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Applying Forward Genetic Approaches to Rare Mendelian Disorders and Complex Traits

Chen, Anlu
http://orcid.org/0000-0003-0559-0882
http://rave.ohiolink.edu/etdc/view?acc_num=case1532522241487661

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Forward genetics utilizes unbiased genetic approaches to locate causal genetic variants of heritable traits. Classic forward genetics approaches were tremendously successful, but are now widely considered too time-consuming and laborious. Technological and methodological innovations, such as next-generation sequencing, have ushered in a new era of forward genetics studies to better understand the genetic basis of disease. In this dissertation, I provided examples of forward genetic approaches that successfully identified novel genetic causes of two rare Mendelian disorders (Chapter 2,3) and further discovered the genetic architecture of metabolism-related complex traits (Chapter 4). Mendelian disorders are caused by variants in a single gene, while complex traits are regulated by multiple genes, which either work independently or interact with each other. In Chapters 2 and 3, we explored the exome sequence of patients from consanguineous families to identify causal genetic variants, which were further studied using cellular and animal models. Our findings unveiled novel functions of the genes MRPS22 and PIK3C2A, and facilitated a better understanding of normal and pathological development of their associated disorders. Our study expanded the phenotypic spectrum of MRPS22 mutations from mitochondrial diseases to now also include primary ovarian insufficiency and elucidated its cell autonomous role in germ cell development. Our study on syndromic short stature associated with cataracts and skeletal abnormalities also identified the first Mendelian disorder associated with PIK3C2A mutations, whose in vivo role was poorly understood. In Chapter 4, we identified widespread epistatic interactions using double chromosome substitution stains in mice and provided strong evidence for the controversial contribution of epistasis to genetically complex traits and diseases. Our findings demonstrated that epistatic interactions controlled the majority of the heritable variation in both fasting plasma glucose levels and hepatic gene expression, even greater than the additive effects on these traits. These findings may partially explain the phenomenon of `missing heritability’ in complex traits. We also identified that the epistatic interactions were prone to keep trait levels at their “normal” level. We hypothesize that this is evolutionarily advantageous, enabling stored genetic variants in the genome without reducing fitness while allowing for rapid adaptation to future environmental challenges.
Hung-Ying Kao (Committee Chair)
Anna Mitchell (Committee Member)
Anthony Wynshaw-Boris (Committee Member)
Eckhard Jankowsky (Committee Member)
David Buchner (Advisor)
198 p.
Genetics
rare Mendelian disorders; complex traits; epistasis; MRPS22; PIK3C2A

Recommended Citations

Citations

  • Chen, A. (2018). Applying Forward Genetic Approaches to Rare Mendelian Disorders and Complex Traits [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1532522241487661

    APA Style (7th edition)

  • Chen, Anlu. Applying Forward Genetic Approaches to Rare Mendelian Disorders and Complex Traits. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1532522241487661.

    MLA Style (8th edition)

  • Chen, Anlu. "Applying Forward Genetic Approaches to Rare Mendelian Disorders and Complex Traits." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1532522241487661

    Chicago Manual of Style (17th edition)

case1532522241487661
348
© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.