Delineating the genetic landscape of mammals on the bases of genome-wide association study and positive selection scan using single nucleotide polymorphism

Abstract

The perpetual goals of human genetics are to comprehend the genetic architecture of complex traits and transfer the genetic findings into medical field in order to improve disease diagnosis and treatment. Similarly, for animals, studies can contribute to enhancing selection methods for genetic improvement of animal production and to better understanding of population history, domestication and breed formation. However, for any one trait, hundreds of single nucleotide polymorphism that are significantly related to complex traits account for only a small fraction of the genetic variation. In this regard, the aim of this thesis is to fill in the gaps in the knowledge of mammalian genetic background underlying complex traits through genome-wide association study and positive selection scan. A new approach of comparative study was demonstrated in Chapter 2 by adopting the concept of an important parameter in genetics, heritability. Heritability is the proportion of phenotypic variation attributed to genetic components and thus provides insights into the biological significance of a certain trait. Common obesity trait for human and pig, the back-fat thickness, was analyzed to suggest candidate markers and genes that possibly control obesity. Furthermore, I noted that human chromosome 2 (syntenic to pig chromosomes 3 and 15) was the most crucial in explaining the phenotypic variance for obesity. Genotype-by-environment interaction (G×E) is considered as one of the most important reasons for observing missing heritability. However, majorly due to the lack of high enough statistical power, G×E studies have not yielded promising results. I analyzed how much G×E contributed to variance on a genome-wide scale to better understand the genetic underpinnings of 49 human complex traits in unrelated Korean cohorts in Chapter 3. The statistically significant proportion of variance was explained by genotype-area interactions in the supra-iliac skinfold thickness trait, which is associated with abdominal obesity. This finding may lead to conceptual advances in the understanding of the mechanisms underlying G×E. The rapid development of large-scale catalogs of genetic variation has led to increased interest in identifying targets of positive selection, as signatures of positive selection delimit regions of the genome that are functionally important. Hence, characterization of such genomic regions can allow us to detect genetic variation that contributes to phenotypic diversity and facilitate functional annotation of the genome more thoroughly. Holstein cattle are a great example of domestication

they provide higher milk yields than most other breeds, and the dominant position of Holstein today is the result of intense selection pressures. In Chapter 4, by performing whole-genome re-sequencing analysis of Holstein and searching for genomic regions with strong evidence of domestication, I identified genes likely involved in the yield and proteins of milk and their distinctive black-and-white markings. Further, in Chapter 5, genetic blueprint behind Korean native black pigs from Jeju Island was deciphered to find the candidate genes potentially under positive selection that support the previous reports of higher marbling score, inferior growth and carcass traits compared to Western breeds. The findings in this study demonstrated the importance of the heritability-based genome-wide association study and signatures of positive selection and thus may contribute to dissecting the dark matter of the genome.