- Email: [email protected]
Old-aged genes
News & Comment
of ω? If so, what might this tell us about their functions? The similar size and location of ω and Rpb6 in their respective RNAP complexes prompted Minakhin et al.1 to re-examine the relationship between these two subunits. Although previously unrecognized, sequence similarities between ω and Rpb6 were detected by PSI-BLAST searches, and this relationship was extended to RpoK, a subunit of archaeal RNAP. Moreover, the tertiary structures of ω and Rpb6 can be superimposed, and the two subunits interact with core RNAP in a structurally similar manner. These similarities were extended to functional similarities by taking advantage of the fortuitous existence of equivalent mutations in the genes encoding the β′ subunit (rpoC) and Rpb1. The rpoC and rpb1 alleles encode single amino acid replacements at the β′–ω or Rpb1–Rpb6 interface and confer temperature-sensitive growth defects. These two RNAP derivatives are also highly unstable in vitro. Minakhin et al.1 went on to show that the growth defects of the bacterial and yeast mutants could be effectively suppressed by overexpression of ω and Rpb6, respectively, and that this effect is allele specific. ‘...all five subunits of bacterial core RNAP [RNA polymerase] have counterparts in eukaryotic (and archaeal) RNAP’ These results clearly define structural and functional relationships between ω and Rpb6. Accordingly, all five subunits of bacterial core RNAP have counterparts in eukaryotic (and archaeal) RNAP. Furthermore, the topological location of ω and Rpb6, and their ability to compensate for RNAP stability defects when overexpressed, suggest that ω and Rpb6 are RNAP assembly factors. This conclusion is consistent with earlier genetic interactions between Rpb1 and Rpb6, and offers an explanation for why bacterial RNAP, assembled in vitro, is functional in the absence of ω. 1 Minakhin, L. et al. (2001) Bacterial RNA polymerase subunit ω and eukaryotic RNA polymerase subunit Rpb6 are sequence, structural, and functional homologs and promote RNA polymerase assembly. Proc. Natl. Acad. Sci. U. S. A. 98, 892–897
Michael Hampsey e-mail: [email protected]
TRENDS in Genetics Vol.17 No.4 April 2001
191
In Brief
A new drug for malaria targets plastids Malaria is responsible for over 2 million deaths world wide each year. Malaria in humans is caused by four species of a protozoal parasite called Plasmodium. Plasmodia contain organelles called plastids that are also found in many plants and algae. Plastids make an excellent target for anti-malarial drugs because they have metabolic pathways that are different from humans. A team of Indian scientists reported that they have found an antibacterial drug, Triclosan, to be effective against infection by Plasmodium berghei in mice and is a potent inhibitor of Plasmodium falciparum in culture. This drug targets an enzyme involved in fatty acid biosynthetic pathway in plastids. Triclosan, already used as a topical antibacterial agent, is very attractive as an antimalaria therapy as resistance to it is not commonly observed. [Surolia, N.
Biogenetic weapons Jonathan Moreno, a bioethicist in the former Clinton administration, warns that the unveiling of the human genome makes biogenetic weapons a probability in only five to ten years unless governments intervene. Moreno said that biological weapons targeting specific ethnic genes could affect birthrates or increase the chances that certain races will contract diseases. At the American Association for the Advancement of Science annual meeting (mid February), Prof. Moreno pointed out that germs were developed in the late 1900s and within 20 years germ-warfare was being investigated. Kathleen Vogel, also at the meeting, expressed her concern that soviet bioweapons are still a threat. Former biological weapons specialists in Russia and the New Independent States have received US funding to redirect their research for peaceful purposes but Vogel beleives that corruption and temptation threaten such initiatives. Scientists are concerned about genetically engineered strains of anthrax and plague bacteria that are antibiotic-resistant and animal pathogens used against agricultural targets. SB
Blood feeding Anopheles gambiae. Photograph courtesy of CDC/James D. Gathany.
and Surolia, A. (2001) Nat. Med. 7, 167–173] AP New targets for anti-malarial drugs are expected to be gained from the genome sequencing projects: information is emerging from the human genome, the genome of Plasmodium falciparum is already available (http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=Genome), and that of the deadliest malaria vector, the mosquito Anopheles gambiae, is underway and expected to be delivered by the end of the year (update at http://konops.imbb.forth.gr/AnoDB/) PL
Molecular archaeology: an in-depth survey of the worm genome A team from Yale has completed a global survey of the entire Caenorhabditis elegans genome to examine the extent and distribution of pseudogenes. As ‘dead’ genes, they are not subject to the same darwinian constraints as the ‘living’ protein population and thus provide information complementary to analyses of these data. The survey has found that one in nine of all genes are pseudogenes, with uneven distribution throughout the genome, and that the most common pseudogene folds differ from those of functional genes, suggesting the loss of certain conformations in favour of more efficient ones. [Harrison, P.M. et al. (2001) Nucleic Acids Res. 29, 818–830; http://bioinfo.mbb.yale.edu/genome/worm/ pseudogene] CH
Old-aged genes A recent study used high-density oligonucleotide arrays to examine agerelated changes in the expression of a number of genes in the brain. Changes were found in a number of key genes involved in neuronal structure and signalling in the
http://tig.trends.com 0168–9525/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
192
News & Comment
cortex and hypothalamus of young and aged mice. These included synaptotagmin I, cAMPdependent protein kinase C, apolipoprotein E, protein phosphatase 2A and prostaglandin D. In addition, many proteases that are essential in the regulation of neuropeptide metabolism, amyloid precursor protein processing and neuronal apoptosis were upregulated in the aged brain. Knowledge of the molecular basis of ageing in the brain could help to provide a better understanding of age-related cognitive decline and neurodegenerative disease. [Jiang, C.H. et al. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 1930–1934). AI
Making pigs less ‘piggy’
William Muir and other Purdue University researchers aim to increase hog production by a unique route – identifying the genes responsible for aggression in pigs. Within groups, aggressive pigs grow better at the expense of less aggressive pigs and overall group productivity. Thus, groups of lessaggressive pigs should grow faster. Muir, who previously found a genetic basis for aggression in chickens, suspects pig aggression will also have a genetic component. He hopes to identify such genes using marker-assisted selection. The stakes are high; even a 20% increase in productivity will result in farmers receiving an additional $2 billion per year. And that’s a lot of bacon! (http://news.uns.purdue.edu/html4ever/ 010119.Muir.hoggenome.html) NJ
The smell of imprinting Genomic imprinting, the parent-of-originspecific gene silencing, might be involved in smell. Nick Allen and colleagues examined odour choice of F1 mice from reciprocal crosses between inbred strains and found that their odour preference depends on the strain of their mother. Furthermore, this preference was not due to previous exposure or learning, and is probably hardwired. The genes most likely to be responsible for this
TRENDS in Genetics Vol.17 No.4 April 2001
effect are those that code for olfactory receptors, as it is already known that these genes are only expressed from one allele – a pre-requisite for genomic imprinting. [Isles, A.R. (2001) Nature 409, 783–784] AI
Fear and loathing in a knockout Female mice with a targeted deletion of the opioid precursor preproenkephalin are more fearful in behavioural tasks assessing anxiety. In addition to anxiety and fear, previous studies have implicated the endogenous opioid system in sexual behaviour and palatable intake. However, Pfaff and colleagues found that their transgenic mice did not differ from controls in food and water intake, or in lordosis and other sexual behaviours. Additionally, the behavioural changes in fear thresholds were stable in independent groups tested across 20 months and different seasons. This led the authors to conclude that ‘these transgenic data strongly suggest that opioids, and particularly enkephalin gene products, are acting naturally to inhibit fear and anxiety.’ [Ragnauth, A. et al. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 1958–1963] AI
Liquid form of DNA developed Chemists at the University of North Carolina at Chapel Hill have developed a liquid form of DNA. DNA is normally used as a dilute solution or as a crystalline solid. By combining negatively charged DNA crystals with positively charged metal complexes with a polyether tail, they were able to produce molten DNA at room temperature that is still double-stranded and is able to conduct electricity. Although its immediate practical application is uncertain, liquid DNA might be used in microelectronic circuits in the future that are capable of archiving and transferring electronic information. [Leone, A.M. et al. (2001) J. Am. Chem. Soc. 123, 218–222] AP
Disease genes in the human genome An initial analysis of the human genome has identified 923 disease-causing genes. Almost 31% of these genes encode enzymes with about half as many genes encoding for proteins that modulate protein function. Interestingly, the peak age at onset of diseases involving various categories of disease genes is distinct – diseases caused by abnormalities in transcription factors
peak in utero, those caused by abnormal enzymes peak in year 1, defective receptors cause the most disease between year 1 and puberty, and conditions caused by aberrant modifiers of protein function peak in early adulthood. The inheritance patterns of diseases also correlated with the type of gene implicated in the disease – those involving enzymes are mainly recessive, whereas those involving transcription factors are more likely to be dominant. [Jimenez-Sanchez, G. et al. (2001) Nature 409, 853–855] AP
Gut pathogen sequence reveals surprises
Food contaminated with Escherichia coli strain O157:H7 is responsible for thousands of deaths world wide. Researchers at the University of Wisconsin, Madison, recently reported the nearly complete genomic sequence of this pathogen in the journal Nature. There are about 1387 new genes specific to the O157:H7 strain found interspersed in its genome, many of which are candidate virulence factors. Several of these genes might have come from other species through horizontal gene transfer. This could help explain the emergence of O157:H7 as a public health problem in recent years, because it allows for rapid acquisition of genetic changes. [Perna, N.T. et al. (2001) Nature 409, 529–533] AP
Suzanne Berry [email protected] Cathy Holding [email protected] Anthony Isles [email protected] Norman A. Johnson [email protected] Petros Ligoxygakis [email protected] Akhilesh Pandey [email protected]
http://tig.trends.com 0168–9525/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
of ω? If so, what might this tell us about their functions? The similar size and location of ω and Rpb6 in their respective RNAP complexes prompted Minakhin et al.1 to re-examine the relationship between these two subunits. Although previously unrecognized, sequence similarities between ω and Rpb6 were detected by PSI-BLAST searches, and this relationship was extended to RpoK, a subunit of archaeal RNAP. Moreover, the tertiary structures of ω and Rpb6 can be superimposed, and the two subunits interact with core RNAP in a structurally similar manner. These similarities were extended to functional similarities by taking advantage of the fortuitous existence of equivalent mutations in the genes encoding the β′ subunit (rpoC) and Rpb1. The rpoC and rpb1 alleles encode single amino acid replacements at the β′–ω or Rpb1–Rpb6 interface and confer temperature-sensitive growth defects. These two RNAP derivatives are also highly unstable in vitro. Minakhin et al.1 went on to show that the growth defects of the bacterial and yeast mutants could be effectively suppressed by overexpression of ω and Rpb6, respectively, and that this effect is allele specific. ‘...all five subunits of bacterial core RNAP [RNA polymerase] have counterparts in eukaryotic (and archaeal) RNAP’ These results clearly define structural and functional relationships between ω and Rpb6. Accordingly, all five subunits of bacterial core RNAP have counterparts in eukaryotic (and archaeal) RNAP. Furthermore, the topological location of ω and Rpb6, and their ability to compensate for RNAP stability defects when overexpressed, suggest that ω and Rpb6 are RNAP assembly factors. This conclusion is consistent with earlier genetic interactions between Rpb1 and Rpb6, and offers an explanation for why bacterial RNAP, assembled in vitro, is functional in the absence of ω. 1 Minakhin, L. et al. (2001) Bacterial RNA polymerase subunit ω and eukaryotic RNA polymerase subunit Rpb6 are sequence, structural, and functional homologs and promote RNA polymerase assembly. Proc. Natl. Acad. Sci. U. S. A. 98, 892–897
Michael Hampsey e-mail: [email protected]
TRENDS in Genetics Vol.17 No.4 April 2001
191
In Brief
A new drug for malaria targets plastids Malaria is responsible for over 2 million deaths world wide each year. Malaria in humans is caused by four species of a protozoal parasite called Plasmodium. Plasmodia contain organelles called plastids that are also found in many plants and algae. Plastids make an excellent target for anti-malarial drugs because they have metabolic pathways that are different from humans. A team of Indian scientists reported that they have found an antibacterial drug, Triclosan, to be effective against infection by Plasmodium berghei in mice and is a potent inhibitor of Plasmodium falciparum in culture. This drug targets an enzyme involved in fatty acid biosynthetic pathway in plastids. Triclosan, already used as a topical antibacterial agent, is very attractive as an antimalaria therapy as resistance to it is not commonly observed. [Surolia, N.
Biogenetic weapons Jonathan Moreno, a bioethicist in the former Clinton administration, warns that the unveiling of the human genome makes biogenetic weapons a probability in only five to ten years unless governments intervene. Moreno said that biological weapons targeting specific ethnic genes could affect birthrates or increase the chances that certain races will contract diseases. At the American Association for the Advancement of Science annual meeting (mid February), Prof. Moreno pointed out that germs were developed in the late 1900s and within 20 years germ-warfare was being investigated. Kathleen Vogel, also at the meeting, expressed her concern that soviet bioweapons are still a threat. Former biological weapons specialists in Russia and the New Independent States have received US funding to redirect their research for peaceful purposes but Vogel beleives that corruption and temptation threaten such initiatives. Scientists are concerned about genetically engineered strains of anthrax and plague bacteria that are antibiotic-resistant and animal pathogens used against agricultural targets. SB
Blood feeding Anopheles gambiae. Photograph courtesy of CDC/James D. Gathany.
and Surolia, A. (2001) Nat. Med. 7, 167–173] AP New targets for anti-malarial drugs are expected to be gained from the genome sequencing projects: information is emerging from the human genome, the genome of Plasmodium falciparum is already available (http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=Genome), and that of the deadliest malaria vector, the mosquito Anopheles gambiae, is underway and expected to be delivered by the end of the year (update at http://konops.imbb.forth.gr/AnoDB/) PL
Molecular archaeology: an in-depth survey of the worm genome A team from Yale has completed a global survey of the entire Caenorhabditis elegans genome to examine the extent and distribution of pseudogenes. As ‘dead’ genes, they are not subject to the same darwinian constraints as the ‘living’ protein population and thus provide information complementary to analyses of these data. The survey has found that one in nine of all genes are pseudogenes, with uneven distribution throughout the genome, and that the most common pseudogene folds differ from those of functional genes, suggesting the loss of certain conformations in favour of more efficient ones. [Harrison, P.M. et al. (2001) Nucleic Acids Res. 29, 818–830; http://bioinfo.mbb.yale.edu/genome/worm/ pseudogene] CH
Old-aged genes A recent study used high-density oligonucleotide arrays to examine agerelated changes in the expression of a number of genes in the brain. Changes were found in a number of key genes involved in neuronal structure and signalling in the
http://tig.trends.com 0168–9525/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
192
News & Comment
cortex and hypothalamus of young and aged mice. These included synaptotagmin I, cAMPdependent protein kinase C, apolipoprotein E, protein phosphatase 2A and prostaglandin D. In addition, many proteases that are essential in the regulation of neuropeptide metabolism, amyloid precursor protein processing and neuronal apoptosis were upregulated in the aged brain. Knowledge of the molecular basis of ageing in the brain could help to provide a better understanding of age-related cognitive decline and neurodegenerative disease. [Jiang, C.H. et al. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 1930–1934). AI
Making pigs less ‘piggy’
William Muir and other Purdue University researchers aim to increase hog production by a unique route – identifying the genes responsible for aggression in pigs. Within groups, aggressive pigs grow better at the expense of less aggressive pigs and overall group productivity. Thus, groups of lessaggressive pigs should grow faster. Muir, who previously found a genetic basis for aggression in chickens, suspects pig aggression will also have a genetic component. He hopes to identify such genes using marker-assisted selection. The stakes are high; even a 20% increase in productivity will result in farmers receiving an additional $2 billion per year. And that’s a lot of bacon! (http://news.uns.purdue.edu/html4ever/ 010119.Muir.hoggenome.html) NJ
The smell of imprinting Genomic imprinting, the parent-of-originspecific gene silencing, might be involved in smell. Nick Allen and colleagues examined odour choice of F1 mice from reciprocal crosses between inbred strains and found that their odour preference depends on the strain of their mother. Furthermore, this preference was not due to previous exposure or learning, and is probably hardwired. The genes most likely to be responsible for this
TRENDS in Genetics Vol.17 No.4 April 2001
effect are those that code for olfactory receptors, as it is already known that these genes are only expressed from one allele – a pre-requisite for genomic imprinting. [Isles, A.R. (2001) Nature 409, 783–784] AI
Fear and loathing in a knockout Female mice with a targeted deletion of the opioid precursor preproenkephalin are more fearful in behavioural tasks assessing anxiety. In addition to anxiety and fear, previous studies have implicated the endogenous opioid system in sexual behaviour and palatable intake. However, Pfaff and colleagues found that their transgenic mice did not differ from controls in food and water intake, or in lordosis and other sexual behaviours. Additionally, the behavioural changes in fear thresholds were stable in independent groups tested across 20 months and different seasons. This led the authors to conclude that ‘these transgenic data strongly suggest that opioids, and particularly enkephalin gene products, are acting naturally to inhibit fear and anxiety.’ [Ragnauth, A. et al. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 1958–1963] AI
Liquid form of DNA developed Chemists at the University of North Carolina at Chapel Hill have developed a liquid form of DNA. DNA is normally used as a dilute solution or as a crystalline solid. By combining negatively charged DNA crystals with positively charged metal complexes with a polyether tail, they were able to produce molten DNA at room temperature that is still double-stranded and is able to conduct electricity. Although its immediate practical application is uncertain, liquid DNA might be used in microelectronic circuits in the future that are capable of archiving and transferring electronic information. [Leone, A.M. et al. (2001) J. Am. Chem. Soc. 123, 218–222] AP
Disease genes in the human genome An initial analysis of the human genome has identified 923 disease-causing genes. Almost 31% of these genes encode enzymes with about half as many genes encoding for proteins that modulate protein function. Interestingly, the peak age at onset of diseases involving various categories of disease genes is distinct – diseases caused by abnormalities in transcription factors
peak in utero, those caused by abnormal enzymes peak in year 1, defective receptors cause the most disease between year 1 and puberty, and conditions caused by aberrant modifiers of protein function peak in early adulthood. The inheritance patterns of diseases also correlated with the type of gene implicated in the disease – those involving enzymes are mainly recessive, whereas those involving transcription factors are more likely to be dominant. [Jimenez-Sanchez, G. et al. (2001) Nature 409, 853–855] AP
Gut pathogen sequence reveals surprises
Food contaminated with Escherichia coli strain O157:H7 is responsible for thousands of deaths world wide. Researchers at the University of Wisconsin, Madison, recently reported the nearly complete genomic sequence of this pathogen in the journal Nature. There are about 1387 new genes specific to the O157:H7 strain found interspersed in its genome, many of which are candidate virulence factors. Several of these genes might have come from other species through horizontal gene transfer. This could help explain the emergence of O157:H7 as a public health problem in recent years, because it allows for rapid acquisition of genetic changes. [Perna, N.T. et al. (2001) Nature 409, 529–533] AP
Suzanne Berry [email protected] Cathy Holding [email protected] Anthony Isles [email protected] Norman A. Johnson [email protected] Petros Ligoxygakis [email protected] Akhilesh Pandey [email protected]
http://tig.trends.com 0168–9525/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.