A genetic mutation is one
in which there is a permanent change in the DNA sequence of a gene that causes
the sequence to be very different from what is present in most people
- A research team
from Brown University has developed a software that can be used to
identify large sections of DNA, within a relatively short span of time.
- It is used to
identify splicing errors that occur during synthesis of proteins from DNA.
- Such a mass
analyzing tool will be effective in screening for mutations among
patients, paving the way for precision medicine.
Dr. William Fairbrother from Brown University states that while it is no longer
difficult to identify gene variations in people, it is important to ascertain
the effect of these mutations on health.
study by Dr. Fairbrother and colleagues, published in the journal Nature
, involved the use of a new technique called "MaPSy", where about
5,000 mutations were sorted and which identified nearly 500 mutations that were
caused due to an error in the processing of genes by cells. The new technique
could also be used to identify the reason behind the error.
Fairbrother stated that it was possible to obtain multiple variants from
individuals and all these variants could be sequenced. However, it is important
to identify which variant led to the development of disease. This would be the
starting point for precision medicine as the response to therapy could be
ascertained from the variations carried in the gene sequence.
‘MaPSy can be used to identify errors that occur during splicing, a process in which segments of DNA that do not code for proteins are removed.’
Gene splicing is a modification that occurs
post transcription, in which a single gene could code for various proteins
It is the process by which sections of DNA that do not code for any protein are
removed. Dr. Fairbrother has allocated the necessary resources to develop newer
methods as well as tools, including biophysical systems similar to MaPSy and
new software to study gene splicing. This is because, while the instructions
carried by the gene are necessary for the synthesis of protein, gene splicing
could also play an important role in the development of diseases.
a simple gene variation, a single amino acid may be altered to another one;
however, in gene splicing, 40 to 50 amino acids could be removed due to a
mutation. The significance of these mutations could therefore be more
is a free web based software that was developed by Dr. Fairbrother's lab in
2012 and which can be used to identify mutations that are likely to result in
errors in splicing. The scientists who were involved in the development of this
software won the CLARITY contest, in which the entire genome of three families
had to be sequenced and the mutations that led to disease in the children were
for 'Massively Parallel Splicing Assay
' that was used for rapidly
screening the gene splicing effects of 4,964
in the Human Gene
Mutation Database (HGMD)
that caused genetic disorders.
This screening tool was developed by Dr.Fairbrother along with
Rachel Soemedi andKamil Cygan.
How Does MaPSy work?
mechanism of action of MaPSY is by generating "pooled" artificial genes that
were made up of
- Normal genes and
- Disease causing
variations of genes
of these artificial genes were then studied under in-vivo
conditions as well as in in-vitro
"pooled" artificial genes were introduced into living cells to study how often
the normal or mutant genes wereprocessed
splicing machinery was removed from the nucleus of the cell and the "pooled"
synthesized RNA was introduced to determine how often the genes were processed.
results of the study were
- Nearly 18 % of the Human Genome Mutation
Database mutations were associated with splicing errors in the in-vivo study.
- Nearly 24 % of the Human Genome Mutation
Database mutations were associated with splicing errors in the in-vitro study.
study identified that nearly 10%
mutations produced splicing errors in both the in-vitro
study as well as the in-vivo
study. This implied that there was a strong likelihood that the mutations were
indeed sources of errors during splicing.
study helped in identifying mutations that were associated with the development
of diseases, arising from splicing errors. Dr. Fairbrother and colleagues
examined the sequence information and the splicing errors to identify the
source of the different splicing error mutations. Combinations of genes that
had a higher likelihood of developing splicing errors were identified; this was
used to predict errors and even 'fix' them.
COL1A2 gene Mutation
an example that was highlighted in the study, a particular variation in COL1A2,
a gene associated with collagen
and bone growth, led to an unwanted binding site for a
protein which blocks splicing. When this binding site was intervened in cells,
the splicing process continued as normal.
Evidence from Patient Samples:
tissue samples from patients were analyzed, it was found that there was
evidence of splicing error as predicted by MaPSy. This technique could prove to
be a powerful tool and can be used for characterization of variations in gene
sequences associated with splicing errors.
- What are single nucleotide polymorphisms (SNPs)? - (https://ghr.nlm.nih.gov/primer/genomicresearch/snp)