Friday, June 20, 2008

Importance Of Gene Regulation For Common Human Disease

Finding: A new study shows 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.

Where are the regions?
This result comes from a study 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.

The challenge of large-scale studies that link a DNA variant to a disease
We predict that variants in regulatory regions make a greater contribution to complex disease than do variants that affect protein sequence. 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.

What the HapMap does
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

Scientists found strong evidence that SNP variation close to genes - where most regulatory regions lie - could have a dramatic effect on gene activity. Although many effects were shared among all four HapMap populations, they also shown that a significant number were restricted to one population.

What about the house keeping genes?
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 one would expect: you can't mess too much with the fundamental life processes and we predicted we would find reduced effects on these genes.

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.

Tuesday, June 17, 2008

Happenstance mutations matter

Scientists show that happenstance mutations matter

Finding: In experiments on bacteria grown in the lab, scientists found that evolving a new trait sometimes depended on previous, happenstance mutations. Without those earlier random mutations, the window of opportunity for the novel trait would never have opened. History might have been different.

Evolutionist Stephen Jay Gould once suggested that the if the evolution of life were “wound back” and played again from the start, it could have turned out very differently.

Though not firmly conclusive, the new research adds a real-world case study of evolution in action to the decades-old debate stirred by Gould’s thought experiment. British paleontologist Simon Conway Morris and others argued that only a few optimal solutions exist for an organism to adapt to its environment, so even if the clock were wound back, environmental pressures would eventually steer evolution toward one of those solutions — regardless of the randomness along the way.

What the scientists did
Scientists obviously can’t turn back the hands of time, but Richard Lenski and his colleagues at Michigan State University in East Lansing did the next best thing. Lenski’s team watched 12 colonies of identical E. coli bacteria evolve under carefully controlled lab conditions for 20 years, which equates to more than 40,000 generations of bacteria. After every 500 generations, the researchers froze samples of bacteria. Those bacteria could later be thawed out to “replay” the evolutionary clock from that point in time.

The evolution of a nutrient absorption ability
After about 31,500 generations, one colony of bacteria evolved the novel ability to use a nutrient that E. coli normally can’t absorb from its environment. Thawed-out samples from after the 20,000-generation mark were much more likely to re-evolve this trait than earlier samples, which suggests that an unnoticed mutation that occurred around the 20,000th generation enabled the microbes to later evolve the nutrient-absorption ability through a second mutation, the researchers report in the Proceedings of the National Academy of Sciences.

By way of contrast with another control group
In the 11 other colonies, this earlier mutation didn’t occur, so the evolution of this novel ability never happened.

Put populations in the same environment and see what happens
This is a direct empirical demonstration of Gould-like contingency in evolution. You can’t do an exact replay in nature, but scientists were able to literally put all these populations in virtually identical environments and show that contingency is really what had occurred.

What was the mutation that occured?
The next step will be to determine what that earlier mutation was and how it made the later change possible. If the first mutation didn’t offer any survival advantage to the microbes on its own, it would make the case airtight that Gould was right. That’s because a mutation that doesn’t improve an organism’s ability to survive and reproduce can’t be favored by evolution, so whether the microbe happens to have that necessary mutation when the second evolutionary change occurs becomes purely a matter of chance. Thus the first mutation must have improved the chance of the organisms survival.

The first mutation gave the microbes a survival advantage. The growth rate and the density of bacteria in the colony jumped up after the second mutation, but not after the first one. The first mutation may have set the stage for what was to come, the second mutation took advantage of the change.