A new approach has been developed by
researchers at the Harvard Medical
School-affiliated Institute for Aging Research at Hebrew Senior Life to track
patterns within regulatory regions in a number of species close or distant to
humans. Genome-wide association studies have previously revealed abundant threat
loci associated with diverse diseases. However, they have also been short on detail. Association
loci don’t necessarily pinpoint the variants, much less give any indication of
the disease-causing mechanisms the variants may activate. But Thanks to researchers
at the Institute for Aging Research at
Hebrew Senior Life, such details will be soon easily available. It is to be
noted that the researchers have proceeded on the assumption that variant
patterns conserved across species are likely to serve important functions.
Institute fellow Melina Claussnitzer, Ph.D
, reported that Presence of numerous disease associated variants was determined
in non-coding part of DNA, where the function of the DNA is largely unknown.These
noncoding variants contribute to disease
through dysregulation of gene expression. But still major challenge is pinpointing the noncoding variants, which
confer this dysregulation.
Dr. Claussnitzer and her colleagues
applied their approach to genetic variants associated with type 2 diabetes, one
of the most prevalent human diseases. Claussnitzer’s team, in their article published January 17 in Cell,
indicated that by using “integrative computational analysis of phylogenetic
conservation with a complexity assessment of co-occurring transcription factor
binding sites (TFBSs),” they were able to identify “cis-regulatory
variants and elucidate their mechanistic role in disease.”
Although, In this particular study, “Leveraging
Cross-Species Transcription Factor Binding Site Patterns: From Diabetes Risk
Loci to Disease Mechanisms,” ,the
underlying genetic causes of type 2 diabetes were discussed, it describes a
methodology that could, in principle, be applied to any general disease
including osteoporosis, Alzheimer's disease, and cancer.
It is described how the researchers sought
conserved patterns of certain sequences that make up transcription factor
binding sites (TFBSs). Data about a given region around a gene variant in the
human genome was analyzed to guide the search for comparable regions in other
vertebrate species, To find these conserved TFBS patterns. The TFBS pattern
conservation of the regions was then scored based on the resemblance of TFBS
arrangement across species. Greater score indicated greater probability that
this variant affects the regulation of genes, thereby pointing to the
underlying mechanism of a disease.
In their paper, the authors wrote that
analysis of established type 2 diabetes risk loci revealed a striking clustering
of distinct homeobox TFBSs. PRRX1 homeobox factor was identified as a repressor ofPPARG2 expression in adipose cells and its
adverse effect on lipid metabolism and systemic insulin sensitivity, dependent
on the rs4684847 risk allele that triggers PRRX1 binding, were demonstrated.
