Study Finds 60 New Genes Controlled By DNA Snippet

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Study Finds 60 New Genes Controlled By DNA Snippet

http://www.medicalnewstoday.com/medicalnews.php?newsid=36983

Researchers worldwide are seeking to define ancient sections of our

genetic code that may soon be as important to medical science as

genes. A new wave of research is concerned with, not how genes work,

but how small regulatory DNA sequences tell genes where, when and to

what degree to " turn on. " As part of this effort, researchers at the

University of Rochester Medical Center scanned through the vast human

DNA code to reveal for the first time 60 genes influenced by one such

sequence, according to an article published today in the journal

Genome Research.

Growing knowledge of how regulatory sequences control gene behavior

has the potential to create new classes of treatment for nerve

disorders and heart failure. Such sequences may also help to explain

why humans are so complex, despite having one-fifth as much genetic

material as wheat for instance. Medical center researchers are

working on just one of more than 100 regulatory sequences identified

so far, each the subject of intense study.

" Most people don't realize that genes make up a very small percentage

of the human DNA code, " said ph M. Miano, Ph.D., senior author of

the journal paper and associate professor within the Cardiovascular

Research Institute at the medical center. " Genes are relatively

straightforward compared to what lies ahead. We believe that the real

genetic gymnastics, the real intelligence of our system, is

controlled by tiny bits of genetic material that tell genes what to

do. "

" Junk DNA " No More

Genes are the chains of deoxyribonucleic acids (DNA) that encode

instructions for the building of proteins, the workhorses that make

up the body's organs and carry its signals. The Human Genome Project,

which first reported results in 2001, produced a near complete

listing of the DNA sequences that make up all human genes (the

genome). Key project findings included that human genetic material

consists of about 3 billion base pairs, the " letters " that make up

the genetic code. Researchers also concluded that genes, specific

batches of code that direct protein construction, comprise just about

2 percent of all human DNA. A central question in genetics has

become: what does the remaining 98 percent of human genetic material

do?

Regulatory sequences are emerging as an important part of the non-

gene majority of human genetic material, once thought of as " junk

DNA. " A new frontier in genetic research is the defining of the

regulome, the complete set of DNA sequences that regulate the

behavior of genes. DNA segments that code for proteins average 200

base pairs in length, whereas regulatory sequences typically include

just six to 10 base pairs, making them hard to find. As a human

embryo develops from a single cell into tens of billions of cells,

DNA must be read and copied again and again to supply each cell with

its needed copy. Over time, random changes, or mutations, are

inserted into the code during the copying process. Some mutations

bring survival advantages and others cause disease. Most known

genetic diseases identified to date result from a mutation within a

gene that directs protein construction, but that may soon change.

" We believe more and more disease-causing mutations will be found

within regulatory sequences that control genes turning on or off, "

Miano said. " We therefore are very interested in defining as many

functional regulatory elements as we can to help geneticists pinpoint

a growing number of disease-causing mutations. "

Study Details

In Miano's study, the regulatory sequence under examination was the

CArG box. The nucleotide building blocks of DNA chains may contain

any one of four nucleobases: adenine (A), thymine (T), guanine (G)

and cytosine ©. Any sequence of code starting with 2 Cs, followed

by any combination of 6 As or Ts, and ending in 2 Gs is a CArG box.

According to Miano, there are 1,216 variations of CArG box that

together occur approximately three million times throughout the human

DNA blueprint.

CArG boxes exert their influence over genes because they are " shaped "

to partner with a nuclear factor called serum response factor (SRF)

and several other proteins within a genetic regulatory network.

Throughout a human life, such networks are believed to " decide " the

timing and location of all gene expression, the process through which

genetic information is converted into templates for protein

construction.

The current study, funded through a grant from the National Heart,

Lung and Blood Institute, sought to survey the human and mouse genome

databases created by the Human Genome Project to find all CArG boxes

that regulate genes. The sheer amount of information involved

requires that such studies use high-powered computer programs to

screen data. In this case, researchers used a high-speed screening to

expand the definition of the functional mammalian CarGome, the

complete set of CArG boxes that regulate genes.

In collaboration with Christian Stoeckert, Ph.D., associate professor

of Genetics at the University of Pennsylvania, Miano's team designed

a set of criteria that a given piece of DNA had to meet in order to

be considered a functional CArG box. Thanks to their work and that of

several other labs, they knew going in all the CArG box variations

and how close they typically lie to the genes they regulate (within

4,000 base pairs).

The data-screening tool also employed comparative genomics, the study

of relationships between the DNA of different species. When a piece

of genetic material, gene or regulatory segment, is conserved by

evolution from mice to humans it suggests that the segment has a

valuable function. Miano's screen required that CArG boxes shared by

humans and mice be included in his expanded version of the CarGome.

CArG boxes identified by the computer screen were then tested to see

if they indeed interacted with SRF and changed the behavior of genes

as predicted.

This approach resulted in the disclosure of more than 100

hypothetical CArG boxes and the same number of genes previously

unknown to be targeted by CArG-SRF. Of those, 60 CArG boxes have been

validated as exerting influence over a gene. Adding the newly

confirmed segments to those already known, authors of the study now

define the functional mammalian CarGome as 161 sequences, a 55

percent increase from the old definition.

Of the genes newly found to be regulated by CArG-SRF, more than half

encode for cytoskeletal or contractile proteins. Past studies have

shown that CArG-SRF network is vital to the development of the

cellular " skeletons " that maintain cell shape and enable cell motion.

Being present in nearly every cell and throughout the human genome,

the CArG-SRF system is believed to contribute to disease in many

bodily tissues.

In cardiology, studies show that a lack of SRF-CArG causes

cardiomyopathy, a weakening of heart muscle cells' ability to

contract. That in turn reduces the pumping strength of heart muscle

and leads to heart failure, according to recent studies. Can

cardiomyopathy be reversed by manipulating CArG-SRF? CArG sequences

also appear near genes that direct the building of nerve cells and

blood vessels, suggesting they may be involved in diseases affecting

those tissues as well.

In the larger picture, regulatory sequences may help to explain why

humans have just 25,000 genes when, given the degree of human

complexity, researchers had expected to find more than 100,000.

Regulatory sequences may be part of the answer because they enable a

single gene to produce the same protein at different times, places

and concentrations with subtly different roles.

" Humans share about one quarter of their genes with fish, " Miano

said. " Something must be at work to explain why we are so many times

more complex. Regulatory sequences offer one of several emerging

explanations for how we do more with fewer genes. "