Middlesex University VAST 2010 Challenge
Genetic Sequences – Tracing the Mutations of a Disease
Authors and
Affiliations:
Ian
Mitchell, School of Engineering and Information Sciences, Middlesex University,
UK, i.mitchell@mdx.ac.uk
Peter
Passmore, School of Engineering and Information Sciences, Middlesex University,
UK, p.passmore@mdx.ac.uk
Kai Xu,
School of Engineering and Information Sciences, Middlesex University, UK, K.Xu@mdx.ac.uk [PRIMARY Contact]
Tool(s):
ClustalW2 (http://www.ebi.ac.uk/Tools/clustalw2/index.html)
was used to align sequences and ClustalW2 and TreeView
(taxonomy.zoology.gla.ac.uk/rod/treeview.html) were used to draw phylogenetic
trees. Analysis was also aided by using Microsoft Excel and some hand coded
programs.
Video:
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ANSWERS:
MC3.1: What is the region or
country of origin for the current outbreak? Please provide your answer as
the name of the native viral strain along with a brief explanation.
Nigeria_B
see phylogram in Figure 3.1 [1]
Figure 3.1 Phylogram of the combined native and current
sequences. The radial tree shows that Nigeria_B is the origin of the current
outbreak sequences.
MC3.2: Over time, the virus
spreads and the diversity of the virus increases as it mutates. Two
patients infected with the Drafa virus are in the
same hospital as Nicolai. Nicolai
has a strain identified by sequence 583. One patient has a strain
identified by sequence 123 and the other has a strain identified by sequence
51. Assume only a single viral strain is in each patient. Which
patient likely contracted the illness from Nicolai
and why? Please provide your answer as the sequence number along with a brief
explanation.
The phylogram in Figure 3.2 clearly shows that sequence 123 is a direct descendent of sequence 583. Whereas, sequence 51 is neither a direct ascendent or descendent of 583. Closer inspection of the sequences reinforced the above findings – sequence 583 is a single mutation from sequence 123, whereas sequence 583 is three mutations from sequence 51.
Figure 3.2 Phylogram of outbreak sequences.
MC3.3: Signs and symptoms
of the Drafa virus are varied and humans react
differently to infection. Some mutant strains from the current outbreak
have been reported as being worse than others for the patients that come in
contact with them.
Identify the top 3 mutations that
lead to an increase in symptom severity (a disease characteristic). The
mutations involve one or more base substitutions. For this question, the
biological properties of the underlying amino acid sequence patterns are not
significant in determining disease characteristics.
For each mutation provide the
base substitutions and their position in the sequence (left to right) where the
base substitutions occurred. For example,
C → G, 456 (C changed to G
at position 456)
G → A, 513 and T → A,
907 (G changed to A at position 513 and T changed to A at position 907)
A → G, 39 (A changed to G
at position 39)
A->G,
223 (sequence
612 classified as Mild symptoms changes to sequence 952, classified as severe
symptoms)
A->C,
269 and C->A, 494 and A->T, 843 (sequence
51, classified as Mild, changes to sequence 99, classified as Severe)
T->C,
311 and A->T, 946 and A->G, 1087 (sequence 49, classified as Mild, changes to
sequence 583, classified as Severe)
There are many other mutations that include combinations of
the above, with a majority including mutation at position 223.
MC3.4: Due to the rapid
spread of the virus and limited resources, medical personnel would like to
focus on treatments and quarantine procedures for the worst of the mutant
strains from the current outbreak, not just symptoms as in the previous
question. To find the most dangerous viral mutants, experts are
monitoring multiple disease characteristics.
Consider each virulence and drug
resistance characteristic as equally important. Identify the top 3
mutations that lead to the most dangerous viral strains. The mutations involve
one or more base substitutions. In a worst case scenario, a very
dangerous strain could cause severe symptoms, have high mortality, cause major
complications, exhibit resistance to anti viral drugs, and target high risk
groups. For this question, the biological properties of the underlying
amino acid sequence patterns are not significant in determining disease
characteristics.
For each mutation provide the
base substitutions and their position in the sequence (left to right) where the
base substitutions occurred. For example,
C → G, 456 (C changed to G
at position 456)
G → A, 513 and T → A,
907 (G changed to A at position 513 and T changed to A at position 907)
A → G, 39 (A changed to G
at position 39).
Each characteristic of the virus is equal to 1. Add up all the characteristic for each of the strains. Add these numbers to the phylogram – see figure 3.2. Identify lowest and highest scores and search the tree for the shortest paths between them. The top 3 are provided below:
|
# |
Symptom |
Mortality |
Complication |
Drug Resistance |
At Risk |
|
867 |
Mild |
Low |
Minor |
Intermediate |
Low |
|
211 |
Moderate |
High |
Major |
Resistant |
Medium |
Table 3.4.1 Characteristics of sequences 867 and 211. Two mutations result in five changes in characteristics.
G → T, 720 and A → G, 821 – Mutations transform sequence 867 to 211. From Table 3.4.1 it can be seen that these mutations result in a viral strain with a high mortality rate.
|
# |
Symptom |
Mortality |
Complication |
Drug Resistance |
At Risk |
|
867 |
Mild |
Low |
Minor |
Intermediate |
Low |
|
952 |
Severe |
Medium |
Major |
Resistant |
Low |
Table 3.4.2 Characteristics of sequences 867 and 952. Two mutations result in five changes in characteristics.
A->G, 223 and G->T, 720. Mutations transform sequence 867 to 952. From Table 3.4.2 it can be seen that these mutations result in a viral strain with severe symptoms and medium mortality rate.
|
# |
Symptom |
Mortality |
Complication |
Drug Resistance |
At Risk |
|
333 |
Moderate |
Low |
Minor |
Resistant |
Medium |
|
501 |
Severe |
High |
Minor |
Resistant |
High |
Table 3.4.3 Characteristics of sequences 333 and 501. One mutation results in three changes in characteristics.
G-> C, 848. This mutation transforms sequence 333 to 501. From Table 3.4.3 it can be seen that this mutation results in a viral strain with severe symptoms and high mortality rate.
There are other combinations that can transform a sequence as in Table 3.4.3, however these transformations require more mutations, whereas the mutation in Table 3.4.3 requires only a single mutation.
References:
[1] Higgins,D.G. and Sharp,P.M. (1989) Fast and sensitive multiple sequence alignments on a microcomputer. CABIOS 5,151-153.