How genes are controlled in mammals
The international FANTOM consortium announces publication of three milestone papers in the prestigious journal Nature Genetics that will challenge current notions of how genes are controlled in mammals.
FANTOM, or Functional Annotation of the Mammalian cDNA, which is organized by RIKEN Omics Science Center (OSC), has leading scientists in Australia, Switzerland, Norway, South Africa, Sweden, Canada, Denmark, Italy, Germany, Singapore, UK, and the United States. The consortium has been providing the scientific community with extensive databases on the mammalian genome that describe molecular function, biology, and cell components. FANTOM has become a world authority on the mammalian transcriptome, the set of all messenger RNA showing active genetic expression at one point in time. Other major discoveries are that approximately 70% of the genome is transcribed and that more than half of the expressed genes are likely non-coding RNAs (ncRNAs) that do not code proteins; thus, the prevailing theory that only 2% of the genome is transcribed into mRNA coding to proteins needed to be reexamined. Now in its fourth stage, FANTOM4, led by OSC’s Dr. Yoshihide Hayashizaki, has in over 3 years of laborious research developed a novel technology for producing a genome-wide promoter expression profile, established a mathematical scheme for describing the data obtained, and extracted key genomic elements that play dominant roles in the maintenance of cellular conditions.
In the current research, OSC has broadened its original technology CAGE (Cap Analysis of Gene Expression) and created deepCAGE, which takes advantage of next-generation sequencing to both precisely identify transcription start sites genome wide as well as to quantify the expression of each start site. The deepCAGE technology was applied to a differentiating acute myeloid leukemia cell line (ACL) to provide genome-wide time course dynamics of expression at the level of individual promoters — specific sequences on the DNA providing binding sites for RNA polymerase and the protein transcription factors that recruit them. The consortium built a quantitative model of the genome-wide gene expression dynamics that identified the key regulator motifs driving the differentiation, the time-dependent activities of the transcription regulators binding the motifs, and the genome-wide target promoters of each motif.
Validation of the model was performed by knocking down each transcription factor with small interfering RNAs. This first report of a large-scale gene network based on experimental data set is certain to generate much excitement in the scientific community. This information is also important for life science and medical researchers who are trying to uncover the processes by which cells undergo conversion or become cancerous, and for those attempting to determine how to control the growth and differentiation of stem cells and ensure their safety for use in regenerative medicine. Dr. Harukazu Suzuki, the scientific coordinator of the consortium, had this to say, “We are proud that we have created groundbreaking research in understanding more about how genes regulate cells at the molecular level and we want to acknowledge all consortium members for their great contribution to the research effort.”
The FANTOM consortium has also expanded earlier discoveries of transcriptional complexity by exploring repetitive elements found throughout mammalian genomes with DeepCAGE. These elements, which constitute up to half of the genome, have been generally considered to be junk or parasitic DNA. However, the team has found that the repetitive elements are broadly expressed and 6 to 30% of mouse and human mRNAs are derived from repetitive element promoters. These RNAs are often tissue-specific and dynamically controlled, and control the output of the genome through a variety of mechanisms. The FANTOM4 collaborators have also identified yet another type of short RNA, referred to as tiRNA (transcription initiation RNA) or tiny RNAs, in the human, chicken, and Drosphilia. They are about 18 nucleotides (nt) in length and are found within -60 to +120 nt of transcription start sites and may actually be widespread in metazoans (animals). A BioMed Central Thematic Series features even more FANTOM 4 research papers in Genome Biology and several BMC journals.
Contact:
RIKEN Omics Science Center
Director: Yoshihide Hayashizaki
Project director: Harukazu Suzuki
TEL: +81-45-503-2222 FAX: +81-45-503-9216
Showing posts with label GENETICS. Show all posts
Showing posts with label GENETICS. Show all posts
Monday, April 20, 2009
Monday, September 29, 2008
Risk factor for narcolepsy
A genetic variant that predisposes to narcolepsy has been identified, according to a study. Narcolepsy is characterized by excessive daytime sleepiness, impaired vision, and muscle weakness that may lead to collapse. It occurs in approximately 1 in 2,500 individuals in the United States and Europe, but is at least 4 times more frequent in Japanese.
Katsushi Tokunaga and colleagues carried out a genome-wide association of Japanese individuals, and found one variant to be significantly associated with risk of narcolepsy. They also found support for the association in Koreans, but not in individuals of European or African descent, probably because the frequency of the risk variant is much lower in the latter two populations.
The risk variant is located between the genes CPT1B and CHKB, each of which is a reasonable candidate to have a role in the disorder. The gene CPT1B encodes an enzyme involved in fatty acid oxidation, which has been implicated in sleep regulation. CHKB encodes an enzyme that catalyzes the production of one of the major components of cellular membranes, which is a precursor to a molecule that has been linked to the sleep-wake cycle.
Author contact:
Katsushi Tokunaga (University of Tokyo, Japan)
Tel: +81 3 5841 3692; E-mail: tokunaga@m.u-tokyo.ac.jp
A genetic variant that predisposes to narcolepsy has been identified, according to a study. Narcolepsy is characterized by excessive daytime sleepiness, impaired vision, and muscle weakness that may lead to collapse. It occurs in approximately 1 in 2,500 individuals in the United States and Europe, but is at least 4 times more frequent in Japanese.
Katsushi Tokunaga and colleagues carried out a genome-wide association of Japanese individuals, and found one variant to be significantly associated with risk of narcolepsy. They also found support for the association in Koreans, but not in individuals of European or African descent, probably because the frequency of the risk variant is much lower in the latter two populations.
The risk variant is located between the genes CPT1B and CHKB, each of which is a reasonable candidate to have a role in the disorder. The gene CPT1B encodes an enzyme involved in fatty acid oxidation, which has been implicated in sleep regulation. CHKB encodes an enzyme that catalyzes the production of one of the major components of cellular membranes, which is a precursor to a molecule that has been linked to the sleep-wake cycle.
Author contact:
Katsushi Tokunaga (University of Tokyo, Japan)
Tel: +81 3 5841 3692; E-mail: tokunaga@m.u-tokyo.ac.jp
Monday, May 12, 2008
Modeling psychiatric disorders in mice
One of the molecular causes of the behavioral and cognitive deficits observed in mice with a small chromosomal deletion has been identified, according to a study published online this week in Nature Genetics. The corresponding deletion in the human genome gives rise to a range of psychiatric disorders, and accounts for approximately 1–2% of cases of schizophrenia in the general population.
Deletion of a small region on chromosome 22 is associated with anxiety, depression, attention-deficit hyperactivity disorder, autism, and deficits in working memory. Approximately 30% of the individuals carrying such a deletion eventually develop schizophrenia.
Maria Karayiorgou, Joseph Gogos and colleagues generated a model in which the corresponding region was deleted in the mouse genome. Mice carrying a single deletion show a range of behavioral and cognitive deficits that mimic some aspects of the human syndrome. Of particular interest is the increased expression of precursors of the small regulatory RNAs known as microRNAs in the brains of the mutant mice. The authors went on to show that loss of one of genes in the deleted region, Dgcr8, is responsible for this increased abundance of precursors, as the normal role of Dgcr8 is to process them into mature microRNAs. By generating mice that have only one copy of Dgcr8, the authors showed that this mutation by itself results in at least some of the deficits observed in mice with the deletion of the surrounding region.
Although the specific downstream targets of altered microRNA expression in the brain are not yet known, the authors suggest these findings could have general implications for understanding the genetic basis of psychiatric disorders.
Author contacts:
Maria Karayiorgou (Columbia University Medical Center, New York, NY, USA)
Tel: +1 212 568 4189; E-mail: mk2758@columbia.edu
Joseph Gogos (Columbia University Medical Center, New York, NY, USA)
Tel: +1 212 305 0744; E-mail: jag90@columbia.edu
One of the molecular causes of the behavioral and cognitive deficits observed in mice with a small chromosomal deletion has been identified, according to a study published online this week in Nature Genetics. The corresponding deletion in the human genome gives rise to a range of psychiatric disorders, and accounts for approximately 1–2% of cases of schizophrenia in the general population.
Deletion of a small region on chromosome 22 is associated with anxiety, depression, attention-deficit hyperactivity disorder, autism, and deficits in working memory. Approximately 30% of the individuals carrying such a deletion eventually develop schizophrenia.
Maria Karayiorgou, Joseph Gogos and colleagues generated a model in which the corresponding region was deleted in the mouse genome. Mice carrying a single deletion show a range of behavioral and cognitive deficits that mimic some aspects of the human syndrome. Of particular interest is the increased expression of precursors of the small regulatory RNAs known as microRNAs in the brains of the mutant mice. The authors went on to show that loss of one of genes in the deleted region, Dgcr8, is responsible for this increased abundance of precursors, as the normal role of Dgcr8 is to process them into mature microRNAs. By generating mice that have only one copy of Dgcr8, the authors showed that this mutation by itself results in at least some of the deficits observed in mice with the deletion of the surrounding region.
Although the specific downstream targets of altered microRNA expression in the brain are not yet known, the authors suggest these findings could have general implications for understanding the genetic basis of psychiatric disorders.
Author contacts:
Maria Karayiorgou (Columbia University Medical Center, New York, NY, USA)
Tel: +1 212 568 4189; E-mail: mk2758@columbia.edu
Joseph Gogos (Columbia University Medical Center, New York, NY, USA)
Tel: +1 212 305 0744; E-mail: jag90@columbia.edu
The origins of the modern tomato
Scientists have identified a genetic mutation that acts as a major contributor to the extreme fruit size associated with the modern tomato, according to a study.
Modern cultivated tomatoes produce fruit as much as 1,000 times larger than their wild progenitors. One clear reason for the increase in tomato size during its domestication is the increased number of carpels – organs – which determines the final number of compartments in the fruit.
Steven Tanksley and colleagues crossed lines of tomatoes with either high or low compartment number, and carried out genetic mapping studies to identify the gene or genes responsible for the variation in carpel number. They identified an insertion of 6–8 kilobases in a gene they call fas only in the tomatoes with high compartment number. Expression of the gene is reduced in the developing flower buds in tomatoes carrying the insertion. A survey of 30 different lines of cerasiforme, the wild form of tomato thought to be related to the smaller progenitors, showed that none carried the insertion.
As the insertion is found exclusively in modern cultivated tomatoes, the authors suggest that the mutation occurred recently in tomato domestication, and then spread rapidly as a result of selection for larger fruit.
Author contact:
Steven Tanksley (Cornell University, Ithaca, NY, USA)
Tel: +1 607 255 1673; E-mail: sdt4@cornell.edu
Scientists have identified a genetic mutation that acts as a major contributor to the extreme fruit size associated with the modern tomato, according to a study.
Modern cultivated tomatoes produce fruit as much as 1,000 times larger than their wild progenitors. One clear reason for the increase in tomato size during its domestication is the increased number of carpels – organs – which determines the final number of compartments in the fruit.
Steven Tanksley and colleagues crossed lines of tomatoes with either high or low compartment number, and carried out genetic mapping studies to identify the gene or genes responsible for the variation in carpel number. They identified an insertion of 6–8 kilobases in a gene they call fas only in the tomatoes with high compartment number. Expression of the gene is reduced in the developing flower buds in tomatoes carrying the insertion. A survey of 30 different lines of cerasiforme, the wild form of tomato thought to be related to the smaller progenitors, showed that none carried the insertion.
As the insertion is found exclusively in modern cultivated tomatoes, the authors suggest that the mutation occurred recently in tomato domestication, and then spread rapidly as a result of selection for larger fruit.
Author contact:
Steven Tanksley (Cornell University, Ithaca, NY, USA)
Tel: +1 607 255 1673; E-mail: sdt4@cornell.edu
Monday, May 05, 2008
Developmental genetics: Starting out on the road to maleness
Growing up male is a genetic lifestyle decision — early in embryonic development, genes on the Y chromosome activate the development of specialized cells that ultimately become the testes. Without this ‘on switch’ for maleness, the developing gonads become ovaries by default and the embryo develops as a female.A study of mice now shows how the developing gonads start out on this road to maleness. In a paper geneticists Robin Lovell-Badge and Ryohei Sekido describe how a gene called Sry, carried on the Y chromosome, boosts another gene elsewhere in the genome that in turn governs the development of sperm-producing cells called Sertoli cells — a crucial component of the testes.By studying gene expression patterns in developing mouse embryos, the researchers deduced that Sry produces a protein that combines with another protein, steroidogenic factor 1 (SF1). This complex then binds to a DNA region that boosts the expression of another gene, Sox9, which controls a host of genes involved in sperm development.Elucidating this pathway not only reveals how maleness develops from the ‘default’ female developmental pathway; defects in this process may also explain how people who are genetically ‘male’ or ‘female’ end up developing the ‘wrong’ sexual anatomy.
contact:
Robin Lovell-Badge (National Institute for Medical Research, London, UK)Tel: +44 20 8816 2126;
Genetic susceptibility to obesity
Scientists have discovered genetic variants that increase the risk of obesity and insulin resistance in the general population, according to two studies published online this week in Nature Genetics. Until now only one locus (FTO) has been associated convincingly with increased risk of obesity.A consortium of investigators led by Mark McCarthy, Ines Barroso and Nicholas Wareham analyzed the genomes of more than 90,000 individuals and found that a variant near MC4R, encoding the melanocortin-4 receptor, increases susceptibility to obesity. Previous studies had shown that the melanocortin-4 receptor is expressed in neurons in the hypothalamus and is a key regulator of food intake and energy expenditure. Although it is unclear how this variant affects MC4R expression or function, the fact that mutations in the gene are known to cause rare cases of severe childhood obesity lends confidence to the association.In a separate study, Jaspal Kooner and colleagues carried out a genome-wide scan of several thousand individuals of Indian Asian or European ancestry, and identified a variant near MC4R as increasing risk of obesity and insulin resistance. The risk variant was more frequent in individuals of Indian Asian ancestry, which the authors suggest may account for the increased burden of obesity in Indian Asians.Author contacts:Mark McCarthy (University of Oxford, UK) Author paper [7]Tel: +44 1865 857 298; E-mail: mark.mccarthy@drl.ox.ac.ukInês Barroso (Wellcome Trust Sanger Institute, Hinxton, UK) Co-author paper [7]Tel: +44 1223 495 341; E-mail: ib1@sanger.ac.ukNicholas Wareham (Addenbrooke’s Hospital, Cambridge, UK) Co-author paper [7]Tel: +44 1223 330 315; E-mail: nick.wareham@mrc-epid.cam.ac.ukJaspal Kooner (Imperial College London, UK) Author paper [8]Tel: +44 20 8383 4751; E-mail: j.kooner@imperial.ac.uk
Growing up male is a genetic lifestyle decision — early in embryonic development, genes on the Y chromosome activate the development of specialized cells that ultimately become the testes. Without this ‘on switch’ for maleness, the developing gonads become ovaries by default and the embryo develops as a female.A study of mice now shows how the developing gonads start out on this road to maleness. In a paper geneticists Robin Lovell-Badge and Ryohei Sekido describe how a gene called Sry, carried on the Y chromosome, boosts another gene elsewhere in the genome that in turn governs the development of sperm-producing cells called Sertoli cells — a crucial component of the testes.By studying gene expression patterns in developing mouse embryos, the researchers deduced that Sry produces a protein that combines with another protein, steroidogenic factor 1 (SF1). This complex then binds to a DNA region that boosts the expression of another gene, Sox9, which controls a host of genes involved in sperm development.Elucidating this pathway not only reveals how maleness develops from the ‘default’ female developmental pathway; defects in this process may also explain how people who are genetically ‘male’ or ‘female’ end up developing the ‘wrong’ sexual anatomy.
contact:
Robin Lovell-Badge (National Institute for Medical Research, London, UK)Tel: +44 20 8816 2126;
Genetic susceptibility to obesity
Scientists have discovered genetic variants that increase the risk of obesity and insulin resistance in the general population, according to two studies published online this week in Nature Genetics. Until now only one locus (FTO) has been associated convincingly with increased risk of obesity.A consortium of investigators led by Mark McCarthy, Ines Barroso and Nicholas Wareham analyzed the genomes of more than 90,000 individuals and found that a variant near MC4R, encoding the melanocortin-4 receptor, increases susceptibility to obesity. Previous studies had shown that the melanocortin-4 receptor is expressed in neurons in the hypothalamus and is a key regulator of food intake and energy expenditure. Although it is unclear how this variant affects MC4R expression or function, the fact that mutations in the gene are known to cause rare cases of severe childhood obesity lends confidence to the association.In a separate study, Jaspal Kooner and colleagues carried out a genome-wide scan of several thousand individuals of Indian Asian or European ancestry, and identified a variant near MC4R as increasing risk of obesity and insulin resistance. The risk variant was more frequent in individuals of Indian Asian ancestry, which the authors suggest may account for the increased burden of obesity in Indian Asians.Author contacts:Mark McCarthy (University of Oxford, UK) Author paper [7]Tel: +44 1865 857 298; E-mail: mark.mccarthy@drl.ox.ac.ukInês Barroso (Wellcome Trust Sanger Institute, Hinxton, UK) Co-author paper [7]Tel: +44 1223 495 341; E-mail: ib1@sanger.ac.ukNicholas Wareham (Addenbrooke’s Hospital, Cambridge, UK) Co-author paper [7]Tel: +44 1223 330 315; E-mail: nick.wareham@mrc-epid.cam.ac.ukJaspal Kooner (Imperial College London, UK) Author paper [8]Tel: +44 20 8383 4751; E-mail: j.kooner@imperial.ac.uk
Monday, April 07, 2008
Common genetic variants influencing adult height
Scientists have discovered dozens of common genetic variants influencing adult human height.
Recently, two independent studies reported that common variants near two genes, HMGA2 and GDF5, are associated with variation in human height in the general population. Using substantially larger sample sizes, three groups now report the discovery of dozens of additional variants influencing adult height.
The newly discovered variants explain up to 4% of normal height variation in populations of European ancestry. Individuals carrying predominantly ‘tall’ versions of these variants are, on average, 5 cm taller than individuals carrying only a few of the ‘tall’ variants.
Many of the height-associated variants reside near genes known or suspected to have a role in skeletal development. Others reside near genes that control how cells grow and divide.
Height is considered a classic complex trait with a strong heritable component. Therefore, understanding the genetic basis of this model trait may shed light on the genetic architecture of other traits, including those influencing risk of common diseases.
Author contacts:
Timothy Frayling (Peninsula Medical School, Exeter, UK)
Tel: +44 1392 262935; E-mail: tim.frayling@pms.ac.uk
Kari Stefansson (deCODE Genetics, Reykjavik, Iceland)
Tel: +354 570 1900; E-mail: kstefans@decode.is
Joel Hirschhorn (Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Tel: +1 617 919 2129; E-mail: joelh@broad.mit.edu
Scientists have discovered dozens of common genetic variants influencing adult human height.
Recently, two independent studies reported that common variants near two genes, HMGA2 and GDF5, are associated with variation in human height in the general population. Using substantially larger sample sizes, three groups now report the discovery of dozens of additional variants influencing adult height.
The newly discovered variants explain up to 4% of normal height variation in populations of European ancestry. Individuals carrying predominantly ‘tall’ versions of these variants are, on average, 5 cm taller than individuals carrying only a few of the ‘tall’ variants.
Many of the height-associated variants reside near genes known or suspected to have a role in skeletal development. Others reside near genes that control how cells grow and divide.
Height is considered a classic complex trait with a strong heritable component. Therefore, understanding the genetic basis of this model trait may shed light on the genetic architecture of other traits, including those influencing risk of common diseases.
Author contacts:
Timothy Frayling (Peninsula Medical School, Exeter, UK)
Tel: +44 1392 262935; E-mail: tim.frayling@pms.ac.uk
Kari Stefansson (deCODE Genetics, Reykjavik, Iceland)
Tel: +354 570 1900; E-mail: kstefans@decode.is
Joel Hirschhorn (Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Tel: +1 617 919 2129; E-mail: joelh@broad.mit.edu
Wednesday, November 07, 2007
Dependence on Illicit and Licit DrugsGenes Play Role in Risk for
Description
The genes that play a role in illegal drug abuse are not entirely the same as those involved in dependence on legal substances like alcohol and nicotine, and caffeine addiction appears to be genetically independent of all the others, according to a study led by Virginia Commonwealth University researchers.
Research Highlights:
• Genes that play a role in illegal drug abuse are not entirely the same as those involved in dependence on legal substances like alcohol and nicotine
• Caffeine addiction appears to be genetically independent of the others
• Findings could guide efforts to localize genes that influence risk for psychoactive drug abuse or dependence
• First study to examine across the sexes and the degree to which risk factors for dependence are shared between illicit and licit drugs
The genes that play a role in illegal drug abuse are not entirely the same as those involved in dependence on legal substances like alcohol and nicotine, and caffeine addiction appears to be genetically independent of all the others, according to a study led by Virginia Commonwealth University researchers.
The findings may guide efforts by researchers to use molecular genetic tools to localize genes that influence risk for psychoactive drug abuse or dependence, or A/D.
In the November issue of the Archives of General Psychiatry, a journal of the American Medical Association, researchers examined the degree to which genetic and environmental risk factors for dependence were shared between illicit and the more commonly used licit psychoactive drugs among men and women.
“We wanted to know whether there was a single set of genes that influence risk for A/D on all substances,” said Kenneth S. Kendler, M.D., a professor of psychiatry and human genetics in VCU’s School of Medicine and lead author on the study.
“Our findings suggested two genetic factors - one which strongly impacted on risk for A/D of illicit drugs, such as cannabis and cocaine, and one that impacted on risk for A/D of licit drugs, including caffeine, nicotine and alcohol. However, these two factors were rather strongly correlated,” he said. “It was also of interest to note that the genes for caffeine A/D were pretty independent of those found for all the other substances.”
Kendler and his colleagues examined lifetime symptoms of abuse of and dependence on marijuana, cocaine, alcohol, caffeine and nicotine among 4,865 male-male and female-female twin pairs through a series of personal interviews. The data collected from the interviews was analyzed using the methods of structural equation modeling.
The twin pairs that participated were from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. These twin pairs were ascertained from the Virginia Twin Registry. The Virginia Twin Registry, now part of the VCU Mid-Atlantic Twin Registry, contains a population-based record of twins from Virginia, North Carolina and South Carolina.
“This study also confirmed the strong role that genetic factors play in influencing our vulnerability to drug abuse and dependence,” Kendler said. Heritability – the proportion of individual differences in risk due to genetic differences – was estimated in this study to be more than 70 percent for cocaine, cannabis and nicotine A/D, nearly 60 percent for alcohol A/D, and, interestingly, quite a bit lower – around 35 percent – for caffeine A/D, he said.
In previous studies, researchers examined an array of illegal substances and did not include commonly used licit drugs, and included only male participates. This was the first study of its kind to examine across the sexes and degree to which risk factors for dependence were shared between illicit and licit drugs.
This work was supported by grants from the National Institutes of Health.
Kendler collaborated with John Meyer, M.S., from the Department of Psychiatry at VCU; and Carol A. Prescott, Ph.D., from the Department of Psychology, University of Southern California.
About VCU and the VCU Medical Center: Virginia Commonwealth University is the largest university in Virginia and ranks among the top 100 universities in the country in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 30,000 students in nearly 200 certificate and degree programs in the arts, sciences and humanities. Sixty-three of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 15 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see http://www.vcu.edu. (Newswise)
Description
The genes that play a role in illegal drug abuse are not entirely the same as those involved in dependence on legal substances like alcohol and nicotine, and caffeine addiction appears to be genetically independent of all the others, according to a study led by Virginia Commonwealth University researchers.
Research Highlights:
• Genes that play a role in illegal drug abuse are not entirely the same as those involved in dependence on legal substances like alcohol and nicotine
• Caffeine addiction appears to be genetically independent of the others
• Findings could guide efforts to localize genes that influence risk for psychoactive drug abuse or dependence
• First study to examine across the sexes and the degree to which risk factors for dependence are shared between illicit and licit drugs
The genes that play a role in illegal drug abuse are not entirely the same as those involved in dependence on legal substances like alcohol and nicotine, and caffeine addiction appears to be genetically independent of all the others, according to a study led by Virginia Commonwealth University researchers.
The findings may guide efforts by researchers to use molecular genetic tools to localize genes that influence risk for psychoactive drug abuse or dependence, or A/D.
In the November issue of the Archives of General Psychiatry, a journal of the American Medical Association, researchers examined the degree to which genetic and environmental risk factors for dependence were shared between illicit and the more commonly used licit psychoactive drugs among men and women.
“We wanted to know whether there was a single set of genes that influence risk for A/D on all substances,” said Kenneth S. Kendler, M.D., a professor of psychiatry and human genetics in VCU’s School of Medicine and lead author on the study.
“Our findings suggested two genetic factors - one which strongly impacted on risk for A/D of illicit drugs, such as cannabis and cocaine, and one that impacted on risk for A/D of licit drugs, including caffeine, nicotine and alcohol. However, these two factors were rather strongly correlated,” he said. “It was also of interest to note that the genes for caffeine A/D were pretty independent of those found for all the other substances.”
Kendler and his colleagues examined lifetime symptoms of abuse of and dependence on marijuana, cocaine, alcohol, caffeine and nicotine among 4,865 male-male and female-female twin pairs through a series of personal interviews. The data collected from the interviews was analyzed using the methods of structural equation modeling.
The twin pairs that participated were from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. These twin pairs were ascertained from the Virginia Twin Registry. The Virginia Twin Registry, now part of the VCU Mid-Atlantic Twin Registry, contains a population-based record of twins from Virginia, North Carolina and South Carolina.
“This study also confirmed the strong role that genetic factors play in influencing our vulnerability to drug abuse and dependence,” Kendler said. Heritability – the proportion of individual differences in risk due to genetic differences – was estimated in this study to be more than 70 percent for cocaine, cannabis and nicotine A/D, nearly 60 percent for alcohol A/D, and, interestingly, quite a bit lower – around 35 percent – for caffeine A/D, he said.
In previous studies, researchers examined an array of illegal substances and did not include commonly used licit drugs, and included only male participates. This was the first study of its kind to examine across the sexes and degree to which risk factors for dependence were shared between illicit and licit drugs.
This work was supported by grants from the National Institutes of Health.
Kendler collaborated with John Meyer, M.S., from the Department of Psychiatry at VCU; and Carol A. Prescott, Ph.D., from the Department of Psychology, University of Southern California.
About VCU and the VCU Medical Center: Virginia Commonwealth University is the largest university in Virginia and ranks among the top 100 universities in the country in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 30,000 students in nearly 200 certificate and degree programs in the arts, sciences and humanities. Sixty-three of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 15 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see http://www.vcu.edu. (Newswise)
Monday, October 01, 2007
The gene-mapper’s best friend
Genetic variants associated with dominant or recessive disease-related traits in dogs can be mapped efficiently and with high confidence. As dogs and humans have a similar complement of genes, the mapping of disease-associated variants in dogs may make an important contribution to the study of human genetic disease.
There are more than 400 genetically distinct dog breeds. As each breed originated in a small number of founder dogs, there is a limited amount of genetic diversity within each breed. This sort of genome structure is ideal for the rough mapping of genes because it allows one to analyze most of the genome with a limited number of genetic markers. Kerstin Lindblad-Toh and colleagues found small regions of the genome to be associated with two traits by assessing a relatively small number of single-nucleotide polymorphisms (27,000) in only 20 dogs.
The authors identified a genomic region containing only one gene—MITF—as responsible for the absence of skin and coat pigmentation in white boxers, which also predisposes them to deafness. They also identified a region associated with the dorsal hair ridge in Ridgeback dogs, which are prone to dermoid sinus, a neural tube defect. In the accompanying paper, Leif Andersson and colleagues carried out fine mapping of the region associated with the Ridgeback hair ridge, and showed that the causative mutation is a duplication containing four different genes—FGF3, FGF4, FGF19 and ORAOV1.
Author contacts:
Kerstin Lindblad-Toh (Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Tel: +1 617 252 1477; E-mail: kersli@broad.mit.edu
Genetic variants associated with dominant or recessive disease-related traits in dogs can be mapped efficiently and with high confidence. As dogs and humans have a similar complement of genes, the mapping of disease-associated variants in dogs may make an important contribution to the study of human genetic disease.
There are more than 400 genetically distinct dog breeds. As each breed originated in a small number of founder dogs, there is a limited amount of genetic diversity within each breed. This sort of genome structure is ideal for the rough mapping of genes because it allows one to analyze most of the genome with a limited number of genetic markers. Kerstin Lindblad-Toh and colleagues found small regions of the genome to be associated with two traits by assessing a relatively small number of single-nucleotide polymorphisms (27,000) in only 20 dogs.
The authors identified a genomic region containing only one gene—MITF—as responsible for the absence of skin and coat pigmentation in white boxers, which also predisposes them to deafness. They also identified a region associated with the dorsal hair ridge in Ridgeback dogs, which are prone to dermoid sinus, a neural tube defect. In the accompanying paper, Leif Andersson and colleagues carried out fine mapping of the region associated with the Ridgeback hair ridge, and showed that the causative mutation is a duplication containing four different genes—FGF3, FGF4, FGF19 and ORAOV1.
Author contacts:
Kerstin Lindblad-Toh (Broad Institute of Harvard and MIT, Cambridge, MA, USA)
Tel: +1 617 252 1477; E-mail: kersli@broad.mit.edu
Monday, September 10, 2007
Diet shapes the human genome
Human populations that have high starch diets have an increase in the number of copies of a gene whose product breaks down starch. Although copy number variation has attracted a lot of recent attention, this is one of the first documented examples of positive selection on gene copy number in humans.
Starch has become a prominent component of the human diet. It is metabolized in part by salivary amylase, and the gene encoding it, AMY1, shows extensive variation in copy number. George Perry and colleagues estimated AMY1 copy number in 50 European Americans and showed that the levels of salivary amylase protein are positively correlated with gene copy number. They went on to show that individuals from three populations with high-starch diets tend to have more copies of AMY1 than individuals from populations with low-starch diets. Finally, the authors compared the extent of variation across the genome between two Asian populations – Japanese (high-starch diet) and Yakut pastoralists (low-starch diet) – and found that variation at AMY1 exceeds that of more than 97% of the other sites in the genome that were assessed.
The authors conclude from this that natural selection favored increased AMY1 copy number in at least some populations with high-starch diets. Interestingly, humans have significantly more copies of AMY1 than chimpanzees, which ingest relatively little starch. Increased AMY1 expression would probably improve the digestion of starchy foods, and possibly maintain energy absorption in the face of intestinal disease.
Author contact:
Nathaniel Dominy (University of California, Santa Cruz, CA, USA)
Tel: +1 831 459 2541; E-mail: njdominy@ucsc.edu
Muscle metabolism and human evolution
A variant of a gene associated with elite athletic performance has been subject to strong, recent positive selection in humans. Experiments on mice suggest that this variant may promote more efficient muscle metabolism.
The gene ACTN3, encoding alpha-actinin-3, is specifically expressed in the fast-twitch muscle fibers that are responsible for generating force at high velocity. ACTN3 exists in a non-functional truncated form in more than a billion people worldwide, and is overrepresented in endurance athletes. By contrast, the functional form is overrepresented in elite sprinters. Kathryn North and colleagues examined the extent of genetic variation in the vicinity of ACTN3 in individuals with the truncated version. They found very little variation, which is consistent with the truncated version of the gene being under positive selection.
To understand better the effect of the truncation on muscle function, the authors generated a line of mice lacking ACTN3, and found that there is a shift in muscle metabolism toward the more efficient aerobic pathway. These mice were also able to run on average 33% further before reaching exhaustion than mice with normal ACTN3 function. The authors conclude that this increased metabolic efficiency could explain the overrepresentation of the truncated form of ACTN3 in endurance athletes.
Author contact:
Kathryn North (Children’s Hospital at Westmead, Sydney, Australia)
Tel: +61 2 9845 3011; E-mail: kathryn@chw.edu.au
Human populations that have high starch diets have an increase in the number of copies of a gene whose product breaks down starch. Although copy number variation has attracted a lot of recent attention, this is one of the first documented examples of positive selection on gene copy number in humans.
Starch has become a prominent component of the human diet. It is metabolized in part by salivary amylase, and the gene encoding it, AMY1, shows extensive variation in copy number. George Perry and colleagues estimated AMY1 copy number in 50 European Americans and showed that the levels of salivary amylase protein are positively correlated with gene copy number. They went on to show that individuals from three populations with high-starch diets tend to have more copies of AMY1 than individuals from populations with low-starch diets. Finally, the authors compared the extent of variation across the genome between two Asian populations – Japanese (high-starch diet) and Yakut pastoralists (low-starch diet) – and found that variation at AMY1 exceeds that of more than 97% of the other sites in the genome that were assessed.
The authors conclude from this that natural selection favored increased AMY1 copy number in at least some populations with high-starch diets. Interestingly, humans have significantly more copies of AMY1 than chimpanzees, which ingest relatively little starch. Increased AMY1 expression would probably improve the digestion of starchy foods, and possibly maintain energy absorption in the face of intestinal disease.
Author contact:
Nathaniel Dominy (University of California, Santa Cruz, CA, USA)
Tel: +1 831 459 2541; E-mail: njdominy@ucsc.edu
Muscle metabolism and human evolution
A variant of a gene associated with elite athletic performance has been subject to strong, recent positive selection in humans. Experiments on mice suggest that this variant may promote more efficient muscle metabolism.
The gene ACTN3, encoding alpha-actinin-3, is specifically expressed in the fast-twitch muscle fibers that are responsible for generating force at high velocity. ACTN3 exists in a non-functional truncated form in more than a billion people worldwide, and is overrepresented in endurance athletes. By contrast, the functional form is overrepresented in elite sprinters. Kathryn North and colleagues examined the extent of genetic variation in the vicinity of ACTN3 in individuals with the truncated version. They found very little variation, which is consistent with the truncated version of the gene being under positive selection.
To understand better the effect of the truncation on muscle function, the authors generated a line of mice lacking ACTN3, and found that there is a shift in muscle metabolism toward the more efficient aerobic pathway. These mice were also able to run on average 33% further before reaching exhaustion than mice with normal ACTN3 function. The authors conclude that this increased metabolic efficiency could explain the overrepresentation of the truncated form of ACTN3 in endurance athletes.
Author contact:
Kathryn North (Children’s Hospital at Westmead, Sydney, Australia)
Tel: +61 2 9845 3011; E-mail: kathryn@chw.edu.au
Subscribe to:
Posts (Atom)
