Identification of Adaptive Signatures in the Cattle Genome

Abstract

Cattle are one of the most common and numerous domestic ungulates. The genomes of domes¬ticated cattle breeds harbor the history of domestication and breed for¬mation due to the combined effect of natural and artificial selection forces. Deciphering the footprints of these selection forces in the genome of cattle breeds is of great interest from the perspective of evolutionary biology seeking to understand the key adaptive features that have generated enormous morphological and production phenotypic variations currently observed within and between populations. Recently, professionals from molecular popu¬lation and evolu¬tionary genetics have shown growing interest in distinguishing neutral molecular vari¬ations from variations that are subject to selection, particularly positive selection, in the genomes of multiple organisms including cattle. The building of the bovine reference genome and the accumulation of single nucleotide polymorphism (SNP) data from geo¬graphically and biologically diverse cattle breeds – due to the emergence of low cost and high throughput Next Generation Sequencing (NGS) technologies – has created unprecedented opportunities and facilitated efforts to uncover and understand this variation. In this doctoral dissertation, the whole genome NGS SNP data from African, NDama, Ankole, Holstein, Hanwoo, and Angus cattle breeds were used to elucidate the footprints of natural and artificial selection forces that have contributed to the major phenotypes of the respective breeds. The cross-population extended haplotype homozygosity (XP-EHH) and cross-population composite likelihood ratio (XP-CLR) statistical methods were used to search for the genes/gene regions affected due to selection. The reference genome of cattle (UMD3.1) was used to annotate genes in outlier regions under selection from these analyses. I used the Database for Annotation, Visualization, and Integrated Discovery (DAVID) gene ontology and annotation tool for gene enrichment analysis to understand the biological functions and pathways of genes iden¬tified under selection. In Chapter 1, I introduced the variations in cattle breeds with special emphasis to African cattle breeds, the principles behind signature of positive selection, and the objectives and methods of identification of signature of positive selection. In addition, previously reported results of studies on selection signatures from genetically diverse cattle breeds were reviewed. In Chapter 2, the genome of African cattle breeds was compared with the genome of Commercial Asian-European taurine cattle breeds to reveal genomic regions under selection in African cattle in relation to tropical environment adaptation traits. African cattle breeds have evolved in a hot tropical climate for millennia, which helped them to develop an inherent superior thermotolerance ability. The study revealed several genes/gene regions under selection that are overrepresented in different biological process (BP) terms and pathways in a gene enrichment analysis. In relation to heat stress response, angiogenesis and regeneration BP terms were enriched. Moreover, several selected genes were involved in anatomical structures, and physi¬ological and/or molecular functions that are associated with heat tolerance mecha¬nisms. These genes are involved in oxidative stress response, osmotic stress response, heat shock response, hair and skin properties, sweat gland devel¬opment and sweating, feed intake and metabolism, and reproduction functions. Therefore, the genes and BP terms identified here directly and/or indirectly con¬tribute to the superior heat tolerance mechanisms of African cattle populations. The high tropical temperature where these cattle breeds have evolved for millennia could be a selec¬tive pressure for the develop¬ment of these thermotolerance mechanisms. In Chapter 3, the genomes of Holstein, Hanwoo, and NDama cattle breeds were explored in order to decipher genomic regions affected due to divergent selection for milk traits, meat production and quality traits, and environ¬mental adaptation traits, respectively. Artificial and natural selection for a particular trait in cattle have signif¬icantly modified the cattle genome. Due to this, several cattle breeds have been developed with a mosaic of morphological, productivity, and environmental adapta¬tion characteristics. Holstein cattle are evolved as dairy cattle and Hanwoo cattle are evolved as beef cattle under artificial selection, whereas NDama cattle are evolved as a general-purpose breed – a breed that does not artificially selected for a particular purpose under natural selection. Identifying genomic regions affected due to artificial and natural selection forces in cattle would give an insight into the history of selection for economically important traits and genetic adaptation to specific environments of populations under consideration. From this study, genes/gene regions that are related to milk traits (e.g., CSN3, PAPPA2, and ADIPOQ), meat production and quality traits (e.g., NCOA2, and PITPN3), and environmental adaptation traits (e.g., SLC40A1, STOM, and COMMD1) were found under positive selection from the genomes of Holstein, Hanwoo and NDama cattle breeds, respectively. Moreover, significant functional annotation cluster terms including milk protein and thyroid hormone signaling pathway, histone acetyl-trans¬ferase activity, and renin secretion were enriched from gene lists identified under selec¬tion in Holstein, Hanwoo, and NDama cattle breeds, respectively. In Chapter 4, the genome of Ankole cattle (African Sanga cattle) was explored in order to identify genes and genomic regions under positive selection in relation to meat quality traits. African Sanga cattle are an intermediate type of cattle resulting from interbreeding between B. taurus and B. indicus sub-species. Recently, experi¬mental evidence on the po¬tential of African Sanga cattle breeds for superior beef quality traits over their indicine coun¬terparts has emerged. In this study, the whole genome SNP data of Ankole (Sanga cattle) was compared with the genome of indicine cattle breeds using XP-EHH and XP-CLR statistical methods. As a result, several genes including those affecting beef quality traits such as tenderness, intramuscular fat (IMF) content, and meat color were found under posi¬tive selection. The genes identified are involved in BP terms and KEGG pathways that affect muscle structure and metabolism, adipose metabolism, and adipogenesis – which in turn affects meat quality traits. This study asserted that Ankole cattle have the potential for higher meat production and quality traits under the prevailing tropical environmental conditions. These results provide a basis for further re-search on the genomic characteristics of Ankole and other Sanga cattle breeds for better quality beef in tropical Africa. In Chapter 5, the genetic blueprint behind the superior beef quality characteristics and other associated phenotypes of Angus cattle were elucidated. Angus cattle have been inten¬sively selected for superior beef quality characteristics for decades. Anno¬tating genomic re¬gions under selection in the genomes of Angus cattle resulted in several genes including those associated with beef quality traits and coat color. In addition, putative genes that po-tentially cause genetic disorders in Angus cattle were identified. The results from this study will help to further improve Angus cattle beef quality, and take a precaution on the associated genetic disorders which ultimately reduce production and productivity. In conclusion, from these studies, a catalog of genes were identified under positive selection from African, NDama, Ankole, Holstein, Hanwoo, and Angus cattle breeds in relation to the major economic and adaptation traits of the respective breeds to which they have been selected for. The findings in this dissertation will help us to better understand the adaptive events that have generated the enormous phenotypic variation observed between cattle breeds prevailing today. Molecular markers that contribute to local environmental adaptations (e.g., thermotolerance mechanisms - markers that are difficult to identify with other laboratory experimental methods) were revealed in addition to those affecting production traits such as milk production and quality, beef production and quality, reproduction and other associated traits. The markers identified in these studies help to understand the genetic merit of the breeds and can be used in genomic selection and breeding programs to further improve the respective breeds.