• A turner syndrome neurocognitive phenotype maps to Xp22.3

      Zinn, AR; Roeltgen, D; Stefanatos, G; Ramos, P; Elder, FF; Kushner, H; Kowal, K; Ross, JL (2007-05-21)
      Background: Turner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. We previously reported evidence that this phenotype results from haploinsufficiency of one or more genes on distal Xp. This inference was based on genotype/phenotype comparisons of individual girls and women with partial Xp deletions, with the neurocognitive phenotype considered a dichotomous trait. We sought to confirm our findings in a large cohort (n = 47) of adult women with partial deletions of Xp or Xq, enriched for subjects with distal Xp deletions. Methods: Subjects were recruited from North American genetics and endocrinology clinics. Phenotype assessment included measures of stature, ovarian function, and detailed neurocognitive testing. The neurocognitive phenotype was measured as a quantitative trait, the Turner Syndrome Cognitive Summary (TSCS) score, derived from discriminant function analysis. Genetic analysis included karyotyping, X inactivation studies, fluorescent in situ hybridization, microsatellite marker genotyping, and array comparative genomic hybridization. Results: We report statistical evidence that deletion of Xp22.3, an interval containing 31 annotated genes, is sufficient to cause the neurocognitive phenotype described by the TSCS score. Two other cardinal TS features, ovarian failure and short stature, as well as X chromosome inactivation pattern and subject's age, were unrelated to the TSCS score. Conclusion: Detailed mapping suggests that haploinsufficiency of one or more genes in Xp22.3, the distal 8.3 megabases (Mb) of the X chromosome, is responsible for a TS neurocognitive phenotype. This interval includes the 2.6 Mb Xp-Yp pseudoautosomal region (PAR1). Haploinsufficiency of the short stature gene SHOX in PAR1 probably does not cause this TS neurocognitive phenotype. Two genes proximal to PAR1 within the 8.3 Mb critical region, STS and NLGN4X, are attractive candidates for this neurocognitive phenotype. © 2007 Zinn et al; licensee BioMed Central Ltd.
    • Elevated Evolutionary Rates among Functionally Diverged Reproductive Genes across Deep Vertebrate Lineages

      Grassa, Christopher J; Kulathinal, Rob J; Kulathinal, Rob|0000-0003-1907-2744 (2011-07-28)
      <jats:p>Among closely related taxa, proteins involved in reproduction generally evolve more rapidly than other proteins. Here, we apply a functional and comparative genomics approach to compare functional divergence across a deep phylogenetic array of egg-laying and live-bearing vertebrate taxa. We aligned and annotated a set of 4,986 1 : 1 : 1 : 1 : 1 orthologs in <jats:italic>Anolis carolinensis</jats:italic> (green lizard), <jats:italic>Danio rerio</jats:italic> (zebrafish), <jats:italic>Xenopus tropicalis</jats:italic> (frog), <jats:italic>Gallus gallus</jats:italic> (chicken), and <jats:italic>Mus musculus</jats:italic> (mouse) according to function using ESTs from available reproductive (including testis and ovary) and non-reproductive tissues as well as Gene Ontology. For each species lineage, genes were further classified as tissue-specific (found in a single tissue) or tissue-expressed (found in multiple tissues). Within independent vertebrate lineages, we generally find that gonadal-specific genes evolve at a faster rate than gonadal-expressed genes and significantly faster than non-reproductive genes. Among the gonadal set, testis genes are generally more diverged than ovary genes. Surprisingly, an opposite but nonsignificant pattern is found among the subset of orthologs that remained functionally conserved across <jats:italic>all</jats:italic> five lineages. These contrasting evolutionary patterns found between functionally diverged and functionally conserved reproductive orthologs provide evidence for pervasive and potentially cryptic lineage-specific selective processes on ancestral reproductive systems in vertebrates.</jats:p>
    • Extracting functional trends from whole genome duplication events using comparative genomics

      Hermansen, RA; Hvidsten, TR; Sandve, SR; Liberles, DA; Liberles, David A|0000-0003-3487-8826 (2016-05-10)
      © 2016 Hermansen et al. Background: The number of species with completed genomes, including those with evidence for recent whole genome duplication events has exploded. The recently sequenced Atlantic salmon genome has been through two rounds of whole genome duplication since the divergence of teleost fish from the lineage that led to amniotes. This quadrupoling of the number of potential genes has led to complex patterns of retention and loss among gene families. Results: Methods have been developed to characterize the interplay of duplicate gene retention processes across both whole genome duplication events and additional smaller scale duplication events. Further, gene expression divergence data has become available as well for Atlantic salmon and the closely related, pre-whole genome duplication pike and methods to describe expression divergence are also presented. These methods for the characterization of duplicate gene retention and gene expression divergence that have been applied to salmon are described. Conclusions: With the growth in available genomic and functional data, the opportunities to extract functional inference from large scale duplicates using comparative methods have expanded dramatically. Recently developed methods that further this inference for duplicated genes have been described.
    • Intrinsic disorder in putative protein sequences

      Midic, U; Obradovic, Z (2012-01-01)
      © 2012 Midic and Obradovic; licensee BioMed Central Ltd. Background: Intrinsically disordered proteins (IDPs) and regions (IDRs) perform a variety of crucial biological functions despite lacking stable tertiary structure under physiological conditions in vitro. State-of-the-art sequencebased predictors of intrinsic disorder are achieving per-residue accuracies over 80%. In a genome-wide study of intrinsic disorder in human genome we observed a big difference in predicted disorder content between confirmed and putative human proteins. We investigated a hypothesis that this discrepancy is not correct, and that it is due to incorrectly annotated parts of the putative protein sequences that exhibit some similarities to confirmed IDRs, which lead to high predicted disorder content. Methods: To test this hypothesis we trained a predictor to discriminate sequences of real proteins from synthetic sequences that mimic errors of gene finding algorithms. We developed a procedure to create synthetic peptide sequences by translation of non-coding regions of genomic sequences and translation of coding regions with incorrect codon alignment. Results: Application of the developed predictor to putative human protein sequences showed that they contain a substantial fraction of incorrectly assigned regions. These regions are predicted to have higher levels of disorder content than correctly assigned regions. This partially, albeit not completely, explains the observed discrepancy in predicted disorder content between confirmed and putative human proteins. Conclusions: Our findings provide the first evidence that current practice of predicting disorder content in putative sequences should be reconsidered, as such estimates may be biased.
    • Mouse ribonuclease III. cDNA structure, expression analysis, and chromosomal location

      Fortin, KR; Nicholson, RH; Nicholson, AW (2002-08-21)
      Background: Members of the ribonuclease III superfamily of double-stranded(ds)-RNA-specific endoribonucleases participate in diverse RNA maturation and decay pathways in eukaryotic and prokaryotic cells. A human RNase III orthologue has been implicated in ribosomal RNA maturation. To better understand the structure and mechanism of mammalian RNase III and its involvement in RNA metabolism we determined the cDNA structure, chromosomal location, and expression patterns of mouse RNase III. Results: The predicted mouse RNase III polypeptide contains 1373 amino acids (∼160 kDa). The polypeptide exhibits a single C-terminal dsRNA-binding motif (dsRBM), tandem catalytic domains, a proline-rich region (PRR) and an RS domain. Northern analysis and RT-PCR reveal that the transcript (4487 nt) is expressed in all tissues examined, including extraembryonic tissues and the midgestation embryo. Northern analysis indicates the presence of an additional, shorter form of the transcript in testicular tissue. Fluorescent in situ hybridization demonstrates that the mouse RNase III gene maps to chromosome 15, region B, and that the human RNase III gene maps to a syntenic location on chromosome 5p13-p14. Conclusions: The broad transcript expression pattern indicates a conserved cellular role(s) for mouse RNase III. The putative polypeptide is highly similar to human RNase III (99% amino acid sequence identity for the two catalytic domains and dsRBM), but is distinct from other eukaryotic orthologues, including Dicer, which is involved in RNA interference. The mouse RNase III gene has a chromosomal location distinct from the Dicer gene. © 2002 Fortin et al; licensee BioMed Central Ltd.
    • Sex-Biased Networks and Nodes of Sexually Antagonistic Conflict in Drosophila

      Hansen, Matthew EB; Kulathinal, Rob J; Kulathinal, Rob|0000-0003-1907-2744 (2013-01-22)
      <jats:p>Sexual antagonism, or conflict, can occur when males and females harbor opposing reproductive strategies. The large fraction of sex-biased genes in genomes present considerable opportunities for conflict to occur, suggesting that sexual antagonism may potentially be a general phenomenon at the molecular level. Here, we employ a novel strategy to identify potential nodes of sexual conflict in <jats:italic>Drosophila melanogaster</jats:italic> by coupling male, female, and sex-unbiased networks derived from genome-wide expression data with available genetic and protein interaction data. We find that sex-biased networks comprise a large fraction (<jats:italic>~</jats:italic>1/3) of the total interaction network with the male network possessing nearly twice the number of nodes (genes) relative to the female network. However, there are far less edges or interaction partners among male relative to female subnetworks as seen in their power law distributions. We further identified 598 sex-unbiased genes that can act as indirect nodes of interlocus sexual conflict as well as 271 direct nodal pairs of potential conflict between male- and female-biased genes. The pervasiveness of such potentially conflicting nodes may explain the rapid evolution of sex-biased as well as non-sex-biased genes via this molecular mechanism of sexual selection even among taxa such as <jats:italic>Drosophila</jats:italic> that are nominally sexually dimorphic.</jats:p>