The importance of gene regulation for common human disease

September 16, 2007

A new study published in Nature Genetics on Sunday 16 September 2007 show that common, complex diseases are more likely to be due to genetic variation in regions that control activity of genes, rather than in the regions that specify the protein code.

This surprising result comes from a study at the Wellcome Trust Sanger Institute of the activity of almost 14,000 genes in 270 DNA samples collected for the HapMap Project. The authors looked at 2.2 million DNA sequence variants (SNPs) to determine which affected gene activity.

They found that activity of more than 1300 genes was affected by DNA sequence changes in regions predicted to be involved in regulating gene activity, which often lie close to, but outside, the protein-coding regions.

"We predict that variants in regulatory regions make a greater contribution to complex disease than do variants that affect protein sequence," explained Dr Manolis Dermitzakis, senior author from the Wellcome Trust Sanger Institute. "This is the first study on this scale and these results are confirming our intuition about the nature of natural variation in complex traits.

"One of the challenges of large-scale studies that link a DNA variant to a disease is to determine how the variant causes the disease: our analysis will help to develop that understanding, a vital step on the path from genetics to improvements in healthcare."

Past studies of rare, monogenic disease, such as cystic fibrosis and sickle-cell anaemia, have focused on changes to the protein-coding regions of genes because they have been visible to the tools of human genetics. With the HapMap and large-scale research methods, researchers can inspect the role of regions that regulate activity of many thousands of genes.

The HapMap Project established cell cultures from participants from four populations as well as, for some samples, information from families, which can help to understand inheritance of genetic variation. The team used these resources to study gene activity in the cell cultures and tie that to DNA sequence variation

‘We have generated an information resource readily available to investigators working in the mapping of variants underlying complex traits. Regions of association can be correlated with signatures of regulatory regions affecting gene expression' explained Dr Panos Deloukas, Senior Investigator at the Wellcome Trust Sanger Institute

"We found strong evidence that SNP variation close to genes - where most regulatory regions lie - could have a dramatic effect on gene activity," said Dr Barbara Stranger, post-doctoral fellow at WT Sanger Institute. "Although many effects were shared among all four HapMap populations, we have also shown that a significant number were restricted to one population."

They also showed that genes required for the basic functions of the cell - so-called housekeeping genes - were less likely to be subject to genetic variation. "This was exactly as we would expect: you can't mess too much with the fundamental life processes and we predicted we would find reduced effects on these genes," said Dr Dermitzakis.

The study also detected SNP variants that affect the activity of genes located a great distance away. Genetic regulation in the human genome is complex and highly variable: a tool to detect such distant effects will expand the search for causative variants. The authors note, however, that the small sample size of 270 HapMap individuals is sensitive enough to detect only the strongest effects.

The results of this study are becoming available in public databases such as Ensembl for researchers to use.

The paper is accompanied by two others examining effects of changes to regulatory DNA in samples from asthma and from heart study patients.

Source: Wellcome Trust Sanger Institute

Explore further: Saving hearts after heart attacks: Overexpression of a gene enhances repair of dead muscle

Related Stories

Saving hearts after heart attacks: Overexpression of a gene enhances repair of dead muscle

October 17, 2017
University of Alabama at Birmingham biomedical engineers report a significant advance in efforts to repair a damaged heart after a heart attack, using grafted heart-muscle cells to create a repair patch. The key was overexpressing ...

Untangling vitamin D activation pathways in inflammation and bone health

October 17, 2017
Researchers have identified a region of the genome that regulates vitamin D activation in the kidneys, opening the door for more sophisticated treatments of diseases, including bone and immune disorders, involving vitamin ...

Mechanism explains how seizures may lead to memory loss

October 16, 2017
Although it's been clear that seizures are linked to memory loss and other cognitive deficits in patients with Alzheimer's disease, how this happens has been puzzling. In a study published in the journal Nature Medicine, ...

Signaling pathway may be key to why autism is more common in boys

October 17, 2017
Researchers aiming to understand why autism spectrum disorders (ASD) are more common in boys have discovered differences in a brain signaling pathway involved in reward learning and motivation that make male mice more vulnerable ...

A piece of the puzzle: Eight autism-related mutations in one gene

September 19, 2017
Scientists have identified a hotspot for autism-related mutations in a single gene.

New gene delivery approach could allow long-term persistence in proliferating cells

September 22, 2017
Researchers added a scaffold/matrix attachment region (S/MAR) to a conventional adeno-associated virus (AAV) vector used for gene transfer, and the modified vectors were able to establish colonies and maintain long-term transgene ...

Recommended for you

New gene editing approach for alpha-1 antitrypsin deficiency shows promise

October 20, 2017
A new study by scientists at UMass Medical School shows that using a technique called "nuclease-free" gene editing to correct cells with the mutation that causes a rare liver disease leads to repopulation of the diseased ...

Maternal diet may program child for disease risk, but better nutrition later can change that

October 20, 2017
Research has shown that a mother's diet during pregnancy, particularly one that is high-fat, may program her baby for future risk of certain diseases such as diabetes. A new study from nutrition researchers at the University ...

Researchers find evidence of DNA damage in veterans with Gulf War illness

October 19, 2017
Researchers say they have found the "first direct biological evidence" of damage in veterans with Gulf War illness to DNA within cellular structures that produce energy in the body.

Researchers drill down into gene behind frontotemporal lobar degeneration

October 19, 2017
Seven years ago, Penn Medicine researchers showed that mutations in the TMEM106B gene significantly increased a person's risk of frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in those ...

New clues to treat Alagille syndrome from zebrafish

October 18, 2017
A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies potential new therapeutic avenues for patients with Alagille syndrome. The discovery, published in Nature Communications, ...

Genetic variants associated with obsessive-compulsive disorder identified

October 18, 2017
(Medical Xpress)—An international team of researchers has found evidence of four genes that can be linked to obsessive-compulsive disorder (OCD). In their paper published in the journal Nature Communications, the group ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.