Myotonic dystrophy type 1 (DM1) is one of a growing number of inherited human diseases whose molecular basis has been implicated as the expansion of a trinucleotide DNA repeat. Expanded disease-associated alleles of >50 CTG repeats are unstable in both the germline and soma. Expansion of the unstable alleles over time and variation of the level of mutation between the somatic tissues of an individual are thought to account at least partially for the tissue specificity and progressive nature of the symptoms. We previously generated a number of transgenic mouse lines containing a large expanded CTG repeat tract that replicated a number of the features of unstable DNA in humans, including frequent sex-specific changes in allele length during intergenerational transmission. Small length change mutations were apparent in the somatic tissues of young mice in all of the lines generated, but the gross instability observed in human DM1 patients was not replicated. We now show that in one of the lines, Dmt -D, spectacular, expansion-biased, tissue-specific instability is observed in older mice. The highest levels of instability were detected in kidney with gains of >500 repeats, representing a tripling of allele length, in some cells. Mosaicism accumulated in an age-dependent manner, but the tissue specificity did not obviously correlate with cell turnover. Such gross somatic mosaicism was not observed in three other lines examined, further emphasizing a role for flanking DNA in modulating repeat stability.

MORAN, COLIN N., CHRISTOS VASSILOPOULOS, ATHANASIOS TSIOKANOS, ATHANASIOS Z. JAMURTAS, MARK E.S. BAILEY, RICHARD H. WILSON, AND YANNIS P. PITSILADIS. Effects of interaction between angiotensin I-converting enzyme polymorphisms and lifestyle on adiposity in adolescent Greeks. Obes Res. 2005;13:1499 -1504. Genetic variation in the human angiotensin I-converting enzyme (ACE) gene has been associated with many heritable traits, including obesity. Herein, we report the results of a study of obesity-related phenotypes and lifestyle in 1016 teen-aged Greeks. We show that there is a strong association (p ϭ 0.001) between subcutaneous fat and the ACE insertion/deletion (I/D) polymorphism in females, possession of genotypes containing the D allele being associated with increased fat thickness. This association is strongest in females who participate in no extra exercise and accounts for 6.5% of the phenotypic variance in fat thickness by ANOVA. The association is additive, with the mean phenotypic values in heterozygotes intermediate between the means of the two homozygotes, and the association acts at both extremes of the fat thickness distribution in a classical polygenic manner. Other ACE polymorphisms (rs4424958, rs4311) that define major haplotypes in European populations fail to provide stronger associations with the subcutaneous fat phenotype. Because ACE I/D is the polymorphism most strongly associated with circulating ACE levels in European populations, we propose that the functional allelic differences that influence circulating ACE levels also mediate the associations with the obesity-related phenotypes studied here. Key words: angiotensin, insertion/deletion, functionality, European population, exerciseTwin and family studies have shown that obesity and fat deposition have a strong heritable component (for review, see ref. 1), which accounts for 30% to 70% of the variation in fat levels in different studies. Other studies have shown that genetic influences on fat deposition interact with environmental factors, such as diet and exercise level (2). Longitudinal twin studies (1) have shown that genetics plays a larger role in younger age groups because the environment has had less time to take effect. Studying genetic influences in younger individuals should, therefore, reveal associations with genotype that may not be detectable in older age groups.A number of genes have been shown to have complex influences on obesity (for review, see ref.3). Angiotensinconverting enzyme (ACE), 1 a key component of the reninangiotensin system (RAS), converts angiotensin I to II (a vasopressor) and degrades bradykinin (a vasodilator) and a variety of other active oligopeptides (4). Although best known for its function in regulation of blood pressure, recent work has shown that ACE also has a role in a number of diverse cellular processes, including cell growth and survival of nonvascular tissues (for review, see ref. 5). Local RAS systems have been described in several tissues, including adipose tissue (6). Although the ...

Genetic variation in the human Angiotensin I-Converting Enzyme (ACE) gene has been associated with many heritable traits, including physical performance. Herein we report the results of a study of several physical, physiological and skill parameters and lifestyle in 1027 teenage Greeks. We show that there is a strong association (Po0.001) between the ACE I/D (insertion/deletion) polymorphism and both handgrip strength and vertical jump in females, homozygotes for the I-allele exhibiting higher performance-related phenotype scores, accounting for up to 4.5% of the phenotypic variance. The association is best explained by a model in which the D-allele is dominant, with the mean phenotypic value in the I/D heterozygotes being close to that of the mean of the DD homozygotes. The association acts across the phenotype distribution in a classical polygenic manner. Other polymorphisms that define major ACE haplotypes in European populations (rs4424958, rs4311) show weaker associations with these performance-related phenotypes than does I/D. Similarly, diplotypes defined by these polymorphisms do not explain significantly larger amounts of the variance than I/D alone. As ACE I/D is the polymorphism most strongly associated with circulating ACE activity in European populations, we propose that the functional allelic differences that influence ACE activity also mediate the associations with the performance-related phenotypes studied here.

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The analysis and experimental results for weakly perturbed, narrow band, backward wave couplers and fibre reflectors, will be presented.Conventional, co-directional fibre couplers -polished, fused or coaxial -can be designed to demonstrate a sufficient wavelength dependence for some filtering and multiplexing applications.While coupled bandwidths can be sufficiently reduced by weakening the coupling between the guides and hence increasing the interaction (beat) length, useful limits of a few nms are reached for interaction lengths of a few cms.These limitations in coupled bandwidth are considerably transformed for contra -directional coupling provided by a periodic perturbation of suitable pitch (half the guide wavelength) imposed on the coupler.The inverse relationship between bandwidth and interaction length still holds, but the magnitudes are substantially improved.Calculations show that we may expect sub -Angstrom bandwidths for interaction lengths in the order of 1cm.These extremely narrow band effects depend on the successful fabrication of regular, weak, periodic perturbations over relatively long fibre lengths.We have fabricated long gratings (-1cm) of periodicity -0.27pm on D-shaped elliptical cored fibres as a first step towards narrow band couplers. These structures can be investigated by observing reflection characteristics at -800nm and the latest results will be described.