The mosaic that is our genome

The discovery of the basis of genetic variation has opened inroads to understanding our history as a species. It has revealed the remarkable genetic similarity we share with other individuals as well as with our closest primate relatives. To understand what make us unique, both as individuals and as a species, we need to consider the genome as a mosaic of discrete segments, each with its own unique history and relatedness to different contemporary and ancestral individuals.     

Human mitochondrial tRNAs in health and disease

The human mitochondrial genome encodes 13 proteins, all subunits of the respiratory chain complexes and thus involved in energy metabolism. These genes are translated by 22 transfer RNAs (tRNAs), also encoded by the mitochondrial genome, which form the minimal set required for reading all codons. Human mitochondrial tRNAs gained interest with the rapid discovery of correlations between point mutations in their genes and various neuromuscular and neurodegenerative disorders. In this review, emerging fundamental knowledge on the structure/function relationships of these particular tRNAs and an overview of the large variety of mechanisms within translation, affected by mutations, are summarized. Also, initial results on wide-ranging molecular consequences of mutations outside the frame of mitochondrial translation are highlighted. While knowledge of mitochondrial tRNAs in both health and disease increases, deciphering the intricate network of events leading different genotypes to the variety of phenotypes requires further investigation using adapted model systems.Received 3 December 2002; received after revision 14 January 2003; accepted 27 January 2003     

Quasi-phase-matched generation of coherent extreme-ultraviolet light

High-harmonic generation is a well-known method of producing coherent extreme-ultraviolet (EUV) light, with photon energies up to about 0.5 keV (refs 1, 2). This is achieved by focusing a femtosecond laser into a gas, and high harmonics of the fundamental laser frequency are radiated in the forward direction. However, although this process can generate high-energy photons, efficient high-harmonic generation has been demonstrated only for photon energies of the order 50-100 eV (ref. 5). Ionization of the gas prevents the laser and the EUV light from propagating at the same speed, which severely limits the conversion efficiency. Here we report a technique to overcome this problem, and demonstrate quasi-phase-matched frequency conversion of laser light into EUV. Using a modulated hollow-core waveguide to periodically vary the intensity of the laser light driving the conversion, we efficiently generate EUV light even in the presence of substantial ionization. The use of a modulated fibre shifts the energy spectrum of the high-harmonic light to significantly higher photon energies than would otherwise be possible. We expect that this technique could form the basis of coherent EUV sources for advanced lithography and high-resolution imaging applications. In future work, it might also be possible to generate isolated attosecond pulses.     

Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6

Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes. Here we have used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye 2 and ruby-eye mice (ru2 and ru, respectively), two 'mimic' mouse models of HPS. We also show that these genes are orthologs of the genes mutated in individuals with HPS types 5 and 6, respectively, and that their protein products directly interact. Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.     

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.