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Basic Science Seminars in Neurology |

Sequence Analysis of the Human Genome:  Implications for the Understanding of Nervous System Function and Disease FREE

Anibal Cravchik, MD, PhD; G. Subramanian, MD, PhD; Samuel Broder, MD; J. Craig Venter, PhD
[+] Author Affiliations

From Celera Genomics, Rockville, Md.


Section Editor: Hassan M. Fathallah-shaykh, MD

More Author Information
Arch Neurol. 2001;58(11):1772-1778. doi:10.1001/archneur.58.11.1772.
Text Size: A A A
Published online

The recent publication of the sequence of the human genome will accelerate the discovery of new genetic susceptibility factors for human disease, leading to the development of novel diagnostics and therapeutics. The exhaustive analysis of the human genome sequence will be the focus of the biomedical research community for many years to come. In particular, comparative analysis of the available eukaryotic genome sequences is an important approach to further our understanding of gene structure, function, and evolution. Our initial analysis of the human genome sequence has revealed many interesting features that are relevant to nervous system function, evolution, and disease. We analyzed the prominent features of predicted human proteins involved in neuronal function and prepared a comparative analysis of 146 human genes that have alleles (or mutations) conferring susceptibility for 168 neurologic diseases.

Figures in this Article

The recent publication of the sequence of the human genome1,2 allows a comparative analysis of genes expressed in the nervous system and genes associated with neurologic disease. The nervous system in vertebrates exhibits a high degree of functional complexity, which is supported by a comparatively large number of genes expressed in the nervous tissue. Many human neurologic diseases resulting from genetic mutations have been described. The human genes that confer susceptibility to neurologic diseases belong to many different families and have a large diversity of functions. Human genes that confer disease risk are, of course, not "disease genes," as they are sometimes referred to, because their primary function is certainly not to cause disease. However, the observation that an alteration in a gene sequence results in a detectable disease suggests that the gene product plays a critical role for the survival of the whole organism. We call such gene sequence alterations disease-predisposing alleles.

The comparative analysis of the human genome with the fruit fly and nematode genomes3,4 is an important approach to further our understanding of gene function and evolution. Any such analysis must take into account that the human genome is estimated to contain 26 000 to 38 000 genes, the fruit fly genome contains about 14 000 genes, and the nematode has about 19 000 genes. The expansion of gene families in the human genome is not uniform, but instead reflects the important roles of developmental and cellular processes that are unique to vertebrates.

An initial comparative analysis of the human genome with the fruit fly and nematode genomes showed a marked expansion in the number of genes coding for proteins involved in neural development, function, and structure.1 This finding correlates with, but does not completely explain, the observation that the human nervous system has a much larger number of different neuronal cell types than the fruit fly and nematode nervous systems.5 Such diversity in neuronal morphology reflects the variety and complexity of gene expression and regulation in the different neuronal cell types of the vertebrate nervous system. Protein families involved in nervous system function and development that are prominently expanded in humans include myelin-related proteins, proteins involved in neuronal signaling (voltage-gated ion channels and connexins), and proteins involved in pathway finding by axons and neuronal network formation (cadherins, ephrins, semaphorins, neuropilins, and plexins) (Figure 1).1,6,7 Of equal interest is the expansion of proteins involved in apoptotic regulation8; the process of programmed cell death or apoptosis is likely to play an important role in neurodegenerative diseases.9 Also expanded in humans are neuronal cytoskeleton protein families such as actins and microtubule-associated proteins (MAPs) of the MAP2/tau family (Figure 1). Several of the proteins involved in neuronal communication are multidomain proteins (a protein domain is described as a region on a protein that shows structural, functional, and evolutionary conservation). The observation of "domain shuffling" (whereby new multidomain protein architectures are built by shuffling or adding different evolutionarily conserved protein domains) is a prominent finding in the multidomain proteins involved in neuronal function and structure.1,2 Therefore, in addition to an increase in the protein repertoire, a substantial increase in the number of protein interactions mediated by those domains is predicted in the human, as compared with the fruit fly and nematode. Selected examples of such novel vertebrate multidomain protein architectures are provided in Figure 2.

Place holder to copy figure label and caption
Figure 1.

Expansions in human protein families involved in neural function, structure, and development. Number of proteins in selected families in the human, fruit fly, and nematode are compared (data from Venter et al1).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Schematic representation of the architecture of neuronal specific proteins that are expanded in humans. Protein domains are represented by convention as different geometric shapes. Domain names are as follows: PDZ, domains found in diverse signaling proteins that may target signaling molecules to submembranous sites; SH3 (Src homology 3), domains often found in proteins involved in signal transduction related to cytoskeletal organization; GuKc, guanylate kinase homologues; IL, interleukin; BIR, baculoviral inhibition of apoptosis protein repeat; NACHT, family of adenosine triphosphatase; LRR, leucine-rich repeats; ANK, ankyrin repeats; and SAM, sterile α motif. Biological descriptions of protein domains and families are available through the Pfam10 (available at: http://www.sanger.ac.uk/Software/Pfam/index.shtml) and SMART11 (available at: http://smart.embl-heidelberg.de/) databases. NMDA indicates N-methyl-D-aspartate.

Graphic Jump Location

A very important evolutionary difference between vertebrate and invertebrate nervous systems is the appearance of myelinating glial cells, which provide axonal insulation and increase the speed of propagation of action potentials. The human genome has at least 10 genes involved in myelin production; only 1 gene related to myelin proteolipids was detected in the fruit fly and none was detected in the nematode. Mutations in genes involved in myelin production can result in severe demyelinating disorders such as Charcot-Marie-Tooth neuropathy types 1A and 1B and Dejerine-Sottas syndrome (Figure 3).

Place holder to copy figure label and caption
Figure 3a.

Comparative analysis of human genes implicated in neurologic diseases. A set of 168 human neurologic diseases resulting from specific alleles of 146 different human genes was selected from Online Mendelian Inheritance in Man (OMIM) for the comparative analysis. The proteins encoded by those genes were used as queries to search the nonredundant GenBank database for related proteins from Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (nematode). BlastP searches were conducted as described,12 and the results were color coded according to their level of statistical significance, reflecting the degree of confidence in their evolutionary and functional relationship. BlastP E-values less than 10−100, representing the highest degree of sequence conservation, are shown as dark-green bars. E-values between 10−100 and 10−40 are represented in blue-green color, indicating an intermediate level of conservation. E-values in the range of 10−40 10−6 are shown in light blue, indicating the lowest level of conservation. E-values greater than 10−6 are shown as white bars, indicating absence of gene conservation. The OMIM disease entry numbers (available at: http://www.ncbi.nlm.nih.gov/Omim/) and cytogenetic locations are listed. APP indicates amyloid precursor protein; SOD1, superoxide dismutase 1; PMP22, peripheral myelin protein 22; GM2, a ganglioside with the addition of N-acetylgalactosamine; FRAXE, fragile site in chromosome Xq28; NAGA, α-N-acetylgalactosaminidase; PTS, 6-pyruvoyltetrahydropterin synthase; RLBP1, retinaldehyde-binding protein 1; and HEXB, hexosaminidase B.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3b.

Comparative analysis of human genes implicated in neurologic diseases. A set of 168 human neurologic diseases resulting from specific alleles of 146 different human genes was selected from Online Mendelian Inheritance in Man (OMIM) for the comparative analysis. The proteins encoded by those genes were used as queries to search the nonredundant GenBank database for related proteins from Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (nematode). BlastP searches were conducted as described,12 and the results were color coded according to their level of statistical significance, reflecting the degree of confidence in their evolutionary and functional relationship. BlastP E-values less than 10−100, representing the highest degree of sequence conservation, are shown as dark-green bars. E-values between 10−100 and 10−40 are represented in blue-green color, indicating an intermediate level of conservation. E-values in the range of 10−40 10−6 are shown in light blue, indicating the lowest level of conservation. E-values greater than 10−6 are shown as white bars, indicating absence of gene conservation. The OMIM disease entry numbers (available at: http://www.ncbi.nlm.nih.gov/Omim/) and cytogenetic locations are listed. APP indicates amyloid precursor protein; SOD1, superoxide dismutase 1; PMP22, peripheral myelin protein 22; GM2, a ganglioside with the addition of N-acetylgalactosamine; FRAXE, fragile site in chromosome Xq28; NAGA, α-N-acetylgalactosaminidase; PTS, 6-pyruvoyltetrahydropterin synthase; RLBP1, retinaldehyde-binding protein 1; and HEXB, hexosaminidase B.

Graphic Jump Location

Other protein families involved in neural development, function, and structure, and absent in the fruit fly and nematode, mediate cell adhesion such as the connexin gap junction proteins. These are subunits of the intercellular channels that form electrical synapses in vertebrates. Mutations in the human connexin genes are involved in diseases like X-linked Charcot-Marie-Tooth neuropathy and autosomal dominant deafness type 3. Several ion channel families show marked expansions in the human genome, for example, the voltage-gated channels (Figure 1). Voltage-gated sodium and potassium channels play a key role in the generation of neuronal action potentials. Mutations in the voltage-gated potassium channel genes are involved in episodic ataxia/myokymia syndrome, autosomal dominant deafness type 2, and benign neonatal epilepsy types 1 and 2. Voltage-gated calcium channels also play a central role in neurotransmitter release; mutations in some members of this gene family are responsible for disorders like episodic ataxia type 2, familial hemiplegic migraine, X-linked congenital night blindness type 2, and spinocerebellar ataxia type 6 (Figure 3). The tubulin-binding proteins of the MAP2/tau family are involved in dendrite and axonal morphologic determination, contributing to the development of neuronal morphologic characteristics. Mutations in the human TAU gene lead to frontotemporal dementia with parkinsonism.

We performed a comparative analysis of 168 neurogenetic diseases selected from Online Mendelian Inheritance in Man. These diseases result from specific alleles of 146 different human genes (Figure 3). The sequence homology analysis was done by means of BlastP as described previously,12 and no subjective judgments were done for orthologous genes, since these are often quite difficult to determine for Caenorhabditis elegans genes.12 For the 146 human genes surveyed, we found similar levels of sequence conservation in the fruit fly and nematode. About 56% of those genes show high or intermediate sequence conservation in Drosophila (83 genes) and C elegans (81 genes). This is surprising given the fact that the nervous system in the fruit fly is significantly more complex than that in the nematode. There are 3 cases of gene conservation with the nematode but not the fruit fly: hypoxanthine phosphoribosyltransferase 1 (involved in Lesch-Nyhan syndrome), the Machado-Joseph disease gene, and phytanoyl–coenzyme A hydroxylase (Refsum disease). Four genes are conserved in the fruit fly but not in the nematode: otoferlin (autosomal recessive deafness type 9), fragile X mental retardation 1, spinocerebellar ataxia 2, and the sonic hedgehog homologue (holoprosencephaly type 3), a gene that was originally characterized in the fruit fly.

Several human genes in our survey had counterparts in the Drosophila and C elegans genomes. Many of these have been well characterized by molecular studies, particularly with the fruit fly used as the animal model. Examples of such genes are diaphanous homologue (autosomal dominant nonsyndromic deafness type 1); notch homologue 3 (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]); presenilin 1, presenilin 2, and amyloid β-precursor protein (familial early-onset Alzheimer disease); and superoxide dismutase 1 (amyotrophic lateral sclerosis). Genetic studies in the fruit fly have made important contributions to our understanding of their cellular function and the molecular mechanisms involved in neurodegeneration (reviewed by Fortini and Bonini13). Deletion of the fruit fly β-amyloid precursor protein–like gene leads to behavioral defects that can be partially rescued by transgenic expression of the human amyloid precursor protein gene.14 Loss-of-function mutations in the fruit fly presenilin gene cause neurogenic and other developmental defects.15 In the nematode, deletion of the presenilin homologue sel-12 causes an egg-laying defective phenotype that can be fully rescued by normal human presenilin but, interestingly, not by human presenilins carrying mutations linked to familial early-onset Alzheimer disease.16 The fruit fly has been a very useful animal model for the study of the pathogenesis of polyglutamine repeat diseases such as Huntington and Machado-Joseph diseases. Expression of polyglutamine-expanded huntingtin and Machado-Joseph disease protein in the fruit fly induced neuronal degeneration.17,18 An important advantage of the fruit fly and nematode animal model systems is the application of large-scale genetic screening methods to identify novel genes that can modulate the molecular mechanisms of disease. A recent genetic screen identified 2 Drosophila genes that appear to modulate the polyglutamine-induced neurodegeneration, which may lead to better understanding of pathogenesis and ultimately to novel therapeutic development.19

Other examples of human genes involved in neurologic diseases that have homologues in the fruit fly and nematode are cyclic nucleotide–gated channel α-3 (achromatopsia), α-thalassemia/mental retardation syndrome gene, adenosine triphosphate–binding cassette D1 (adrenoleukodystrophy), platelet-activating factor acetylhydrolase 1b α-subunit (lissencephaly type 1), Niemann-Pick disease C1 gene, phenylalanine hydroxylase (phenylketonuria), cyclic nucleotide–gated channel α-1 (retinitis pigmentosa), tyrosine hydroxylase (Segawa syndrome), and aldehyde dehydrogenase 3A2 (Sjögren-Larsson syndrome).

About 44% of the human genes in our selected set appear to have no counterparts in the fruit fly and nematode, including the genes involved in myelin production, gap junctions, and voltage-gated ion channels discussed above. Other examples of those nonconserved genes are neuronal ceroid-lipofuscinosis 2, 5, and 8; dentatorubropallidoluysian atrophy; fragile X mental retardation 2; monoamine oxidase A (Brunner syndrome); Norrie disease gene; prion protein gene (Creutzfeldt-Jakob disease, Gerstmann-Strausler-Scheinker syndrome, and fatal familial insomnia); spinocerebellar ataxia 7 and 10; and α-synuclein (familial Parkinson disease). Although the gene encoding α-synuclein is absent in the fruit fly, expression of human α-synuclein in Drosophila has been shown to produce loss of dopaminergic neurons, filamentous intraneuronal inclusions, and locomotor dysfunction reminiscent of Parkinson disease.20 This suggests that fruit flies have some conservation in the mechanisms leading to neurodegeneration in Parkinson disease, even though one of its components (α-synuclein) may be absent.

More than 1000 interchromosomal segmental duplications have been detected in the human genome.1 Many of these large block duplications appear to have an ancient origin and are likely to predate most vertebrate divergences, having undergone many subsequent deletions and rearrangements.1 The block duplications range in size from a few genes to segments covering most of a chromosome. Interestingly, many genes that have disease-associated alleles are present in the duplicated segments. Furthermore, in some instances the genes in both duplicated segments have alleles associated with similar diseases. We present examples of interchromosomal duplicated segments associated with neurologic diseases (Table 1). The homeobox genes sine oculis homologues 3, 1, and 6 are located in duplicated segments in human chromosomes 2 and 14. The Drosophila sine oculis gene is a transcription factor that plays a crucial role in morphogenesis, and its mutant alleles lead to defects in eye morphologic features and neuronal development. Mutations in the human sine oculis homeobox homologue 3 gene are associated with neurodevelopmental alterations in holoprosencephaly type 2. The G protein α-transducing activity polypeptide 1 gene in human chromosome 3 encodes a transducin α-subunit involved in the stimulation of cyclic guanosine monophosphate–phosphodiesterase in rod photoreceptors, and its mutations are associated with congenital stationary night blindness. A duplicated segment containing the G protein α-inhibiting subunit 1 gene is present in chromosome 7 (Table 1).

Table Graphic Jump LocationParalogous Genes on Duplicated Genome Segments That Have Alleles Involved in Neurologic Diseases*

The α-synuclein gene, associated with familial Parkinson disease, is located in a chromosome 4 segment that is duplicated in chromosome 10, where the γ-synuclein gene is located. The chromosome 15 gene hexosaminidase A is associated with Tay-Sachs disease, an autosomal recessive progressive neurodegenerative disorder that is prevalent in the Ashkenazi Jewish population. A duplicated segment in chromosome 5 contains the hexosaminidase B β gene, which is associated with Sandhoff disease, a disorder clinically similar to Tay-Sachs disease, but observed mostly in non-Jewish patients. Another example of 2 paralog genes associated with neurogenetic disease is phenylalanine hydroxylase and tyrosine hydroxylase, which are, respectively, part of a segment duplicated in chromosomes 12 and 11. Phenylalanine hydroxylase mutations are associated with phenylketonuria, and tyrosine hydroxylase mutations are linked to autosomal recessive Segawa syndrome, a disease with levodopa-responsive parkinsonism that appears early in infancy (Table 1). The gene coding for voltage-gated potassium ion channel 1, linked to episodic ataxia syndrome, is located in a chromosome 12 segment that has duplications in chromosome 1 containing 2 paralog genes of the Shaker-related subfamily of voltage-gated potassium ion channels (Table 1). The cochlin precursor gene in chromosome 14 linked to autosomal dominant deafness type 9 is duplicated in chromosome 2. The gene coding for microtubule-associated protein tau in chromosome 17, associated with frontotemporal dementia with parkinsonism (familial Pick disease), is part of a segment duplicated in chromosome 2 that contains the gene coding for the related tubulin-binding protein MAP2. The gene in chromosome 17 linked to lissencephaly type 1, in which there is an abnormality in early neuronal migration and development of the cerebral cortex leading to agyria (lack of cortical convolutions or gyri), is part of a segment duplicated in chromosome 5. The gene for gap junction protein connexin 32, associated with X-linked Charcot-Marie-Tooth neuropathy, is part of a segment duplicated in chromosome 13 that contains 3 paralogous genes coding for connexin 26 (linked to autosomal dominant deafness type 3), connexin 30, and connexin 46 (Table 1).

The availability of an assembled human genome sequence will significantly accelerate the discovery of genetic susceptibility factors for human disease. Millions of human single nucleotide polymorphisms and other forms of DNA sequence variations have been added to the single nucleotide polymorphism databases; these markers will enhance the genetic approaches for the identification of disease susceptibility factors. Comparative analyses of genomes from different species and phyla bring a new perspective to the study of gene function and evolution and will be an important tool for furthering our understanding of the role of alleles in conferring disease predisposition. The sequencing and assembly of the human genome have also enabled the detection of interchromosomal block duplications containing novel paralogous genes. Further investigation of the novel genes resulting from ancient duplication of genes with disease-associated alleles is required to determine if they are also involved in similar genetic diseases. Moreover, research on those genes may reveal new insights into pathogenesis and therapeutic development. Genomics and bioinformatics will merge with neurobiology to provide powerful new approaches for advancing our understanding of the complex biology and pathology of the human nervous system.

Accepted for publication July 27, 2001.

Corresponding author and reprints: Anibal Cravchik, MD, PhD, Celera Genomics, 45 W Gude Dr, Rockville, MD 20850 (e-mail: Anibal.Cravchik@celera.com).

Venter  JCAdams  MDMyers  EW  et al The sequence of the human genome. Science.2001;291:1304-1351.
Lander  ESLinton  LMBirren  B  et al Initial sequencing and analysis of the human genome. Nature.2001;409:860-921.
Adams  MDCelniker  SEHolt  RA  et al The genome sequence of Drosophila melanogasterScience.2000;287:2185-2195.
The C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science.1998;282:2012-2018.
Kandel  ERSchwartz  JHJessell  T Principles of Neural Science. 4th ed. New York, NY: McGraw-Hill Inc; 2000.
Missler  MSudhof  TC Neurexins: three genes and 1001 products. Trends Genet.1998;14:20-26.
Ranscht  B Cadherins: molecular codes for axon guidance and synapse formation. Int J Dev Neurosci.2000;18:643-651.
Aravind  LDixit  VMKoonin  EV Apoptotic molecular machinery: vastly increased complexity in vertebrates revealed by genome comparisons. Science.2001;291:1279-1284.
Yuan  JYankner  BA Apoptosis in the nervous system. Nature.2000;407:802-809.
Bateman  ABirney  EDurbin  REddy  SRHowe  KLSonnhammer  EL The Pfam protein families database. Nucleic Acids Res.2000;28:263-266.
Schultz  JCopley  RRDoerks  TPonting  CPBork  P SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res.2000;28:231-234.
Rubin  GMYandell  MDWortman  JR  et al Comparative genomics of the eukaryotes. Science.2000;287:2204-2215.
Fortini  MEBonini  NM Modeling human neurodegenerative diseases in Drosophila: on a wing and a prayer. Trends Genet.2000;16:161-167.
Luo  LTully  TWhite  K Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron.1992;9:595-605.
Ye  YLukinova  NFortini  ME Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants. Nature.1999;398:525-529.
Levitan  DDoyle  TGBrousseau  D  et al Assessment of normal and mutant human presenilin function in Caenorhabditis elegansProc Natl Acad Sci U S A.1996;93:14940-14944.
Jackson  GRSalecker  IDong  X  et al Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron.1998;21:633-642.
Warrick  JMPaulson  HLGray-Board  GL  et al Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in DrosophilaCell.1998;93:939-949.
Kazemi-Esfarjani  PBenzer  S Genetic suppression of polyglutamine toxicity in DrosophilaScience.2000;287:1837-1840.
Feany  MBBender  WW A Drosophila model of Parkinson's disease. Nature.2000;404:394-398.

Figures

Place holder to copy figure label and caption
Figure 1.

Expansions in human protein families involved in neural function, structure, and development. Number of proteins in selected families in the human, fruit fly, and nematode are compared (data from Venter et al1).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Schematic representation of the architecture of neuronal specific proteins that are expanded in humans. Protein domains are represented by convention as different geometric shapes. Domain names are as follows: PDZ, domains found in diverse signaling proteins that may target signaling molecules to submembranous sites; SH3 (Src homology 3), domains often found in proteins involved in signal transduction related to cytoskeletal organization; GuKc, guanylate kinase homologues; IL, interleukin; BIR, baculoviral inhibition of apoptosis protein repeat; NACHT, family of adenosine triphosphatase; LRR, leucine-rich repeats; ANK, ankyrin repeats; and SAM, sterile α motif. Biological descriptions of protein domains and families are available through the Pfam10 (available at: http://www.sanger.ac.uk/Software/Pfam/index.shtml) and SMART11 (available at: http://smart.embl-heidelberg.de/) databases. NMDA indicates N-methyl-D-aspartate.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3a.

Comparative analysis of human genes implicated in neurologic diseases. A set of 168 human neurologic diseases resulting from specific alleles of 146 different human genes was selected from Online Mendelian Inheritance in Man (OMIM) for the comparative analysis. The proteins encoded by those genes were used as queries to search the nonredundant GenBank database for related proteins from Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (nematode). BlastP searches were conducted as described,12 and the results were color coded according to their level of statistical significance, reflecting the degree of confidence in their evolutionary and functional relationship. BlastP E-values less than 10−100, representing the highest degree of sequence conservation, are shown as dark-green bars. E-values between 10−100 and 10−40 are represented in blue-green color, indicating an intermediate level of conservation. E-values in the range of 10−40 10−6 are shown in light blue, indicating the lowest level of conservation. E-values greater than 10−6 are shown as white bars, indicating absence of gene conservation. The OMIM disease entry numbers (available at: http://www.ncbi.nlm.nih.gov/Omim/) and cytogenetic locations are listed. APP indicates amyloid precursor protein; SOD1, superoxide dismutase 1; PMP22, peripheral myelin protein 22; GM2, a ganglioside with the addition of N-acetylgalactosamine; FRAXE, fragile site in chromosome Xq28; NAGA, α-N-acetylgalactosaminidase; PTS, 6-pyruvoyltetrahydropterin synthase; RLBP1, retinaldehyde-binding protein 1; and HEXB, hexosaminidase B.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3b.

Comparative analysis of human genes implicated in neurologic diseases. A set of 168 human neurologic diseases resulting from specific alleles of 146 different human genes was selected from Online Mendelian Inheritance in Man (OMIM) for the comparative analysis. The proteins encoded by those genes were used as queries to search the nonredundant GenBank database for related proteins from Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (nematode). BlastP searches were conducted as described,12 and the results were color coded according to their level of statistical significance, reflecting the degree of confidence in their evolutionary and functional relationship. BlastP E-values less than 10−100, representing the highest degree of sequence conservation, are shown as dark-green bars. E-values between 10−100 and 10−40 are represented in blue-green color, indicating an intermediate level of conservation. E-values in the range of 10−40 10−6 are shown in light blue, indicating the lowest level of conservation. E-values greater than 10−6 are shown as white bars, indicating absence of gene conservation. The OMIM disease entry numbers (available at: http://www.ncbi.nlm.nih.gov/Omim/) and cytogenetic locations are listed. APP indicates amyloid precursor protein; SOD1, superoxide dismutase 1; PMP22, peripheral myelin protein 22; GM2, a ganglioside with the addition of N-acetylgalactosamine; FRAXE, fragile site in chromosome Xq28; NAGA, α-N-acetylgalactosaminidase; PTS, 6-pyruvoyltetrahydropterin synthase; RLBP1, retinaldehyde-binding protein 1; and HEXB, hexosaminidase B.

Graphic Jump Location

Tables

Table Graphic Jump LocationParalogous Genes on Duplicated Genome Segments That Have Alleles Involved in Neurologic Diseases*

References

Venter  JCAdams  MDMyers  EW  et al The sequence of the human genome. Science.2001;291:1304-1351.
Lander  ESLinton  LMBirren  B  et al Initial sequencing and analysis of the human genome. Nature.2001;409:860-921.
Adams  MDCelniker  SEHolt  RA  et al The genome sequence of Drosophila melanogasterScience.2000;287:2185-2195.
The C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science.1998;282:2012-2018.
Kandel  ERSchwartz  JHJessell  T Principles of Neural Science. 4th ed. New York, NY: McGraw-Hill Inc; 2000.
Missler  MSudhof  TC Neurexins: three genes and 1001 products. Trends Genet.1998;14:20-26.
Ranscht  B Cadherins: molecular codes for axon guidance and synapse formation. Int J Dev Neurosci.2000;18:643-651.
Aravind  LDixit  VMKoonin  EV Apoptotic molecular machinery: vastly increased complexity in vertebrates revealed by genome comparisons. Science.2001;291:1279-1284.
Yuan  JYankner  BA Apoptosis in the nervous system. Nature.2000;407:802-809.
Bateman  ABirney  EDurbin  REddy  SRHowe  KLSonnhammer  EL The Pfam protein families database. Nucleic Acids Res.2000;28:263-266.
Schultz  JCopley  RRDoerks  TPonting  CPBork  P SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res.2000;28:231-234.
Rubin  GMYandell  MDWortman  JR  et al Comparative genomics of the eukaryotes. Science.2000;287:2204-2215.
Fortini  MEBonini  NM Modeling human neurodegenerative diseases in Drosophila: on a wing and a prayer. Trends Genet.2000;16:161-167.
Luo  LTully  TWhite  K Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron.1992;9:595-605.
Ye  YLukinova  NFortini  ME Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants. Nature.1999;398:525-529.
Levitan  DDoyle  TGBrousseau  D  et al Assessment of normal and mutant human presenilin function in Caenorhabditis elegansProc Natl Acad Sci U S A.1996;93:14940-14944.
Jackson  GRSalecker  IDong  X  et al Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron.1998;21:633-642.
Warrick  JMPaulson  HLGray-Board  GL  et al Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in DrosophilaCell.1998;93:939-949.
Kazemi-Esfarjani  PBenzer  S Genetic suppression of polyglutamine toxicity in DrosophilaScience.2000;287:1837-1840.
Feany  MBBender  WW A Drosophila model of Parkinson's disease. Nature.2000;404:394-398.

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