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Human Y chromosome mapped, but not fully sequenced
SCIENCE AND MEDICINE
Tying the genetic sequence to human disease f the 35 000 genes sequenced by the human genome project, just 923 are “disease genes” according to David Valle (Johns Hopkins University School of Medicine, Baltimore, MA, USA) in his analysis paper (Nature 2001; 409: 853–55). Most of these are responsible for rare single-gene disorders, and as Jaakko Kaprio (University of Helsinki, Finland) points out, “the complexity of even single-gene disorders such as cystic fibrosis suggests that the path from structural knowledge to practical applications will be much longer than many would like to believe”. Although some of the genes responsible for monogenic traits are well characterised, our knowledge of genes that contribute to common complex traits such as cardiovascular disease is still preliminary. “The availability of the complete and ordered genome sequence, combined with simultaneous analysis of large numbers of genes
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using DNA array technology, will greatly facilitate mapping and identification of candidate disease genes for polygenic disorders such as hypertension and atherosclerosis”, says Kelly Amber (Denver Health Medical Center, Denver, CO, USA). Kaprio agrees but stresses that the sequence itself will not make the genetic component in such diseases any larger: “The same environmental factors that affected them last year are still there.” Applying sequence information to medicine may be achieved primarily by studying single nucleotide polymorphisms (SNPs), rather than the sequence of entire genes. Other developments will also be needed to fully understand the significance of genome sequencing. “One area is bioinformatics—we need advances in computer technology to help us organise and connect the vast amounts of data that are generated by genome sequencing and related studies”, says Amber.
A second focus will be to determine the physical structures of new gene products, devising novel computational methods to predict the three dimensional structure of a protein from its primary sequence, and to develop structural models for interacting protein assemblies. “Ultimately, the linear information in the human genome will need to be translated into a three dimensional picture of the functional architecture of the cell”, says Amber’s colleague, Dale Brown. And Kaprio warns that even new information about genetic variation and the function of proteins in the cell will need to be followed up by epidemiological studies. “In different environments, the same genetic differences may have very different results in the organism’s makeup—genes and gene defects do not map one-on-one with phenotype and disease”, he says. Kathryn Senior
Human Y chromosome mapped, but not fully sequenced he human Y chromosome has proved difficult to sequence, but this week David Page (Massachusetts Institute of Technology, Cambridge, MA, USA) and colleagues describe the first complete map of the non-combining region of the Y chromosome (NRY). “This paper represents an extraordinary achievement in characterising the physical structure of perhaps the most intractable of all human chromosomes”, says Mark Jobling (University of Leicester, UK). Analysing the NRY has been difficult because it does not undergo recombination during meiosis, making linkage analysis impossible. “It also has a high content of repeated sequence; and much of it shows high homology to the X chromosome, making it difficult to be sure that Y-derived clones are being analysed”, explains Jobling. The clinical implications of this
work are considerable. For example, deletions have severe defects of sperthe isolation of genes that contribute matogenesis.” However, Jobling to the development of Turner’s synwarns that “the Y chromosome drome should clarify the timing of shows a high degree of polymorkey developmental processes and phism in human populations; other should also help deterYs in the population, mine why some girls which we may be Rights were not with Turner’s syninterested in because drome develop of male infertility, for granted to include gonadoblastoma, a example, may have this image in benign tumour with very different strucelectronic media. significant malignant tures to the reference Please refer to the potential, predicts s e q u e n c e . ” printed journal. Claus Gravholt, McElreavey agrees but (Aarhus University is convinced that Hospital, Denmark). knowledge of the Y Ken McElreavey sequence will eventu(Institute Pasteur, ally help to understand France) points out Map reading for males spermatogenesis. that the identification “Since sperm counts of human fertility genes is also a are reported to be declining in some vitally important goal. “We know European countries, this informathat genes on the long arm of the tion is urgently required”, he says. Y chromosome are involved in male Kathryn Senior fertility because men with these Science Photo Library
T
1915 A father and son, William and Laurence Bragg, share the Nobel prize for physics, for their work on the X-ray diffraction of crystals. Cambridge’s community of theoreticians is shaken by the appointment of William Bragg to the chair in physics but it is to be in that university that the structure of DNA is solved. According to Perutz, it was Bragg who prevented Bernal (a communist) from being thrown out of the Cavendish Laboratory by Rutherford. If that had happened, “Watson and Crick would never have met”. In 1937 Astbury, who had already demonstrated the crystalline orderliness of proteins, such as silk fibroin and hair, shows that nucleic acids too have a crystal structure, but the structure itself is not revealed. Much later Astbury and Wilkins visited Chargaff (a chemist) in the United States, who gave them samples of DNA for crystallographic study. He questioned the quality of those samples but as so often on the road to the human genome it is the be the interactions of people from across very different disciplines that is so important.
532
THE LANCET • Vol 357 • February 17, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.
Tying the genetic sequence to human disease f the 35 000 genes sequenced by the human genome project, just 923 are “disease genes” according to David Valle (Johns Hopkins University School of Medicine, Baltimore, MA, USA) in his analysis paper (Nature 2001; 409: 853–55). Most of these are responsible for rare single-gene disorders, and as Jaakko Kaprio (University of Helsinki, Finland) points out, “the complexity of even single-gene disorders such as cystic fibrosis suggests that the path from structural knowledge to practical applications will be much longer than many would like to believe”. Although some of the genes responsible for monogenic traits are well characterised, our knowledge of genes that contribute to common complex traits such as cardiovascular disease is still preliminary. “The availability of the complete and ordered genome sequence, combined with simultaneous analysis of large numbers of genes
O
using DNA array technology, will greatly facilitate mapping and identification of candidate disease genes for polygenic disorders such as hypertension and atherosclerosis”, says Kelly Amber (Denver Health Medical Center, Denver, CO, USA). Kaprio agrees but stresses that the sequence itself will not make the genetic component in such diseases any larger: “The same environmental factors that affected them last year are still there.” Applying sequence information to medicine may be achieved primarily by studying single nucleotide polymorphisms (SNPs), rather than the sequence of entire genes. Other developments will also be needed to fully understand the significance of genome sequencing. “One area is bioinformatics—we need advances in computer technology to help us organise and connect the vast amounts of data that are generated by genome sequencing and related studies”, says Amber.
A second focus will be to determine the physical structures of new gene products, devising novel computational methods to predict the three dimensional structure of a protein from its primary sequence, and to develop structural models for interacting protein assemblies. “Ultimately, the linear information in the human genome will need to be translated into a three dimensional picture of the functional architecture of the cell”, says Amber’s colleague, Dale Brown. And Kaprio warns that even new information about genetic variation and the function of proteins in the cell will need to be followed up by epidemiological studies. “In different environments, the same genetic differences may have very different results in the organism’s makeup—genes and gene defects do not map one-on-one with phenotype and disease”, he says. Kathryn Senior
Human Y chromosome mapped, but not fully sequenced he human Y chromosome has proved difficult to sequence, but this week David Page (Massachusetts Institute of Technology, Cambridge, MA, USA) and colleagues describe the first complete map of the non-combining region of the Y chromosome (NRY). “This paper represents an extraordinary achievement in characterising the physical structure of perhaps the most intractable of all human chromosomes”, says Mark Jobling (University of Leicester, UK). Analysing the NRY has been difficult because it does not undergo recombination during meiosis, making linkage analysis impossible. “It also has a high content of repeated sequence; and much of it shows high homology to the X chromosome, making it difficult to be sure that Y-derived clones are being analysed”, explains Jobling. The clinical implications of this
work are considerable. For example, deletions have severe defects of sperthe isolation of genes that contribute matogenesis.” However, Jobling to the development of Turner’s synwarns that “the Y chromosome drome should clarify the timing of shows a high degree of polymorkey developmental processes and phism in human populations; other should also help deterYs in the population, mine why some girls which we may be Rights were not with Turner’s syninterested in because drome develop of male infertility, for granted to include gonadoblastoma, a example, may have this image in benign tumour with very different strucelectronic media. significant malignant tures to the reference Please refer to the potential, predicts s e q u e n c e . ” printed journal. Claus Gravholt, McElreavey agrees but (Aarhus University is convinced that Hospital, Denmark). knowledge of the Y Ken McElreavey sequence will eventu(Institute Pasteur, ally help to understand France) points out Map reading for males spermatogenesis. that the identification “Since sperm counts of human fertility genes is also a are reported to be declining in some vitally important goal. “We know European countries, this informathat genes on the long arm of the tion is urgently required”, he says. Y chromosome are involved in male Kathryn Senior fertility because men with these Science Photo Library
T
1915 A father and son, William and Laurence Bragg, share the Nobel prize for physics, for their work on the X-ray diffraction of crystals. Cambridge’s community of theoreticians is shaken by the appointment of William Bragg to the chair in physics but it is to be in that university that the structure of DNA is solved. According to Perutz, it was Bragg who prevented Bernal (a communist) from being thrown out of the Cavendish Laboratory by Rutherford. If that had happened, “Watson and Crick would never have met”. In 1937 Astbury, who had already demonstrated the crystalline orderliness of proteins, such as silk fibroin and hair, shows that nucleic acids too have a crystal structure, but the structure itself is not revealed. Much later Astbury and Wilkins visited Chargaff (a chemist) in the United States, who gave them samples of DNA for crystallographic study. He questioned the quality of those samples but as so often on the road to the human genome it is the be the interactions of people from across very different disciplines that is so important.
532
THE LANCET • Vol 357 • February 17, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.