate Regions and Genes Associated With Fat Deposition and Tail Morphology in Ethiopian Indigenous Sheep

Variations in body weight and in the distribution of body fat are associated with feed availability, thermoregulation, and energy reserve. Ethiopia is characterized by distinct agro-ecological and human ethnic farmer diversity of ancient origin, which have impacted on the variation of its indigenous livestock. Here, we investigate autosomal genome-wide profiles of 11 Ethiopian indigenous sheep populations using the Illumina Ovine 50 K SNP BeadChip assay. Sheep from the Caribbean, Europe, Middle East, China, and western, northern and southern Africa were included to address globally, the genetic variation and history of Ethiopian populations. Population relationship and structure analysis separated Ethiopian indigenous fat-tail sheep from their North African and Middle Eastern counterparts. It indicates two main genetic backgrounds and supports two distinct genetic histories for African fat-tail sheep. Within Ethiopian sheep, our results show that the short fat-tail sheep do not represent a monophyletic group. Four genetic backgrounds are present in Ethiopian indigenous sheep but at different proportions among the fat-rump and the long fat-tail sheep from western and southern Ethiopia. The Ethiopian fat-rump sheep share a genetic background with Sudanese thin-tail sheep. Genome-wide selection signature analysis identified eight putative candidate regions spanning genes influencing growth traits and fat deposition (NPR2, HINT2, SPAG8, INSR), development of limbs and skeleton, and tail formation (ALX4, HOXB13, BMP4), embryonic development of tendons, bones and cartilages (EYA2, SULF2), regulation of body temperature (TRPM8), body weight and height variation (DIS3L2), control of lipogenesis and intracellular transport of long-chain fatty acids (FABP3), the occurrence and morphology of horns (RXFP2), and response to heat stress (DNAJC18). Our findings suggest that Ethiopian fat-tail sheep represent a uniquely admixed but distinct genepool that presents an important resource for understanding the genetic control of skeletal growth, fat metabolism and associated physiological processes

Long-range linkage disequilibrium events on the genome of dromedary camels as a signal of epistatic and directional positive selection

The genome of dromedary camels has been subjected to various evolutionary forces, such as genetic admixture, natural positive selection, and epistatic selection. These forces are considered as main factors associated with the formation of long-range linkage disequilibrium (LRLD) events. We have analyzed whole-genome data of 56 dromedary camel samples from different geographical regions across the Arabian Peninsula for two main purposes: first, to assess the level of linkage disequilibrium, and second, to identify autosomal LRLD events. The analysis revealed a mean r2 value of 0.25 (±0.028) over the dromedary autosomes, with a continuous decay until reaching a plateau at inter-variant distances >400 kb. A total of 1847 LRLD events were identified within the dromedary autosomes, which harbor 36 prevalent haplotypes. A level of genetic admixture was observed among the dromedary populations analyzed, which might be a source for the observed LRLD events. Four functional interactions were revealed among the genes found within the LRLD events, with some genes overlapping with prevalent haplotypes, indicative of potential epistatic selection. Genes related to renal function, fertility, thermal regulation, bone structure, and insulin regulation were found among the LRLD genes. These genes, along with the defined prevalent haplotypes, can be considered as hotspots for natural positive selection associated with the LRLD distribution on dromedary genomes. In this study, we have for the first time analyzed the genome of dromedary camels for LRLD events possibly influenced by forces including genetic admixture, epistatic and positive selection. The revealed LRLD elements and prevalent haplotypes should be accounted for when designing breeding programmes to conserve the genetic stock of this well-adapted domestic species

Tuberculosis and autoimmune hemolytic anemia: Case report and literature review

Tuberculosis (TB) is a mycobacterial infectious disease that can affect any organ system. The wide varieties of manifestations that TB can present with make the disease a challenge for treating physicians. Anemia is commonly seen in patients with TB, and it is usually anemia of chronic disease. However, the occurrence of autoimmune hemolytic anemia in the setting of TB infection is rare

Polymorphisms in MC1R and ASIP Genes are associated with Coat Color Variation in the Arabian Camel

Pigmentation in mammals is primarily determined by the distribution of eumelanin and pheomelanin, the ratio of which is mostly controlled by the activity of melanocortin 1 receptor (MC1R) and agouti signaling protein (ASIP) genes. Using 91 animals from 10 Arabian camel populations, that included the 4 predominant coat color phenotypes observed in the dromedary (light brown, dark brown, black, and white), we investigated the effects of the MC1R and ASIP sequence variants and identified candidate polymorphisms associated with coat color variation. In particular, we identified a single nucleotide polymorphism (SNP), found in the coding region of MC1R (901C/T), linked to the white coat color, whereas a 1-bp deletion (23delT/T) and a SNP (25G/A) in exon 2 of ASIP are associated with both black and dark-brown coat colors. Our results also indicate support that the light-brown coat color is likely the ancestral coat color for the dromedary. These sequence variations at the MC1R and ASIP genes represent the first documented evidence of candidate polymorphisms associated with Mendelian traits in the dromedary