314
Xenopus
SNPs appear inside the coding region and have no effect on
the amino acid sequence or the protein function. However,
some synonymous SNPs have been linked to human disease
(Sauna and Kimchi-Sarfaty, 2011). (2) SNPs within the coding region that cause protein sequence changes are classif ed
as non-synonymous. These can be missense SNPs that result
in amino acid changes or nonsense (stop codon) SNPs that
cause premature termination of the protein. (3) SNPs located
in non-protein coding regions can affect the sequence and
structure of the encoded RNA, regulatory elements or promoters, splicing properties, or RNA stability.
Other common polymorphisms in the human genome
include short tandem repeats (STRs), insertions/deletions
(indels), transposable elements (TEs) or Alu repeats, structural
variations (SVs), and copy number variations (CNVs). STRs
(microsatellites) are tandem 1–6 bp repeats that make up ~3%
of the human genome. Most are polymorphic in nature and
thus are used in forensic DNA typing (Novroski et al., 2018;
Saini et al., 2018). STRs can be located within promoters,
exons, introns, or intergenic regions; they can modulate gene
expression and alter proteins by coding for repeated amino
acids, as in some nervous system diseases (Saini et al., 2018).
Other types of repeats include minisatellites (10–100 bp) and
macrosatellites (>100 bp) (Richard et al., 2008). Indels can
range from 1 to several hundred bps in length, are widespread
across the genome, and are the second most common type of
genetic variability. Indels cause extensive variation in human
genes; those located in functionally important sites are likely
to affect traits and disease susceptibility (Barton and Zeng,
2018; Montgomery et al., 2013; Mullaney et al., 2010).
SVs refer to architectural and quantitative chromosomal
rearrangements, usually involving DNA segments of 1Kb
or more. SVs include deletions, duplications, insertions, and
translocations (Spielmann et al., 2018). If the SV causes
changes in the diploid status of a genomic region, it is def ned
as a copy number variation (Spielmann et al., 2018; Zarrei
et al., 2015). SVs contribute to the genetic diversity of the
human genome and play important roles in cancer genetics,
rare diseases, and evolutionary genetics. SVs can affect either
coding or non-coding regions or the three-dimensional organization of the DNA by disrupting higher-order chromatin
structure infuencing the expression of distant genes, thereby
causing disease (Spielmann et al., 2018).
Transposable elements are segments of DNA that can
move around the genome and were previously referred
to as “junk DNA,” but today we know they are important
for gene regulation and evolution ( Biémont and Vieira,
2006 ). Sometimes TE insertion disrupts a gene’s function
or expression pattern or triggers chromosomal rearrangements that are involved in cancer and other diseases ( Jönsson
et al., 2020 ).
22.1.2. THE CONTRIBUTION OF GENETIC
POLYMORPHISMS TO HUMAN DISEASE
Numerous studies have analyzed the involvement of genetic
polymorphisms in human disease. For example, drug
metabolism performed by cytochrome P450 (CYP) enzymes
can be affected by genetic polymorphisms, resulting in differences in drug response between individuals and even
adverse drug reactions (Manikandan and Nagini, 2018; Zhou
et al., 2009, 2017). Depending on the CYP polymorphism,
individuals can metabolize drugs either poorly, extensively,
or ultrarapidly. Many polymorphisms are ethnic group
dependent, leading to differences in drug responsiveness
between world populations (Bachtiar et al., 2019; McGraw
and Waller, 2012).
Polymorphisms also affect the severity of defects seen
in fetal alcohol spectrum disorder (FASD), a complex set
of congenital malformations, neurobehavioral anomalies,
and intellectual disabilities resulting from maternal alcohol
consumption during pregnancy. The biochemical similarity
between ethanol metabolism and retinoic acid (RA) biosynthesis led to the suggestion that ethanol clearance competes
with the metabolism of retinol (vitamin A), thus reducing
RA signaling (reviewed in Fainsod et al., 2020; Shabtai and
Fainsod, 2018). Epidemiological studies indicate that the
incidence and severity of FASD phenotypes have a genetic
component (Eberhart and Parnell, 2016; Garic et al., 2014;
Green et al., 2007). Studies focusing on the ADH1B gene
found “protective” polymorphisms. ADH1B has 3 common
alleles encoding for isozymes with different kinetic characteristics. The ADH1B * 2 and ADH1B * 3 isozymes have
a turnover rate over 80 times greater than the ADH1B *
1 variant. Expression of the “fast” alleles results in rapid
acetaldehyde accumulation at the same blood alcohol
concentration compared to individuals carrying the ADH1B
* 1 allele (Hurley and Edenberg, 2012). Except for one study,
all studies found that ADH1B*3 lowers the risk of FASD
(Green and Stoler, 2007).
The pathologies of many infectious, autoimmune, and
malignant diseases are infuenced by the profles of cytokine production in pro-infammatory (TH1) and antiinfammatory (TH2) T cells. Individual differences in
cytokine profles appear to be due, at least in part, to
genetic polymorphisms within regulatory regions of cytokine genes (Bidwell et al., 1999). Toll-like receptor (TLR)
genes, whose proteins are an important link between innate
and adaptive immunity, exhibit SNPs, small-scale indels,
polymorphic repetitive elements, and microsatellite variation. Polymorphic variants of TLRs are associated with
several infammatory disorders, including a higher risk of
prostate cancer (Sun et al., 2006), protection against leprosy
(Johnson et al., 2007), higher risk of developing tuberculosis
(Wu and Yang, 2015), susceptibility to inf ammatory bowel
disease (Török et al., 2017), increased risk for gram-negative
bacteremia and sepsis, and increased prevalence of hepatitis
B virus infection (Vijay, 2018).
22.2. SUMMARY OF THE FIELD
Although genetic polymorphisms impact human health and
disease, research has commonly been performed in animals
that share extensive genotypic composition to minimize the
Xenopus
SNPs appear inside the coding region and have no effect on
the amino acid sequence or the protein function. However,
some synonymous SNPs have been linked to human disease
(Sauna and Kimchi-Sarfaty, 2011). (2) SNPs within the coding region that cause protein sequence changes are classif ed
as non-synonymous. These can be missense SNPs that result
in amino acid changes or nonsense (stop codon) SNPs that
cause premature termination of the protein. (3) SNPs located
in non-protein coding regions can affect the sequence and
structure of the encoded RNA, regulatory elements or promoters, splicing properties, or RNA stability.
Other common polymorphisms in the human genome
include short tandem repeats (STRs), insertions/deletions
(indels), transposable elements (TEs) or Alu repeats, structural
variations (SVs), and copy number variations (CNVs). STRs
(microsatellites) are tandem 1–6 bp repeats that make up ~3%
of the human genome. Most are polymorphic in nature and
thus are used in forensic DNA typing (Novroski et al., 2018;
Saini et al., 2018). STRs can be located within promoters,
exons, introns, or intergenic regions; they can modulate gene
expression and alter proteins by coding for repeated amino
acids, as in some nervous system diseases (Saini et al., 2018).
Other types of repeats include minisatellites (10–100 bp) and
macrosatellites (>100 bp) (Richard et al., 2008). Indels can
range from 1 to several hundred bps in length, are widespread
across the genome, and are the second most common type of
genetic variability. Indels cause extensive variation in human
genes; those located in functionally important sites are likely
to affect traits and disease susceptibility (Barton and Zeng,
2018; Montgomery et al., 2013; Mullaney et al., 2010).
SVs refer to architectural and quantitative chromosomal
rearrangements, usually involving DNA segments of 1Kb
or more. SVs include deletions, duplications, insertions, and
translocations (Spielmann et al., 2018). If the SV causes
changes in the diploid status of a genomic region, it is def ned
as a copy number variation (Spielmann et al., 2018; Zarrei
et al., 2015). SVs contribute to the genetic diversity of the
human genome and play important roles in cancer genetics,
rare diseases, and evolutionary genetics. SVs can affect either
coding or non-coding regions or the three-dimensional organization of the DNA by disrupting higher-order chromatin
structure infuencing the expression of distant genes, thereby
causing disease (Spielmann et al., 2018).
Transposable elements are segments of DNA that can
move around the genome and were previously referred
to as “junk DNA,” but today we know they are important
for gene regulation and evolution ( Biémont and Vieira,
2006 ). Sometimes TE insertion disrupts a gene’s function
or expression pattern or triggers chromosomal rearrangements that are involved in cancer and other diseases ( Jönsson
et al., 2020 ).
22.1.2. THE CONTRIBUTION OF GENETIC
POLYMORPHISMS TO HUMAN DISEASE
Numerous studies have analyzed the involvement of genetic
polymorphisms in human disease. For example, drug
metabolism performed by cytochrome P450 (CYP) enzymes
can be affected by genetic polymorphisms, resulting in differences in drug response between individuals and even
adverse drug reactions (Manikandan and Nagini, 2018; Zhou
et al., 2009, 2017). Depending on the CYP polymorphism,
individuals can metabolize drugs either poorly, extensively,
or ultrarapidly. Many polymorphisms are ethnic group
dependent, leading to differences in drug responsiveness
between world populations (Bachtiar et al., 2019; McGraw
and Waller, 2012).
Polymorphisms also affect the severity of defects seen
in fetal alcohol spectrum disorder (FASD), a complex set
of congenital malformations, neurobehavioral anomalies,
and intellectual disabilities resulting from maternal alcohol
consumption during pregnancy. The biochemical similarity
between ethanol metabolism and retinoic acid (RA) biosynthesis led to the suggestion that ethanol clearance competes
with the metabolism of retinol (vitamin A), thus reducing
RA signaling (reviewed in Fainsod et al., 2020; Shabtai and
Fainsod, 2018). Epidemiological studies indicate that the
incidence and severity of FASD phenotypes have a genetic
component (Eberhart and Parnell, 2016; Garic et al., 2014;
Green et al., 2007). Studies focusing on the ADH1B gene
found “protective” polymorphisms. ADH1B has 3 common
alleles encoding for isozymes with different kinetic characteristics. The ADH1B * 2 and ADH1B * 3 isozymes have
a turnover rate over 80 times greater than the ADH1B *
1 variant. Expression of the “fast” alleles results in rapid
acetaldehyde accumulation at the same blood alcohol
concentration compared to individuals carrying the ADH1B
* 1 allele (Hurley and Edenberg, 2012). Except for one study,
all studies found that ADH1B*3 lowers the risk of FASD
(Green and Stoler, 2007).
The pathologies of many infectious, autoimmune, and
malignant diseases are infuenced by the profles of cytokine production in pro-infammatory (TH1) and antiinfammatory (TH2) T cells. Individual differences in
cytokine profles appear to be due, at least in part, to
genetic polymorphisms within regulatory regions of cytokine genes (Bidwell et al., 1999). Toll-like receptor (TLR)
genes, whose proteins are an important link between innate
and adaptive immunity, exhibit SNPs, small-scale indels,
polymorphic repetitive elements, and microsatellite variation. Polymorphic variants of TLRs are associated with
several infammatory disorders, including a higher risk of
prostate cancer (Sun et al., 2006), protection against leprosy
(Johnson et al., 2007), higher risk of developing tuberculosis
(Wu and Yang, 2015), susceptibility to inf ammatory bowel
disease (Török et al., 2017), increased risk for gram-negative
bacteremia and sepsis, and increased prevalence of hepatitis
B virus infection (Vijay, 2018).
22.2. SUMMARY OF THE FIELD
Although genetic polymorphisms impact human health and
disease, research has commonly been performed in animals
that share extensive genotypic composition to minimize the