Link uncovered between variation in humans with extreme body mass and abnormal splicing

Today researchers report new insights into how genetic variation may create phenotypic differences between individuals. This study, which investigates the influence of mutations associated with obesity on the mechanism of splicing, is published online in Genome Research.

Many visible differences are apparent between individuals, ranging from height and weight to hair and eye color. While the extent of genetic variation between individuals is relatively small (0.1%-0.5%), it is estimated that this variation includes approximately 3 million single nucleotide polymorphisms (SNPs). These single base-pair differences in the genome have previously been thought to produce changes in the protein sequence encoded by a gene (non-synonymous SNPs). However, studies have indicated that a significant number of SNPs do not alter the predicted protein sequence (synonymous SNPs), suggesting that other regulatory mechanisms might be influenced.

In the study published today, a research group led by Dr. Gil Ast of Tel Aviv University has analyzed a newly described dataset of SNPs found in individuals with extreme body mass index (BMI) values. Interestingly, nearly 40% of the SNPs associated with obesity do not alter the protein-coding sequence of genes. “We demonstrated that the SNPs found in extreme BMI individuals that do not alter protein sequence information affect the way genetic information is processed: these SNPs alter mRNA splicing,” explains Amir Goren, co-lead author of the study. Splicing is the process whereby the RNA transcribed from a gene is edited by linking together the protein-coding regions (exons) and removing the intervening, non-coding sequences (introns), generating a mature messenger RNA (mRNA). The translation of mRNA into functional proteins requires proper maintenance of the splicing mechanism.

Goren and colleagues find that synonymous SNPs associated with extreme BMI are located near splice sites in exons and exhibit a tendency to reside within splicing regulatory regions, suggesting that these SNPs could alter the normal splicing pattern. Furthermore, it was discovered that the exons harboring these SNPs exhibit weak splice sites, indicating that these exons could be prone to reduced frequency of splicing, potentially disrupting function of the translated protein.

“When a certain exon is added only to a fraction of the mRNA molecules and not the others, the mRNA molecules without the exon cannot support proper protein synthesis and the overall level of required protein is reduced,” describes co-lead author Eddo Kim, suggesting that in addition to phenotypes attributable to non-synonymous SNPs, alterations in the processing of RNA due to synonymous SNPs could also contribute to phenotypic differences and genetic disorders.

Kim suggests that it is difficult to observe severe shifts in splicing patterns that are likely to result in lethality during development. Slight alterations in splicing are more likely to be non-fatal, yet produce a discernible phenotype. “Subtle changes in genes that are involved, for example, in metabolism of fats might be phenotypically visible later in life as unusual weight gain.”

While current genetic variation databases contain millions of SNPs, most were identified from a small number of individuals, hinting that many more SNPs remain undiscovered. “Deep re-sequencing efforts could uncover many otherwise overlooked SNPs,” explains Kim. “We might end up finding that SNPs that affect the splicing process explain many of the phenotypic differences between individuals.”

Source: Cold Spring Harbor Laboratory

Related stories:

Tiny genetic differences have huge consequences
A study led by McGill University researchers has demonstrated that small differences between individuals at the DNA level can lead to dramatic differences in the way genes produce proteins. These, in turn, are responsible for the vast array of differences in physical characteristics between individuals.
Early onset gene for inflammatory bowel diseases identified
A study of Crohn's disease and ulcerative colitis in children has identified a gene that influences whether children get these diseases early in life, and points to a potential new target for treatment. The findings of the international team that performed the study were published online this week by the journal Nature Genetics.
Researchers uncover new genetic links to psoriasis
In the first comprehensive study of the genetic basis of psoriasis, researchers at Washington University School of Medicine in St. Louis have discovered seven new sites of common DNA variation that increase the risk of the troublesome skin condition. They also found that variations in one genetic region link psoriasis and a related joint disorder, psoriatic arthritis, to four autoimmune diseases: type 1 diabetes, Grave's disease, celiac disease and rheumatoid arthritis. The study's results appear April 4 in the open-access journal PLoS Genetics.
New technique puts DNA profiling of E. coli on fast track
Using new genetic techniques, scientists are unlocking the secrets of how E coli bacteria contaminate food and make people sick.
Gene protects adults abused as children from depression
Some forms of a gene that controls the body's response to stress hormones appear to protect adults who were abused in childhood from depression, psychiatrists have found.
Genetic differences may help explain response to multiple sclerosis treatment
By comparing the DNA of patients with multiple sclerosis whose symptoms are reduced by interferon beta therapy to the DNA of those who continue to experience relapses, researchers may have identified important genetic differences between the two, according to an article posted online today that will appear in the March 2008 print issue of Archives of Neurology, one of the JAMA/Archives journals. These differences could eventually be used to help predict which treatments will help which patients.
Scientists associate 6 new genetic variants with heart disease risk factor
Using new techniques for rapidly scanning the human genome, researchers have associated levels of cholesterol and triglycerides, two fats in the blood, to 18 genetic variants, six of which represent new DNA regions never before associated with the traits. The findings, appearing in the January 13 advance online issue of Nature Genetics, help explain some of the variability in cholesterol and triglyceride levels that arises from genes.
Human genetic variation -- Science's 'Breakthrough of the Year'
In 2007, researchers were dazzled by the degree to which genomes differ from one human to another and began to understand the role of these variations in disease and personal traits. Science and its publisher, AAAS, the nonprofit science society, recognize “Human Genetic Variation” as the Breakthrough of the Year, and identify nine other of the year’s most significant scientific accomplishments in the 21 December issue.

News discussion:

Medicine & Health news