Showing papers by "Xiaohui Xie published in 2006"

Systematic identification of human mitochondrial disease genes through integrative genomics.

Abstract: The majority of inherited mitochondrial disorders are due to mutations not in the mitochondrial genome (mtDNA) but rather in the nuclear genes encoding proteins targeted to this organelle. Elucidation of the molecular basis for these disorders is limited because only half of the estimated 1,500 mitochondrial proteins have been identified. To systematically expand this catalog, we experimentally and computationally generated eight genome-scale data sets, each designed to provide clues as to mitochondrial localization: targeting sequence prediction, protein domain enrichment, presence of cis-regulatory motifs, yeast homology, ancestry, tandem-mass spectrometry, coexpression and transcriptional induction during mitochondrial biogenesis. Through an integrated analysis we expand the collection to 1,080 genes, which includes 368 novel predictions with a 10% estimated false prediction rate. By combining this expanded inventory with genetic intervals linked to disease, we have identified candidate genes for eight mitochondrial disorders, leading to the discovery of mutations in MPV17 that result in hepatic mtDNA depletion syndrome. The integrative approach promises to better define the role of mitochondria in both rare and common human diseases.

Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression.

Abstract: Background Two distinct classes of regulators have been implicated in regulating neuronal gene expression and mediating neuronal identity: transcription factors such as REST/NRSF (RE1 silencing transcription factor) and CREB (cAMP response element-binding protein), and microRNAs (miRNAs). How these two classes of regulators act together to mediate neuronal gene expression is unclear.

A large family of ancient repeat elements in the human genome is under strong selection

Abstract: Although conserved noncoding elements (CNEs) constitute the majority of sequences under purifying selection in the human genome, they remain poorly understood. CNEs seem to be largely unique, with no large families of similar elements reported to date. Here, we search for CNEs among the ancestral repeat classes in the human genome and report the discovery of a large CNE family containing >900 members. This family belongs to the MER121 class of repeats. Although the MER121 family members show considerable sequence variation among one another, the individual copies show striking conservation in orthologous locations across the human, dog, mouse, and rat genomes. The element is also present and conserved in orthologous locations in the marsupial, but its genome-wide dispersal postdates the divergence from birds. The comparative genomic data indicate that MER121 does not encode a family of either protein-coding or RNA genes. Although the precise function of these elements remains unknown, the evidence suggests that this unusual family may play a cis-regulatory or structural role in mammalian genomes.

A family of conserved noncoding elements derived from an ancient transposable element

Abstract: The evolutionary origin of the conserved noncoding elements (CNEs) in the human genome remains poorly understood but may hold important clues to their biological functions. Here, we report the discovery of a CNE family with ≈124 instances in the human genome that demonstrates a clear signature of having been derived from an ancient transposon. The CNE family is also present in the chicken genome, although typically not at orthologous locations. The CNE family is closely related to the active transposon SINE3 in zebrafish and also to a previously uncharacterized transposon in the coelacanth, the so-called “living fossil” belonging to the lobe-finned fish lineage. The mammal, bird, zebrafish, and coelacanth families all share a highly similar core element of ≈180 bp but have important differences in their 5′ and 3′ ends. The core element has thus been preserved over 450 million years of evolution, implying an important biological function. In addition, we identify 95 additional CNE families that likely predate the mammalian radiation. The results highlight both the creative role of transposons and the importance of CNE families.

A molecular-properties-based approach to understanding PDZ domain proteins and PDZ ligands

Abstract: PDZ domain-containing proteins and their interaction partners are mutated in numerous human diseases and function in complexes regulating epithelial polarity, ion channels, cochlear hair cell development, vesicular sorting, and neuronal synaptic communication. Among several properties of a collection of documented PDZ domain-ligand interactions, we discovered embedded in a large-scale expression data set the existence of a significant level of co-regulation between PDZ domain-encoding genes and these ligands. From this observation, we show how integration of expression data, a comparative genomics catalog of 899 mammalian genes with conserved PDZ-binding motifs, phylogenetic analysis, and literature mining can be utilized to infer PDZ complexes. Using molecular studies we map novel interaction partners for the PDZ proteins DLG1 and CARD11. These results provide insight into the diverse roles of PDZ-ligand complexes in cellular signaling and provide a computational framework for the genome-wide evaluation of PDZ complexes.