PNAS News Archive: October 28 - November 1, 2002

  Selected articles appearing in PNAS the week of October 28 . . .
 

Combined Techniques Unravel Complex Genetics

Combining genetic mapping techniques with the power of DNA microarrays could greatly simplify the identification of genes responsible for highly complex traits. Many traits, such as behaviors, involve the intricate interplay of multiple genes, making it difficult for scientists to know where to start looking for candidate genes. Mapping helps narrow the search. Quantitative trait locus (QTL) mapping finds genomic regions that correlate with a trait. Fine mapping techniques can further reduce the thousands of candidate genes within these regions, but may still leave hundreds of potential genes that require testing. In PNAS this week, Marta Wayne and Lauren McIntyre from University of Florida demonstrate that analyzing gene expression patterns using DNA microarrays can further shrink the list of candidate genes to a number feasible for study. The researchers sought genes that determine how many ovarioles develop in female fruit flies, a number that varies among different fly populations and relates to fecundity. QTL mapping found two genomic regions that correlate with ovariole number, together encompassing 5286 genes. Fine mapping reduced that number to 548 genes. DNA microarrays identified a smaller subset of genes with expression patterns suggestive of a role in ovariole number determination. The shortlist included CG17327, a relative of a human gene targeted by estrogen, yellow-f, a relative of genes that make the "royal jelly" protein fed to honeybee larvae destined to become reproductive queens, and Su(fu), which interacts with a gene known to influence ovariole number. These results demonstrate that combining experimental approaches can select a reasonable number of genes for in-depth analysis of a complex genetic trait.

"Combining mapping and arraying: An approach to candidate gene identification" by M. L. Wayne and L. M. McIntyre

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"Spooky Action at a Distance" Rises Again

A decades-long debate over the meaning of certain counterintuitive results predicted by quantum theory continues in PNAS this week. In the 1930s, Einstein and colleagues conducted a "thought experiment" in which quantum theory seemed to predict "spooky action at a distance," whereby measurements of one particle instantaneously influence the apparent properties of another particle arbitrarily far away. Disturbed by this outcome, Einstein suggested that quantum theory must be incomplete. A complete theory might be characterized by additional "hidden variables." In the 1960s, John Bell offered a theorem stating that if these hidden variables exist, and do not violate Einstein's relativity, then the variables should produce observable effects. To date such effects have not been found, suggesting that the hidden variables do not exist. Hess and Philipp challenged Bell's theorem in PNAS last year (see Hess & Phillip, 2001a and 2001b), arguing that the theorem is flawed because it ignores a whole class of possible time-dependent variables, and thus the lack of observable effects do not rule out the existence of hidden variables. In the current article, Richard Gill from the University of Utrecht and colleagues counter this argument, saying that time is irrelevant, given the freedom of the experimenter to control the experimental setting. The authors further point out that the Hess-Philipp model violates Einstein's relativity, thereby undermining the challenge of Bell's theorem and leaving "spooky action at a distance" in place.

"No time loophole in Bell's theorem: The Hess—Philipp model is nonlocal" by R. D. Gill, G. Weihs, A. Zeilinger, and M. Zukowski

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Sporadic Diseases May Swim in the Gene Pool

Scientists searching for the cause of one sporadic and apparently random disease have instead found it linked to a recessive gene. Patent ductus arteriosus (PDA) is the second most common congenital heart disease. PDA occurs when a major artery fails to remodel in the fetus, potentially resulting in pulmonary hypertension and heart failure. With diseases like PDA that occur sporadically, it is hard to tease out the cause. One cause could be a recessive gene with weak penetrance--that is, a genetic mutation that makes only a few of its carriers sick. Because recessive genes are more likely to manifest in disease when family members intermarry, Richard Lifton of the Yale University School of Medicine and coauthors studied the occurrence of PDA in places where inbreeding, or consanguinity, is common. In Iran, the authors found that PDA accounted for 15% of congenital heart disease, compared to 7% in countries where consanguinity is less common. Moreover, Iranian PDA cases demonstrated a marked increase in parental consanguinity (63%), compared to the general Iranian population (25%). Studying the genes of these patients and their parents allowed the authors to identify a gene implicated in PDA, named PDA1. The strategy may prove useful in the search for genetic causes of other sporadic diseases.

"Finding genetic contributions to sporadic disease: A recessive locus at 12q24 commonly contributes to patent ductus arteriosus" by Arya Mani, Seyed-Mahmoud Meraji, Roozbeh Houshyar, Jayaram Radhakrishnan, Alaleh Mani, Mehrabeh Ahangar, Tayebeh M. Rezaie, Mohammad-Ali Taghavinejad, Behrooz Broumand, Hongyu Zhao, Carol Nelson-Williams, and Richard P. Lifton

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Herpes Viruses Hedge Their Bets

An unusual characteristic of herpes viruses may allow them to flourish even when the availability of hosts is highly unpredictable, report scientists in PNAS this week. Herpes simplex 1 and 2, Epstein-Barr virus, and varicella zoster virus all share a trait characteristic of herpes viruses: a relatively long latency period separating an initial infectious phase (e.g., chickenpox) from a later infectious phase (e.g., shingles). Until now, scientists thought that latency periods evolved to allow the viruses to survive in small host populations. Michael Stumpf of Oxford University and colleagues offer an alternative explanation: the viruses are hedging their bets against the possibility that a sudden outbreak will immunize a large part of the population, an effect that can drastically and unpredictably reduce the pool of potential hosts even in large populations. The researchers used a mathematical model of how viruses spread through host populations to determine whether viruses with latency periods can outcompete viruses without latency periods. When the availability of hosts was unpredictable, viruses with latency periods had an evolutionary advantage, and the magnitude of the advantage grew as the amount of unpredictability increased. The authors note that similar dynamics can be found in other realms, such as portfolio and fund management, where a balance between immediate action and patience is required.

"Herpes viruses hedge their bets" by Michael P. H. Stumpf, Zoe Laidlaw, and Vincent A. A. Jansen

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Nicotine "Cooks" Serum Proteins

Nicotine produces a reaction in the body similar to that which scorches sugars and causes food to go bad, report scientists in PNAS this week. Tobin Dickerson and Kim Janda of The Scripps Research Institute suspected that nornicotine, a breakdown product of nicotine, might act as a catalyst in the formation of advanced glycation endproducts (AGEs). These protein byproducts of cellular reactions gone bad are similar to scorched sugar and have been implicated in the development of a variety of diseases and the aging process. When the researchers added nornicotine to serum proteins and glucose, they observed the formation of a new AGE derived from nornicotine. Furthermore, serum collected from smokers' blood had a higher concentration of this nornicotine AGE than nonsmoker's, despite the fact that nornicotine is only a minor nicotine metabolite. The authors also found that nornicotine reacted with a commonly prescribed steroid, prednisone, suggesting that smoking may lead to drug interactions. These results highlight the need for increased research into the consequences of exposure to secondary nicotine metabolites and their potential pathology.

"A previously undescribed chemical link between smoking and metabolic disease" by Tobin J. Dickerson and Kim D. Janda

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