M7 Application assignment - Mutation Results for Elise
Finlay (She/Her/Hers)
Correct answers are hidden.
Score for this attempt: 31 out of 31
Submitted Jun 24 at 1:54pm
This attempt took 5 minutes.
Question 1
pts
LO51 Identify the concept and importance of mutations
LO55 Explain the differences between incorporated and replicated mutations
The following is an excerpt of the article "EPAS1 Gain-of-Function Mutation Contributes to High-
Altitude Adaptation in Tibetan Horses (https://academic.oup.com/mbe/article/36/11/2591/5526924)
"Recent functional genomic studies have revealed the genetic basis of adaption to high-altitude
hypoxia in Tibetan people (Simonson et al. 2010; Yi et al. 2014), Tibetan dogs (Wang et al. 2014),
antelopes (Ge et al. 2013) and gray wolves (Zhang et al. 2014). Although other selection targets have
been reported, the endothelial PAS domain protein 1 (EPAS1) gene often appears as a common
selection target, providing a striking example of convergent evolution across a range of mammals
exposed to similar environmental pressure in the Qinghai-Tibetan (QT) Plateau. The EPAS1 gene
encodes one subunit of the hypoxia-inducible factor (HIF) and shows multifarious effects, including
the regulation of angiogenesis, hemoglobin concentration (HMG) and erythrocytosis (Beall et al.
2010).
In this study, we undertook the first genomic analysis of selection signatures in Tibetan horses, aiming
at identifying the genetic basis for adaptation to high-altitude hypoxia in the QT Plateau. To achieve
this, we sequenced the genome of 138 Chinese horses spanning a wide range of altitudes, from the
lowland regions of the Northeastern Plain to the mountains of the QT Plateau. (We identified a) total
of 10,376,152 single nucleotide polymorphisms[...]. Less than 1% of the SNP variants were located in
exonic regions (30,094 [0.279%] were missense, 57,270 [0.456%] synonymous) (supplementary table
S3, Supplementary Material online). Approximately 10% were present in downstream or upstream
gene regulatory regions whereas the remaining dominant fraction (∼89%), spread across intergenic
and intronic
,regions.
We noticed that two SNPs within the most significant selection region represent missense variants of
the EPAS1 gene (fig. 3 and supplementary tables S21–S23, Supplementary Material online). They
are located at positions 52,566,293 and 52,552,723 of chromosome 15 [...] The EPAS1 protein is
highly conserved among mammals, with two heterodimerization PAS domains showing close to 100%
sequence similarity amongst 22 different species, including humans and horses living at low altitude.
The missense variants (hereafter referred to as EPAS1 R144C and E263D , respectively) are not
present in Przewalski’s horses, suggesting that they arose in an independent genetic background.
Under hypoxic conditions, the EPAS1 protein is known to be translocated into the nucleus, where it
binds the aryl hydrocarbon receptor nuclear translocator ARNT (HIF-1β). The resulting heterodimer
can then bind to DNA hypoxia response elements (HRE) where it initiates the transcription of key
genes involved in the response to hypoxia, such as erythropoietin (EPO), lactate dehydrogenase A
(LDHA), endothelin (EDN1), vascular endothelial growth factor A (VEGFA), von Hippel-Lindau (VHL)
and prolyl pydroxylase domain-containing protein 2 (PHD2, also EGLN1; Lee et al. 2011).
Coimmunoprecipitation assays confirmed the strong protein–protein interaction between the wild-type
EPAS1
and ARNT proteins. This interaction was greatly enhanced in the EPAS1 R144C mutant but did not
significantly change for the E263D mutant.
The mRNA expression levels of four out of the seven downstream genes tested (EDN1, LDHA, VHL
and EPO) were significantly increased in R144C transfected cells"
Select the statements that are true considering that a Single nucleotide polymorphism represents a
change in the sequence of nucleotides compared to a wild type (regular horse)
Mutations found are replicated errors compared to the wild type
All ~10 million SNPs are considered mutations
All mutations found are useful because they increase respiratory capacity of Tibetan Horses
No mutations found are useful, because mutations always cause disease
Only some mutations have an effect on the respiratory capacity phenotype of Tibetan horses
Mutations found are incorporated errors compare to wild horses
The research proved that there are also mutations in EDN1, LDHA, VHL and EPO genes too
Question 2
pts
LO53 Identify the causes of mutations and how the cell prevents most of them
, The following diagrams show examples of causes of mutations. Select the statements that are true
All examples can cause indels or substitutions
A is an example of a spontaneous error
E is an example of an induced error
B is an example of spontaneous error
D is an example of induced error
All examples can be fixed by the DNA polymerase if the error has not been replicated
All examples can be fixed by the RNA polymerase if the error has not been incorporated
Dystrophin is a protein that forms part of a vital protein complex that connects the cytoskeleton of
a muscle fiber cell to the extracellular matrix. This connection strengthens and shapes the muscle
fibers.
Dystrophin is coded by the DMD gene. This is one of the longest human genes known, covering
2,300,000 base pairs (0.08% of the human genome) It is located in chromosome 21. The immature
mRNA is 2,100,000 bases long and takes 16 hours to transcribe. It contains 79 exons. The mature
mRNA measures 14,000 and codes for a protein with 3,685 amino acids.
Abnormal expression of dystrophin leads to severe symptoms like muscle weakness and fatigability, a
disease that is called muscular dystrophy. Most patients with muscular dystrophy become wheelchair
dependent early in life. Cardiac muscle is also affected which results typically in premature death (~
second or third decade of life). Several mutations in this gene have led to the production of low levels
of dystrophin or of a defective, shortened (but partially functional) protein.
The table below contains the following nucleotide changes found in the dystrophyn gene when
comparing the DNA sequence of a healthy individual (Elijah) and an individual with muscular
dystrophy (Liam). Use your knowledge to learn about mutations and determine which change is the
most likely cause of Liam’s disease.
Change Elijah Liam Location
1 A G Promoter
Finlay (She/Her/Hers)
Correct answers are hidden.
Score for this attempt: 31 out of 31
Submitted Jun 24 at 1:54pm
This attempt took 5 minutes.
Question 1
pts
LO51 Identify the concept and importance of mutations
LO55 Explain the differences between incorporated and replicated mutations
The following is an excerpt of the article "EPAS1 Gain-of-Function Mutation Contributes to High-
Altitude Adaptation in Tibetan Horses (https://academic.oup.com/mbe/article/36/11/2591/5526924)
"Recent functional genomic studies have revealed the genetic basis of adaption to high-altitude
hypoxia in Tibetan people (Simonson et al. 2010; Yi et al. 2014), Tibetan dogs (Wang et al. 2014),
antelopes (Ge et al. 2013) and gray wolves (Zhang et al. 2014). Although other selection targets have
been reported, the endothelial PAS domain protein 1 (EPAS1) gene often appears as a common
selection target, providing a striking example of convergent evolution across a range of mammals
exposed to similar environmental pressure in the Qinghai-Tibetan (QT) Plateau. The EPAS1 gene
encodes one subunit of the hypoxia-inducible factor (HIF) and shows multifarious effects, including
the regulation of angiogenesis, hemoglobin concentration (HMG) and erythrocytosis (Beall et al.
2010).
In this study, we undertook the first genomic analysis of selection signatures in Tibetan horses, aiming
at identifying the genetic basis for adaptation to high-altitude hypoxia in the QT Plateau. To achieve
this, we sequenced the genome of 138 Chinese horses spanning a wide range of altitudes, from the
lowland regions of the Northeastern Plain to the mountains of the QT Plateau. (We identified a) total
of 10,376,152 single nucleotide polymorphisms[...]. Less than 1% of the SNP variants were located in
exonic regions (30,094 [0.279%] were missense, 57,270 [0.456%] synonymous) (supplementary table
S3, Supplementary Material online). Approximately 10% were present in downstream or upstream
gene regulatory regions whereas the remaining dominant fraction (∼89%), spread across intergenic
and intronic
,regions.
We noticed that two SNPs within the most significant selection region represent missense variants of
the EPAS1 gene (fig. 3 and supplementary tables S21–S23, Supplementary Material online). They
are located at positions 52,566,293 and 52,552,723 of chromosome 15 [...] The EPAS1 protein is
highly conserved among mammals, with two heterodimerization PAS domains showing close to 100%
sequence similarity amongst 22 different species, including humans and horses living at low altitude.
The missense variants (hereafter referred to as EPAS1 R144C and E263D , respectively) are not
present in Przewalski’s horses, suggesting that they arose in an independent genetic background.
Under hypoxic conditions, the EPAS1 protein is known to be translocated into the nucleus, where it
binds the aryl hydrocarbon receptor nuclear translocator ARNT (HIF-1β). The resulting heterodimer
can then bind to DNA hypoxia response elements (HRE) where it initiates the transcription of key
genes involved in the response to hypoxia, such as erythropoietin (EPO), lactate dehydrogenase A
(LDHA), endothelin (EDN1), vascular endothelial growth factor A (VEGFA), von Hippel-Lindau (VHL)
and prolyl pydroxylase domain-containing protein 2 (PHD2, also EGLN1; Lee et al. 2011).
Coimmunoprecipitation assays confirmed the strong protein–protein interaction between the wild-type
EPAS1
and ARNT proteins. This interaction was greatly enhanced in the EPAS1 R144C mutant but did not
significantly change for the E263D mutant.
The mRNA expression levels of four out of the seven downstream genes tested (EDN1, LDHA, VHL
and EPO) were significantly increased in R144C transfected cells"
Select the statements that are true considering that a Single nucleotide polymorphism represents a
change in the sequence of nucleotides compared to a wild type (regular horse)
Mutations found are replicated errors compared to the wild type
All ~10 million SNPs are considered mutations
All mutations found are useful because they increase respiratory capacity of Tibetan Horses
No mutations found are useful, because mutations always cause disease
Only some mutations have an effect on the respiratory capacity phenotype of Tibetan horses
Mutations found are incorporated errors compare to wild horses
The research proved that there are also mutations in EDN1, LDHA, VHL and EPO genes too
Question 2
pts
LO53 Identify the causes of mutations and how the cell prevents most of them
, The following diagrams show examples of causes of mutations. Select the statements that are true
All examples can cause indels or substitutions
A is an example of a spontaneous error
E is an example of an induced error
B is an example of spontaneous error
D is an example of induced error
All examples can be fixed by the DNA polymerase if the error has not been replicated
All examples can be fixed by the RNA polymerase if the error has not been incorporated
Dystrophin is a protein that forms part of a vital protein complex that connects the cytoskeleton of
a muscle fiber cell to the extracellular matrix. This connection strengthens and shapes the muscle
fibers.
Dystrophin is coded by the DMD gene. This is one of the longest human genes known, covering
2,300,000 base pairs (0.08% of the human genome) It is located in chromosome 21. The immature
mRNA is 2,100,000 bases long and takes 16 hours to transcribe. It contains 79 exons. The mature
mRNA measures 14,000 and codes for a protein with 3,685 amino acids.
Abnormal expression of dystrophin leads to severe symptoms like muscle weakness and fatigability, a
disease that is called muscular dystrophy. Most patients with muscular dystrophy become wheelchair
dependent early in life. Cardiac muscle is also affected which results typically in premature death (~
second or third decade of life). Several mutations in this gene have led to the production of low levels
of dystrophin or of a defective, shortened (but partially functional) protein.
The table below contains the following nucleotide changes found in the dystrophyn gene when
comparing the DNA sequence of a healthy individual (Elijah) and an individual with muscular
dystrophy (Liam). Use your knowledge to learn about mutations and determine which change is the
most likely cause of Liam’s disease.
Change Elijah Liam Location
1 A G Promoter
