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PubMed2004

Protein networks, pleiotropy and the evolution of senescence.

The number of interactions, or connectivity, among proteins in the yeast protein interaction network follows a power law. I compare patterns of connectivity for subsets of yeast proteins associated with senescence and with five other traits. I find that proteins associated with ageing have significantly higher connectivity than expected by chance, a pattern not seen for most other datasets. The pattern holds even when controlling for other factors also associated with connectivity, such as localization of protein expression within the cell. I suggest that these observations are consistent with the antagonistic pleiotropy theory for the evolution of senescence. In further support of this argument, I find that a protein's connectivity is positively correlated with the number of traits it influences or its degree of pleiotropy, and further show that the average degree of pleiotropy is greatest for proteins associated with senescence. I explain these results with a simple mathematical model combining assumptions of the antagonistic pleiotropy theory for the evolution of senescence with data on network topology. These findings integrate molecular and evolutionary models of senescence, and should aid in the search for new ageing genes.

Aging↗
PubMed1991

The Xlr (X-linked lymphocyte regulated) gene family (a candidate locus for an X-linked primary immune deficiency).

The murine Xlr (X-chromosome linked lymphocyte-regulated) gene family was originally identified by subtractive cDNA cloning and hybridization. A single predominant functional transcript encoding a 25 kDa peptide was initially found to be expressed in lymphoid cell lines corresponding to late stages of differentiation. A second functional Xlr gene has now been defined. It is expressed in differentiating male germ cells. Both the lymphoid and the germinal cell Xlr proteins are located in the cell nucleus and are closely homologous to each other. In parallel with the small number of currently known functional transcripts, the Xlr family comprises 50-75 sequences per haploid genome of which a majority is nonfunctional and that are localized on the proximal half of the X-chromosome and also on the Y-chromosome. This accumulation of pseudogenes may be related to the evolutionarily recent amplification of Xlr in rodents. Although murine Xlr probes do not cross-hybridize with human DNA, the existence of a human homolog for Xlr should be nevertheless postulated because of the conservation of X-chromosomal organization in mammals. Possible relationships of Xlr with X-linked primary immune deficiencies in man and mouse are finally discussed.

Animals↗
PubMed1999

Is Hsp90 a regulator of evolvability?

In a recent paper, Rutherford and Lindquist (1998. Nature 396:336-342) identified mutations in the Hsp90 protein that act to unmask hidden genetic variation with a variety of phenotypic effects. The Hsp90 protein has a number of properties that suggest a role in regulating the expression of genetic variation and therefore in adjusting the evolvability of the organism. In this paper we reflect upon the evolutionary feasibility of such mechanisms and suggest some possible ways of testing the adaptation-for-evolvability hypothesis in more detail. We conclude that Hsp90 holds promise as a molecular model system for the evolution of evolvability. J. Exp. Zool. ( Mol. Dev. Evol. ) 285:116-118, 1999.

Animals↗
PubMed2005

Methods for studying the evolution of plant reproductive structures: comparative gene expression techniques.

A major component of evolutionary developmental (evo-devo) genetics is the analysis of gene expression patterns in nonmodel species. This comparative approach can take many forms, including reverse-transcriptase polymerase chain reaction, Northern blot hybridization, and in situ hybridization. The choice of technique depends on several issues such as the availability of fresh tissue, as well as the expected expression level and pattern of the candidate gene in question. Although the protocols for these procedures are fairly standard, optimization is often required because of the specific characteristics of the species under analysis. This chapter describes several methods commonly used to determine gene expression patterns in angiosperms, particularly in floral tissues. Suggestions for adapting basic protocols for diverse taxa and troubleshooting are also extensively discussed.

Biological Evolution↗
PubMed2005

The silent revolution: RNA interference as basic biology, research tool, and therapeutic.

RNA interference (RNAi) is an evolutionarily conserved mechanism for silencing gene expression. In primitive organisms, RNAi protects the genome from viruses and other insertable genetic elements and regulates gene expression during development. The antisense (guide) strand of short double-stranded RNAs is incorporated into an RNA-induced silencing complex that can either suppress protein expression or direct degradation of messenger RNAs that contain homologous sequence(s). The discovery that RNAi works in mammalian cells has sparked intense investigation into its role in normal mammalian cell function, its use as a tool to understand or screen for genes functioning in cellular pathways in healthy and diseased cells and animals, and its potential for therapeutic gene silencing. RNAi may provide an important new therapeutic modality for treating infection, cancer, neurodegenerative disease, and other illnesses, although in vivo delivery of small interfering RNAs into cells remains a significant obstacle.

Animals↗
PubMed2005

Mucosal-associated invariant T (MAIT) cells: an evolutionarily conserved T cell subset.

Besides mainstream TCRalphabeta T cells harboring a very diverse repertoire, two subsets display an evolutionarily conserved invariant repertoire. This striking conservation indicates important and unique functions. CD1d-restricted NK-T cells expressing an invariant Valpha14 TCRalpha chain have been implicated in microbial and tumor responses as well as in auto-immunity. In this review, we describe the other subset, which bears the canonical hValpha7.2/mValpha19-Jalpha33 TCRalpha chain paired with a restricted set of Vbeta segments. These invariant T cells are present in mice, humans and cattle. They are preferentially located in the gut lamina propria (LP) of humans and mice and are therefore called mucosal-associated invariant T (MAIT) cells. Selection/expansion of this population requires B lymphocytes expressing MR1, a monomorphic major histocompatibility complex class I-related molecule that is also strikingly conserved in diverse mammalian species. MAIT cells are not present in germ-free mice, indicating that commensal flora is required for their expansion in the gut LP. The nature of the ligand and the putative functions of these MAIT cells are discussed.

Animals↗
PubMed1999

Molecular genetics of gynoecium development in Arabidopsis.

Carpels are the ovule-bearing structural units in angiosperms. In Arabidopsis, the specification of carpel identity is achieved by at least two separate pathways: a pathway mediated by the C class gene AG and an AG-independent pathway. Both pathways are negatively regulated by A class genes. Two genes, SPT and CRC, can promote differentiation of carpel tissue independently of AG and are thus components of the AG-independent pathway. CRC and SPT appear to act in a redundant manner to promote the differentiation of subsets of carpel tissues. The carpel primordium is subdivided into regional domains, both medial versus lateral and abaxial versus adaxial. Based on morphological and gene expression analyses, it appears likely that these domains define developmental compartments. The medial domain appears fated to differentiate into the marginal tissue types of the carpel (septum with transmitting tract and placenta with ovules), whereas the lateral domain gives rise to the ovary walls. The expression of ETT defines the abaxial domain, and this gene is involved in the abaxial-adaxial and, possibly, the apical-basal patterning of tissues in the carpel. Once regional domains have been established, the differentiation of tissue and cell types occurs. The MADS-box gene FUL and AGLI/5 are involved in the differentiation of specific tissue types in the valves and valve margins. Thus, the genes identified can be arranged in a functional hierarchy: specification of carpel identity, patterning of the carpel primordium and directing the differentiation of the specialized tissues of the carpel.

Arabidopsis↗
PubMed1999

Domain organization, genomic structure, evolution, and regulation of expression of the aggrecan gene family.

Proteoglycans are complex macromolecules, consisting of a polypeptide backbone to which are covalently attached one or more glycosaminoglycan chains. Molecular cloning has allowed identification of the genes encoding the core proteins of various proteoglycans, leading to a better understanding of the diversity of proteoglycan structure and function, as well as to the evolution of a classification of proteoglycans on the basis of emerging gene families that encode the different core proteins. One such family includes several proteoglycans that have been grouped with aggrecan, the large aggregating chondroitin sulfate proteoglycan of cartilage, based on a high number of sequence similarities within the N- and C-terminal domains. Thus far these proteoglycans include versican, neurocan, and brevican. It is now apparent that these proteins, as a group, are truly a gene family with shared structural motifs on the protein and nucleotide (mRNA) levels, and with nearly identical genomic organizations. Clearly a common ancestral origin is indicated for the members of the aggrecan family of proteoglycans. However, differing patterns of amplification and divergence have also occurred within certain exons across species and family members, leading to the class-characteristic protein motifs in the central carbohydrate-rich region exclusively. Thus the overall domain organization strongly suggests that sequence conservation in the terminal globular domains underlies common functions, whereas differences in the central portions of the genes account for functional specialization among the members of this gene family.

Aggrecans↗
PubMed1996

HERV-K: the biologically most active human endogenous retrovirus family.

The human genome contains a wide variety of endogenous retrovirus-like sequences. The human endogenous retrovirus type K (HERV-K) family comprises 30-50 members per haploid genome in humans and is highly conserved in Old World monkeys and apes. Some proviruses are displaying open reading frames (ORF) with coding capacity for viral particles. HERV-K sequences most likely code for the previously described human teratocarcinoma-derived virus (HTDV) and correlated expression of HERV-K Gag has been demonstrated by immunoelectron microscopy studies. Protease, but not yet reverse transcriptase (RT), enzymatic activity was demonstrated for recombinant HERV-K proteins. However, an ultrasensitive RT assay revealed specific polymerase activity associated with the HTDV particles. HERV-K transcription is specifically regulated by viral long terminal repeats and RNA is expressed at low steady-state levels in a variety of human tissues and tumours. In teratocarcinoma cell lines, HERV-K is highly expressed in a complex pattern showing full-length as well as subgenomic envelope (env) and two alternatively spliced small transcripts. The doubly spliced 1.8-kb mRNA codes for cORF protein which resembles Rev of HIV-1 and is located in the nucleolus. In addition, the cORF sequence acts as a leader and is essential for effective expression of glycosylated HERV-K Env protein. Although HERV-K sequences code for all necessary retroviral proteins, infectious particles could not yet be demonstrated. The putative implication of HERV sequences in pathophysiological processes, for example, testicular malignancies, remains to be elucidated.

Animals↗
PubMed2002

Generation and iterative affinity maturation of antibodies in vitro using hypermutating B-cell lines.

We show that iterative antigen-mediated selection of B-cell lines that constitutively hypermutate their immunoglobulin V genes during culture can be exploited to generate antibodies in vitro. From Ramos, a hypermutating human B-cell line expressing IgM of unknown specificity, we derived descendants that exhibit stepwise improved binding to streptavidin. Binding is initially conferred by mutations in complementarity-determining regions (CDRs), but maturation is due to strategic framework mutations. A more powerful system is provided by a hypermutating chicken B-lymphoma line, owing to its rapid proliferation, high rate of mutation accumulation, and genetic tractability. Starting from a single cell, we selected parallel lineages of derivatives, making mutated antibodies of increasing affinity to independent test antigens. Selection is initiated at an exceedingly low affinity threshold, but antibodies can be delivered with nanomolar affinities. The strategy could prove useful for in vitro generation of antigen-specific monoclonal antibodies and may be extendable to the maturation of other protein-ligand interactions.

Animals↗
PubMed2006

Microsatellite evolution: Markov transition functions for a suite of models.

This paper takes from the collection of models considered by Whittaker et al. [2003. Likelihood-based estimation of microsatellite mutation rates. Genetics 164, 781-787] derived from direct observation of microsatellite mutation in parent-child pairs and provides analytical expressions for the probability distributions for the change in number of repeats over any given number of generations. The mathematical framework for this analysis is the theory of Markov processes. We find these expressions using two approaches, approximating by circulant matrices and solving a partial differential equation satisfied by the generating function. The impact of the differing choice of models is examined using likelihood estimates for time to most recent common ancestor. The analysis presented here may play a role in elucidating the connections between these two approaches and shows promise in reconciling differences between estimates for mutation rates based on Whittaker's approach and methods based on phylogenetic analyses.

Biological Evolution↗
PubMed2005

The rhythm and blues of gene expression in the rodent pineal gland.

In all vertebrates, melatonin is rhythmically synthesized in the pineal gland and functions as a hormonal message, encoding for the duration of night. In rodents, the nocturnal rise and fall of the arylalkylamine N-ace-tyltransferase (AA-NAT) activity controls the rhythmic synthesis of melatonin. This rhythm is centered around the transcriptional regulation of the AA-NAT by two norepinephrine-inducible transcription factors, the activator CREB (Ca2+/cAMP-response element binding protein) and the inhibitor ICER (inducible cAMP early repressor). CREB is activated by phosphorylation, which is one of the fastest responses in pinealocytes upon adrenergic stimulation, occurring within minutes. ICER in turn accumulates only after several hours, a time gap resulting from the required de novo protein synthesis upon adrenergic stimulation. However, these molecular components of neuroendocrine signaling in the rodent pineal gland are supplemented by the impact of a variety of neurotransmitters and neuromodulators, and by translational and post-translational mechanisms. By molecular crosstalk, those different inputs on pinealocytes seem to fine-tune the shape of the melatonin signal, by interacting at various levels with the NE/cAMP/pCREB/ICER pathway. In addition, these alternate signaling routes may be important in acute "emergency" situations. Together, concerted signaling events in the rodent pineal gland help to generate a stable and reliable hormonal message of darkness for the body, that, however, can be altered rapidly upon sudden and unexpected "error" signals.

Animals↗
PubMed2001

A possible meiotic function of the peculiar patterns of gene expression in mammalian spermatogenic cells.

This review focuses on the striking differences in the patterns of transcription and translation in somatic and spermatogenic cells in mammals. In early haploid cells, mRNA translation evidently functions to restrict the synthesis of certain proteins, notably protamines, to transcriptionally inert late haploid cells. However, this does not explain why a substantial proportion of virtually all mRNA species are sequestered in translationally inactive free-messenger ribonucleoprotein particles (free-mRNPs) in meiotic cells, since most mRNAs undergo little or no increase in translational activity in transcriptionally active early haploid cells. In addition, most mRNAs in meiotic cells appear to be overexpressed because they are never fully loaded on polysomes and the levels of the corresponding protein are often much lower than the mRNA and are sometimes undetectable. A large number of genes are expressed at grossly higher levels in meiotic and/or early haploid spermatogenic cells than in somatic cells, yet they too are translated inefficiently. Many genes utilize alternative promoters in somatic and spermatogenic cells. Some of the resulting spermatogenic cell-altered transcripts (SCATs) encode proteins with novel functions, while others contain features in their 5'-UTRs, secondary structure or upstream reading frames, that are predicted to inhibit translation. This review proposes that the transcriptional machinery is modified to provide access to specific DNA sequences during meiosis, which leads to mRNA overexpression and creates a need for translational fine-tuning to prevent deleterious consequences of overproducing proteins.

Animals↗
PubMed2001

KIR: diverse, rapidly evolving receptors of innate and adaptive immunity.

KIR genes have evolved in primates to generate a diverse family of receptors with unique structures that enable them to recognize MHC-class I molecules with locus and allele-specificity. Their combinatorial expression creates a repertoire of NK cells that surveys the expression of almost every MHC molecule independently, thus antagonizing the spread of pathogens and tumors that subvert innate and adaptive defense by selectively downregulating certain MHC class I molecules. The genes encoding KIR that recognize classical MHC molecules have diversified rapidly in human and primates; this contrasts with conservation of immunoglobulin- and lectin-like receptors for nonclassical MHC molecules. As a result of the variable KIR-gene content in the genome and the polymorphism of the HLA system, dissimilar numbers and qualities of KIR:HLA pairs function in different humans. This diversity likely contributes variability to the function of NK cells and T-lymphocytes by modulating innate and adaptive immune responses to specific challenges.

Alleles↗
PubMed2003

Regulatory modules in the developing heart.

Fragments of regulatory DNA of cardiac genes drive reporter gene expression in sometimes unexpected subdomains of the heart. These patterns have revealed that the regulatory DNA of genes consists of distinct subfragments (regulatory modules) that are active in different regions of the developing heart. In this review we give an overview of the activity of regulatory modules in vivo. Furthermore, we investigated the relationship between the activity domains of the regulatory modules, the building blocks of the heart and the developmental patterning of the myocardium. Most of the regulatory modules show a domain of activity broader than the morphological boundary of a cardiac compartment and seem to respond to a patterning program along the antero-posterior axis.

Animals↗
PubMed1992

The small genome of Arabidopsis contains at least six expressed alpha-tubulin genes.

The goal of our investigations is to define the genetic control of microtubule-based processes in a higher plant. The available evidence suggests that we have achieved our first objective: the characterization of the complete alpha-tubulin and beta-tubulin gene families of Arabidopsis. Four additional alpha-tubulin genes (TUA2, TUA4, TUA5, and TUA6) of Arabidopsis have been cloned and sequenced to complete the analysis of the gene structure for all six alpha-tubulin genes detectable on DNA gel blots of Arabidopsis genomic DNA hybridized with alpha-tubulin coding sequences. TUA1 and TUA3 were characterized earlier in our laboratory. Noncoding gene-specific hybridization probes have been constructed for all six alpha-tubulin genes and used in RNA gel blot analyses to demonstrate that all six genes are transcribed. The six genes encode four different alpha-tubulin isoforms; TUA2 and TUA4 encode a single isoform, as do TUA3 and TUA5. Two-dimensional protein gel immunoblot analyses have resolved at least four alpha-tubulin isoforms from plant tissues, suggesting that all of the predicted TUA gene products are synthesized in vivo.

Amino Acid Sequence↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2000

Light microscopic detection of BCR-ABL transcripts after in-cell RT-PCR: fusion gene expression might correlate with clinical evolution of chronic myeloid leukemia.

A procedure for in-cell amplification of the hybrid BCR-ABL mRNA by reverse transcription and polymerase chain reaction (RT-PCR) without extraction of the nucleic acids was performed directly in fixed and permeabilized cells of leukemia patients (22 patients with Ph'-positive chronic myeloid leukaemia-CML and 1 with Ph'-positive acute leukaemia-AL, as well as 7 Ph'-negative cases) and Ph'-positive human leukaemia cell lines (K562, LAMA-84, BV173). The labelling of the amplified sequences was done employing biotinylated primers and a second PCR in a semi-nested fashion with a low number of cycles. An enzymatic system based on biotin-streptavidin-chromogen reaction was used for the detection of labeled PCR product, thus producing a coloured product, visible to the eye under a standard light microscope. All samples from patients with cytogenetic and molecular evidence of BCR-ABL rearrangement showed specific cytoplasmic staining at the site of the amplified hybrid transcripts. It allowed definite distinction between positive and negative cells. K562, LAMA-84, BV173 cells were characterized with strong diffuse staining while an interesting finding of the present study was the presence of variable quantities of colour product in patients' samples which might be due to different mRNA expression. Early and intermediate stages of myeloid maturation showed more intense reactivity. Cases with an aggressive course of accelerated or blast phase CML and AL were found to have a considerable subset of cells with strongly expressed signal while cases in chronic phase were characterised with uniform weak to moderate reaction. Our observations support the hypothesis that the amount of BCR-ABL transcript expression within neoplastic cells may play a role in dictating the eventual behaviour of the leukaemic clone. Future studies at a single cell level of larger series of consecutive cases with a follow up might be able to identify those patients who are prone to transformation and provide certain indications for further therapeutic decisions.

Adolescent↗