Krüppel-type zinc finger (ZNF) motifs are prevalent components of transcription factor proteins in all eukaryotes. KRAB-ZNF proteins, in which a potent repressor domain is attached to a tandem array of DNA-binding zinc-finger motifs, are specific to tetrapod vertebrates and represent the largest class of ZNF proteins in mammals. To define the full repertoire of human KRAB-ZNF proteins, we searched the genome sequence for key motifs and then constructed and manually curated gene models incorporating those sequences. The resulting gene catalog contains 423 KRAB-ZNF protein-coding loci, yielding alternative transcripts that altogether predict at least 742 structurally distinct proteins. Active rounds of segmental duplication, involving single genes or larger regions and including both tandem and distributed duplication events, have driven the expansion of this mammalian gene family. Comparisons between the human genes and ZNF loci mined from the draft mouse, dog, and chimpanzee genomes not only identified 103 KRAB-ZNF genes that are conserved in mammals but also highlighted a substantial level of lineage-specific change; at least 136 KRAB-ZNF coding genes are primate specific, including many recent duplicates. KRAB-ZNF genes are widely expressed and clustered genes are typically not coregulated, indicating that paralogs have evolved to fill roles in many different biological processes. To facilitate further study, we have developed a Web-based public resource with access to gene models, sequences, and other data, including visualization tools to provide genomic context and interaction with other public data sets.

Most genes are conserved in mammals, but certain gene families have acquired large numbers of lineage-specific loci through repeated rounds of gene duplication, divergence, and loss that have continued in each mammalian group. One such family encodes KRAB-zinc finger (KRAB-ZNF) proteins, which function as transcriptional repressors. One particular subfamily of KRAB-ZNF genes, including ZNF91, has expanded specifically in primates to comprise more than 110 loci in the human genome. Genes of the ZNF91 subfamily reside in large gene clusters near centromeric regions of human chromosomes 19 and 7 with smaller clusters or isolated copies in other locations. Phylogenetic analysis indicates that many of these genes arose before the split between the New and Old World monkeys, but the ZNF91 subfamily has continued to expand and diversify throughout the evolution of apes and humans. Paralogous loci are distinguished by divergence within their zinc finger arrays, indicating selection for proteins with different regulatory targets. In addition, many loci produce multiple alternatively spliced transcripts encoding proteins that may serve separate and perhaps even opposing regulatory roles because of the modular motif structure of KRAB-ZNF genes. The tissue-specific expression patterns and rapid structural divergence of ZNF91 subfamily genes suggest a role in determining gene expression differences between species and the evolution of novel primate traits.

A substantial fraction of the vertebrate gene repertoireis conserved across the animal kingdom and beyond (Lander et al. 2001; Aparicio et al. 2002; Lespinet et al. 2002).In addition, unique 1:1 ortholog pairings reveal substantialdomains of syntenic conservation when closely relatedgenomes are compared (see, e.g., Dehal et al. 2001; Waterston et al. 2002). However, for certain gene types, 1:1orthologous relationships are the exception and not therule, apparently because duplicate copies of these geneshave been generated and fixed at unusually high rates.These ongoing duplication events have yielded substantialnumbers of lineage-specific genes, giving rise to generepertoire differences that distinguish even very closelyrelated species. Examples include genes encoding olfactory receptors (OR) and Krüppel-type zinc finger (KZNF)proteins, which together comprise 2–5% of known mammalian genes. Importantly, most of the genes in theserapidly expanding families exist in contiguous familialclusters, consistent with the model that they have arisenthrough a process of repeated tandem duplications (Ohno1970; Huntley et al. 2003). Although the mechanismsdriving these in situ duplications require more study, theevolutionary generation of such tandem gene arrays is responsible for the overwhelming majority of gene repertoire expansion in metazoans (Friedman and Hughes2003). What underlies this dramatic difference in evolutionary fate between these "fast-lane" genes and those inthe conserved core genome...

Objective: To evaluate a 4-week programme of surface neuromuscular electrical stimulation (sNMES) to the shoulder following acute stroke. Design: Pragmatic randomised controlled trial.