Keeping Chromosomes From Cuddling Up!

ScienceDaily (Dec. 3, 2008) — If chromosomes snuggle up too closely at the wrong times, the results can be genetic disaster.

Now researchers have found the molecular machines in fruit flies that yank chromosomes, the DNA-carrying structures, apart when necessary.

The machines, proteins called condensin II, separate chromosomes by twisting them into supercoils that kink up and therefore can no longer touch.

Scientists had known of condensin II but did not know how it functioned inside cells.
Keeping specific parts of chromosomes from touching can change how the instructions carried in the DNA are read, said research team leader Giovanni Bosco of The University of Arizona in Tucson.

"It's like picking up your favorite book and, depending on what chair you chose to sit in, it turned into a different story -- even though the printed words in the book never changed," Bosco, a UA assistant professor of molecular and cellular biology, wrote in an e-mail.

"This now changes the way we think about genetic information. Taking a literal reading of it is not what actually happens," he wrote. "Instead, context matters."

The team also found that condensin II plays a key role in making sure that fruit fly sperm cells each receive the proper number of chromosomes -- not too many, not too few.

Bosco suspects that condensin II plays the same role in the formation of human sperm and eggs.
Having too many or too few chromosomes in egg or sperm cells is the source of several important genetic disorders, including Down syndrome.

Abnormalities in chromosome number is also the cause of some miscarriages of early-term fetuses in humans.

The National Institutes of Health and the National Science Foundation funded the research.
Learning how cells control chromosomes and how DNA is transcribed will lead to better understanding of how an organism's DNA affects the organism's final form.

Scientists have known for about 50 years that when chromosomes are in direct contact, the transcription machinery can choose to transcribe either the gene from the mother or the gene from the father.

Many researchers investigated how the specific genes were brought close together so that process, known as transvection, could happen.

Bosco wondered, what if the chromosomes stayed stuck together?

To find something that separated chromosomes, he looked for female fruit flies that were sterile because chromosomes in their eggs had stuck together.

Once he had those fruit flies, Hartl isolated the gene that kept the chromosomes from coming apart. He found that the gene coded for condensin II, indicating that the sterile flies couldn't make condensin II.

To be able to watch how condensin II affects chromosomes, the researchers used the salivary glands from normal Drosophila melanogaster fruit flies. Fruit fly salivary glands are unusual, because they have many copies of the same chromosome coiled together like a rope.
Hartl said, "You can actually see chromosomes, because the cells are so huge and the chromosomes are so huge."

The team inserted an additional gene into the chromosomes that would turn the condensin II-producing gene off at 77 F (21 C) and on at 95 F (35 C). The researchers also marked one gene on the chromosomes with green fluorescent protein, or GFP, to be able to see changes in the chromosomes' positions.

The scientists then looked at the salivary glands at the two temperatures to see what happened when condensin II was present and when it was absent.

Bosco said, "Simply turning the condensin gene on or off, we could watch the chromosomes move right before our eyes, demonstrating that condensin was mostly likely the tiny machine that was ripping the chromosomes apart."

He said these findings are significant because more and more genetic tests to sequence people's DNA are becoming available, but the DNA sequence alone does not completely determine what diseases the person will have.

Even if it's in the genes, it might not show, he said. "It's what your cells are doing with your genes that's important."

To pull the chromosomes apart, condensin II changes its shape. Smith said the team's next step is figuring out how condensin II proteins are recruited to the chromosomes and how the condensin II proteins use the cellular energy packets known as ATP to change shape.
Journal references:

Hartl et al. Chromosome Alignment and Transvection Are Antagonized by Condensin II. Science, 2008; 322 (5906): 1384 DOI: 10.1126/science.1164216
Hartl et al. Condensin II Resolves Chromosomal Associations to Enable Anaphase I Segregation in Drosophila Male Meiosis. PLoS Genetics, 2008; 4 (10): e1000228 DOI: 10.1371/journal.pgen.1000228
Adapted from materials provided by University of Arizona, via EurekAlert!, a service of AAAS.

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Alcoholism & Genetics!!!

A Person's High Or Low Response To Alcohol Says Much About Their Risk For Alcoholism

ScienceDaily (May 25, 2009) — Someone who has a low level of response (LR) to alcohol, meaning relatively little reaction to alcohol, has a higher risk for developing alcohol-use disorders (AUDs). A study that examined the influence of LR in conjunction with other characteristics – like family history of AUDs and age of drinking onset – has found that LR is a unique risk factor for AUDs across adulthood and is not simply a reflection of a broader range of risk factors.

"If a person needs more alcohol to get a certain effect, that person tends to drink more each time they imbibe," explained Marc A. Schuckit, director of the Alcohol Research Center, Veterans Affairs San Diego Healthcare System, professor of psychiatry at the University of California, San Diego, and corresponding author for the study.

"Other studies we have published have shown that these individuals also choose heavy drinking peers, which helps them believe that what they drink and what they expect to happen in a drinking evening are 'normal,'" he said. "This low LR, which is perhaps a low sensitivity to alcohol, is genetically influenced."

Schuckit and his colleagues examined 297 men participating in the San Diego Prospective Study, originally recruited and tested on their level of reaction to alcohol when they were 18 to 25 years old. Each reported on family history of AUDs, typical drinking quantity, age of drinking onset, body mass index, and initial age at recruitment for the study. AUDs were evaluated at 10-, 15-, 20-, and 25-year follow-ups.

Results showed that a low LR to alcohol predicted AUD occurrence over the course of adulthood even after controlling for the effects of other robust risk factors. In short, LR is a unique risk factor for AUDs across adulthood, and not simply a reflection of a broader range of risk factors.

"A low LR at age 20 was not just a reflection of being a heavier drinker at age 20 when we tested these men, and it wasn't an artifact of an earlier onset of drinking," said Schuckit. "We showed that a low LR at 20 predicts later heavy drinking and alcoholism even if you control for all these other predictors of alcohol problems at age 20."

Schuckit added that the study's method of examination – establishing multiple predictors at age 20, revisiting participants about every five years, and securing a response rate of about 94 percent – strongly show that LR is consistent and powerful in predicting alcoholism."

"Because alcoholism is genetically influenced, and because a low LR is one of the factors that adds to the risk of developing alcoholism," said Schuckit, "if you're an alcoholic, you need to tell your kids they are at a four-fold increased risk for alcoholism. If your kid does drink, find out if they can 'drink others under the table,' and warn them that that is a major indication they have the risk themselves. Keep in mind, however, that the absence of a low LR doesn't guarantee they won't develop alcoholism, as there are other risk factors as well."

It's not all bad news, Schuckit added. "We are looking for ways to identify this risk early in life, and to find ways to decrease the risk even if you carry a low LR … so there is hope for the future."


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Journal reference:

. The Relationships of the Level of Response to Alcohol and Additional Characteristics to Alcohol Use Disorders across Adulthood: A Discrete-Time Survival Analysis. Alcoholism: Clinical & Experimental Research, In Print September 2009

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