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An overview of a research project focused on predicting human diseases by identifying likely disease-causing mutations. The team, led by dr. Mark miller, uses multiple sequence alignment and grantham variation (gv) and deviation (gd) to categorize mutations as deleterious or neutral. The document also includes methods, tools, and a research plan.
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Advisor: Advisor:
Dr Mark Miller Dr Mark Miller
Team Members: Team Members:
Lakshmi Pillai Lakshmi Pillai
Anusha Davuluri Anusha Davuluri
Rajesh Kolla Rajesh Kolla
Ability to predict accurately the effects Ability to predict accurately the effects
of genetic difference of genetic difference –
helpful towards
predicting diseases predicting diseases
Personalized Medicine Personalized Medicine
Screening
for
inherited
metabolic
Screening
for
inherited
metabolic
diseases in newborn infants diseases in newborn infants
Not
all
missense
mutations
lead
to
Not
all
missense
mutations
lead
to
appreciable protein changes appreciable protein changes
Diseases:
Sickle
Diseases:
Sickle-
cell
disease,
cell
disease,
Epidermolysis
bullosa
(skin),
Cervical
Epidermolysis
bullosa
(skin),
Cervical
cancer,
Stomach
cancer
(gastric
cancer,
Stomach
cancer
(gastric
cancer) etc cancer) etc
Predict the human disease mutations: Predict the human disease mutations:
Identify
the
likely
Identify
the
likely-
disease
causing
disease
causing
mutations
prevent
human
mutations
prevent
human
dev
dev
disorders disorders
Evaluate
and
Improve
on
existing
Evaluate
and
Improve
on
existing
prediction methods prediction methods
To test the reliability of Align To test the reliability of Align-
Multiple Sequence Alignment Multiple Sequence Alignment
Sequence Alignment? Sequence Alignment?
MSA? MSA?
Fig : A sequence alignment, produced by Fig : A sequence alignment, produced by
ClustalWClustalW
between two between two
human human
zinc finger zinc finger
proteins identified by proteins identified by
GenBankGenBank
accession number. accession number.
( (
Key Key
) )
20 80 60 40
120 100 140
4 5 6 7 8 9
10
volume
composition
polarity
Arg
Leu
Ser
Pro
Cys
is
calculated
as
Euclidean
distance
between mutation and theclosest point on the boxdefined by MSA
if
mutation
lies
within box
difference
between
mutation
and
observed
interspecific
variation
at
site
Grantham Deviation (GD) Grantham Deviation (GD)
If GD=0, then mutation is likely neutral If GD=0, then mutation is likely neutral
If (GV > 61.3) and (0<GD<=61.3), then the mutation is If (GV > 61.3) and (0<GD<=61.3), then the mutation is
likely neutral likely neutral
If (GV=0) and (GD>0) then the mutation is likely If (GV=0) and (GD>0) then the mutation is likely
deleterious deleterious
If (0<GV<=61.3) and (GD > 0) then the mutation is If (0<GV<=61.3) and (GD > 0) then the mutation is
likely deleterious likely deleterious
[
1921
[
1921
1980] 1980]
#human
TTTAGCTCAAAACTCATGGGATGTGATTCTTTCGACCAATTTAGTGC
#human
TTTAGCTCAAAACTCATGGGATGTGATTCTTTCGACCAATTTAGTGC
AGAAAGAAGAAAT AGAAAGAAGAAAT
#olive_baboon
TTTAGCTCAAAACTCATGGGATATGATTCTTTCGACCAATTTAGTGC
#olive_baboon
TTTAGCTCAAAACTCATGGGATATGATTCTTTCGACCAATTTAGTGC
AGAAAGAAGAAAT AGAAAGAAGAAAT
#macaca_mulatta
TTTAGCTCAAAACTCATGGGATATGATTCTTTCGACCAATTTAGTGC
#macaca_mulatta
TTTAGCTCAAAACTCATGGGATATGATTCTTTCGACCAATTTAGTGC
AGAAAGAAGAAAT AGAAAGAAGAAAT
#cow
TTCAGCTCGAAGCTCATGGGATGTGACACTTTCGACCAGTTTACTGC
#cow
TTCAGCTCGAAGCTCATGGGATGTGACACTTTCGACCAGTTTACTGC
AGAACGAAGAAAT AGAACGAAGAAAT
#sheep
TTCAGCTCGAAGCTCATGGGATGTGACACTTTCGACCAGTTTACTGC
#sheep
TTCAGCTCGAAGCTCATGGGATGTGACACTTTCGACCAGTTTACTGC
AGAACGAAGAAAC AGAACGAAGAAAC
#new_rabbit
TTTAGCTCAAAGCTCATGGGATATGATTCTTTTGACCAGTTTAGTGC
#new_rabbit
TTTAGCTCAAAGCTCATGGGATATGATTCTTTTGACCAGTTTAGTGC
AGAAAGAAGAAAT AGAAAGAAGAAAT
#mouse
TTCAGTTCGAAACTCATGGGGTATGATACTTTTGACCAGTTTACTGA
#mouse
TTCAGTTCGAAACTCATGGGGTATGATACTTTTGACCAGTTTACTGA
GGAAAGAAGAAGT GGAAAGAAGAAGT
#killifish
TTTAGCTCCCTCCTGCTTGGGCTTGGATCTTATGACAACATCAGTGC
#killifish
TTTAGCTCCCTCCTGCTTGGGCTTGGATCTTATGACAACATCAGTGC
AGAGCGCCGCAGC AGAGCGCCGCAGC
#salmon
TTCAGCTCCCTGCTCCTGGGCCTGGAGGCCTACGACAACATCAAAGC
#salmon
TTCAGCTCCCTGCTCCTGGGCCTGGAGGCCTACGACAACATCAAAGC
CGAACGCCGCAGC CGAACGCCGCAGC
[
1981
[
1981
2040] 2040]
#human
TCAATCCTAACTGAGACCTTACACCGTTTCTCATTAGAAGGAGATGC
#human
TCAATCCTAACTGAGACCTTACACCGTTTCTCATTAGAAGGAGATGC
TCCTGTCTCCTGG TCCTGTCTCCTGG
#olive_baboon
TCAATCCTAACTGAGACCTTGCGCCGTTTCTCATTAGAAGGAGATGC
#olive_baboon
TCAATCCTAACTGAGACCTTGCGCCGTTTCTCATTAGAAGGAGATGC
TCCTGTCTCCTGG TCCTGTCTCCTGG
#macaca_mulatta
TCAATCCTAACTGAGACCTTACGCCGTTTCTCATTAGAAGGAGATGC
#macaca_mulatta
TCAATCCTAACTGAGACCTTACGCCGTTTCTCATTAGAAGGAGATGC
TCCTGTCTCCTGG TCCTGTCTCCTGG
#cow
TCAATCATAACTGAGACTTTACGGCGTTTCTCATTAGAAGGAGATAC
#cow
TCAATCATAACTGAGACTTTACGGCGTTTCTCATTAGAAGGAGATAC
TTCTGTGTCCTGG TTCTGTGTCCTGG
#sheep
TCAATCATAACCGAGACTTTACGGCGTTTCTCATTAGAAGGAGATAC
#sheep
TCAATCATAACCGAGACTTTACGGCGTTTCTCATTAGAAGGAGATAC
TTCTGTGTCCTGG TTCTGTGTCCTGG
#new_rabbit
TCAATCCTAACTGAGACCTTACGGCGTTTCTCATTAGAAGGAGATGC
#new_rabbit
TCAATCCTAACTGAGACCTTACGGCGTTTCTCATTAGAAGGAGATGC
TAGCATCTCCTGG TAGCATCTCCTGG
#mouse
TCAATTCTAACTGAGACCTTACGCAGGTTCTCAGTAGAC
#mouse
TCAATTCTAACTGAGACCTTACGCAGGTTCTCAGTAGAC
--- ---
GATTCCTCTGCCCCGTGGGATTCCTCTGCCCCGTGG
#killifish
TCCATCCTCACAGAAACCCTTCGCAGAGTCTCAGTGGATGAAACGGC
#killifish
TCCATCCTCACAGAAACCCTTCGCAGAGTCTCAGTGGATGAAACGGC
TGGTTTCCGAGGC TGGTTTCCGAGGC
#salmon
TCCATCCTCACCGAGACCCTCCGACGCGTCTCTATCGATGAATCCAC
#salmon
TCCATCCTCACCGAGACCCTCCGACGCGTCTCTATCGATGAATCCAC
CGTCTTCCGTGGC CGTCTTCCGTGGC
File reader program File reader program
Preprocess Preprocess
Map: Universal genetic code Map: Universal genetic code
Æ Æ
amino acid amino acid
sequence sequence
Compare
this
sequence
with
Deleterious
Compare
this
sequence
with
Deleterious
mutation sequence mutation sequence
Plot each amino acid on a 3 Plot each amino acid on a 3-
d graph(CPV) d graph(CPV)
Using Align Using Align-
GVGD, we predict the effects of GVGD, we predict the effects of
categorized mutants (calculate GV, GD ) categorized mutants (calculate GV, GD )
(1) File Reader Program(2) Preprocess(3) Mapping
July 11
Tasks to be done
Date
Plot amino acids on 3 Plot amino acids on 3-
d graph (CVP) d graph (CVP)
Calculate GV, GD values Calculate GV, GD values
Analyze the results. Analyze the results.
Alternate
approaches
for
Alternate
approaches
for
calculations. calculations.
