Xenopus
22 A Model to Study Natural Genetic
Variation and Its Disease Implications
Avi Leibovich, Sally A. Moody, Steven L. Klein, and Abraham Fainsod
CONTENTS
22.1. Historical Background ............................................................................................................................................. 313
22.1.1. Natural Polymorphisms in the Human Genome ....................................................................................... 313
22.1.2. The Contribution of Genetic Polymorphisms to Human Disease ............................................................. 314
22.2. Summary of the Field ............................................................................................................................................... 314
22.2.1. Mouse Inbred Lines .................................................................................................................................. 315
22.2.2. Common Fish Lines .................................................................................................................................. 315
22.2.3. Available Xenopus Lines ........................................................................................................................... 315
22.3. Present State of the Field ......................................................................................................................................... 316
22.3.1. The Advantages of Outbred Lines............................................................................................................. 316
22.3.2. Using Xenopus to Study the Impact of Genetic Variation on Development and Disease ......................... 316
22.4. Future Outlook ......................................................................................................................................................... 320
Acknowledgments ................................................................................................................................................................ 320
Funding ................................................................................................................................................................................ 320
References ............................................................................................................................................................................ 320
Polymorphisms in protein-coding exons can result in nonfunctional, hypomorphic, or hyperactive proteins, whereas
those in regulatory elements can inf uence penetrance,
dominance, expressivity, and pleiotropy. For nearly 40
years, research to understand the function of individual
genes has focused on utilizing inbred animals to eliminate
the confounding infuences of polymorphisms, second-site
mutations, and modifer genes. However, it has become
increasingly clear that these genetic polymorphisms in
the human population are very prevalent and contribute to
variable phenotypes, disease susceptibility, and responses
to environmental factors and therapies. This chapter summarizes the relationship between human genetic variation
and disease, discusses why inbred experimental models are
inadequate for examining this relationship, and summarizes the important role of the frog, Xenopus, as an excellent
outbred experimental system to study the effects of genetic
polymorphisms in human disease.
22.1. HISTORICAL BACKGROUND
22.1.1. NATURAL POLYMORPHISMS IN THE HUMAN GENOME
Even though the frst draft of the human genome sequence
was released nearly 20 years ago, the current human reference genome is still predominantly derived from a very
limited number of individuals (International Human Genome
Sequencing Consortium, 2004; Lander et al., 2001; Venter et
al., 2001). Accordingly, it does not represent the considerable
genetic variation that exists across the world’s human population (Ballouz et al., 2019; Wong et al., 2020). We now appreciate the signifcance of this defciency because this genetic
variation helps to explain why different populations are differentially susceptible to certain diseases and exhibit different
responses to environmental factors and medical treatments
(Choudhury et al., 2014; Posey, 2019; Zerbino et al., 2020).
Accordingly, there is growing interest in understanding these
genetic variations and in constructing databases that catalogue them.
Genetic diversity among ethnicities, called genetic polymorphisms (Kruglyak and Nickerson, 2001), make up only
about 1% of the genome and are responsible for common differences between humans such as eye, skin, and hair color
(Pavan and Sturm, 2019; White and Rabago-Smith, 2011)
but can also affect susceptibility to disease. A “genetic polymorphism” is a variation in a given gene locus that occurs
with a frequency of 1% or more in a given population. Less
common variations are referred to as “mutations” (Karki
et al., 2015; Kruglyak and Nickerson, 2001; Stenson et al.,
2017). The most common form is the substitution of a single base pair, known as a single-nucleotide polymorphism
(SNP) (Kruglyak and Nickerson, 2001). This small change
can have different consequences depending on the location or degree of change within the gene: (1) Synonymous
DOI: 10.1201/9781003050230-25
313
22 A Model to Study Natural Genetic
Variation and Its Disease Implications
Avi Leibovich, Sally A. Moody, Steven L. Klein, and Abraham Fainsod
CONTENTS
22.1. Historical Background ............................................................................................................................................. 313
22.1.1. Natural Polymorphisms in the Human Genome ....................................................................................... 313
22.1.2. The Contribution of Genetic Polymorphisms to Human Disease ............................................................. 314
22.2. Summary of the Field ............................................................................................................................................... 314
22.2.1. Mouse Inbred Lines .................................................................................................................................. 315
22.2.2. Common Fish Lines .................................................................................................................................. 315
22.2.3. Available Xenopus Lines ........................................................................................................................... 315
22.3. Present State of the Field ......................................................................................................................................... 316
22.3.1. The Advantages of Outbred Lines............................................................................................................. 316
22.3.2. Using Xenopus to Study the Impact of Genetic Variation on Development and Disease ......................... 316
22.4. Future Outlook ......................................................................................................................................................... 320
Acknowledgments ................................................................................................................................................................ 320
Funding ................................................................................................................................................................................ 320
References ............................................................................................................................................................................ 320
Polymorphisms in protein-coding exons can result in nonfunctional, hypomorphic, or hyperactive proteins, whereas
those in regulatory elements can inf uence penetrance,
dominance, expressivity, and pleiotropy. For nearly 40
years, research to understand the function of individual
genes has focused on utilizing inbred animals to eliminate
the confounding infuences of polymorphisms, second-site
mutations, and modifer genes. However, it has become
increasingly clear that these genetic polymorphisms in
the human population are very prevalent and contribute to
variable phenotypes, disease susceptibility, and responses
to environmental factors and therapies. This chapter summarizes the relationship between human genetic variation
and disease, discusses why inbred experimental models are
inadequate for examining this relationship, and summarizes the important role of the frog, Xenopus, as an excellent
outbred experimental system to study the effects of genetic
polymorphisms in human disease.
22.1. HISTORICAL BACKGROUND
22.1.1. NATURAL POLYMORPHISMS IN THE HUMAN GENOME
Even though the frst draft of the human genome sequence
was released nearly 20 years ago, the current human reference genome is still predominantly derived from a very
limited number of individuals (International Human Genome
Sequencing Consortium, 2004; Lander et al., 2001; Venter et
al., 2001). Accordingly, it does not represent the considerable
genetic variation that exists across the world’s human population (Ballouz et al., 2019; Wong et al., 2020). We now appreciate the signifcance of this defciency because this genetic
variation helps to explain why different populations are differentially susceptible to certain diseases and exhibit different
responses to environmental factors and medical treatments
(Choudhury et al., 2014; Posey, 2019; Zerbino et al., 2020).
Accordingly, there is growing interest in understanding these
genetic variations and in constructing databases that catalogue them.
Genetic diversity among ethnicities, called genetic polymorphisms (Kruglyak and Nickerson, 2001), make up only
about 1% of the genome and are responsible for common differences between humans such as eye, skin, and hair color
(Pavan and Sturm, 2019; White and Rabago-Smith, 2011)
but can also affect susceptibility to disease. A “genetic polymorphism” is a variation in a given gene locus that occurs
with a frequency of 1% or more in a given population. Less
common variations are referred to as “mutations” (Karki
et al., 2015; Kruglyak and Nickerson, 2001; Stenson et al.,
2017). The most common form is the substitution of a single base pair, known as a single-nucleotide polymorphism
(SNP) (Kruglyak and Nickerson, 2001). This small change
can have different consequences depending on the location or degree of change within the gene: (1) Synonymous
DOI: 10.1201/9781003050230-25
313