X-linked dominant hypophosphatemic rickets (HYP) is the most common form of hereditary rickets. R... more X-linked dominant hypophosphatemic rickets (HYP) is the most common form of hereditary rickets. Recently we have cloned thePEX gene and shown it to be mutated and deleted in HYP individuals. We have now completely sequenced a 243-kb genomic region containing PEX and have identified all intron–exon boundary sequences. We show that PEX, homologous to members of a neutral endopeptidase family, has an exon organization that is very similar to neprilysin. We have performed an extensive mutation analysis examining all 22 PEX coding exons in 29 familial and 14 sporadic cases of hypophosphatemia. Sequence changes include missense, frameshift, nonsense, and splice site mutations and intragenic deletions. A mutation was found in 25 (86%) of the 29 familial cases and 8 (57%) of the 14 sporadic cases. Our data provide the first evidence that most of the familial and also a large number of the sporadic cases of hypophosphatemia are caused by loss-of-function mutations in PEX.[The sequence data d...
After the completion of a draft human genome sequence, the International Human Genome Sequencing ... more After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evo...
Mutations in the humanAIREgene (hAIRE) result in the development of an autoimmune disease named A... more Mutations in the humanAIREgene (hAIRE) result in the development of an autoimmune disease named APECED (autoimmunepolyendocrinopathycandidiasisectodermaldystrophy; OMIM 240300). Previously, we have cloned hAIREand shown that it codes for a putative transcription-associated factor. Here we report the cloning and characterization ofAire, the murine ortholog of hAIRE. Comparative genomic sequencing revealed that the structure of theAIREgene is highly conserved between human and mouse. The conceptual proteins share 73% homology and feature the same typical functional domains in both species. RT–PCR analysis detected three splice variant isoforms in various mouse tissues, and interestingly one isoform was conserved in human, suggesting potential biological relevance of this product. In situ hybridization on mouse and human histological sections showed that AIRE expression pattern was mainly restricted to a few cells in the thymus, calling for a tissue-specific function of the gene product.
Functional characterization of the mouse genome requires the availability of a comprehensive phys... more Functional characterization of the mouse genome requires the availability of a comprehensive physical map to obtain molecular access to chromosomal regions of interest. Positional cloning remains a crucial way of linking phenotype with particular genes. A key step and frequent stumbling block in positional cloning is making a contig of a genetically defined candidate region. The most efficient first step is isolating YAC (Yeast Artificial Chromosome) clones. A robust, detailed YAC contig map is thus an important tool. Employing Interspersed Repetitive Sequence (IRS)-PCR genomics, we have generated an advanced second-generation YAC contig map of the mouse genome that doubles both the depth of clones and the density of markers available. In addition to the primarily YAC-based map, we located 1942 BAC (Bacterial Artificial Chromosome) clones. This allows us to present for the first time a dense framework of BACs spanning the genome of the mouse, which, for instance, can serve as a nucl...
Proceedings of the National Academy of Sciences, 2000
Results of a first-stage Sea Urchin Genome Project are summarized here. The species chosen was St... more Results of a first-stage Sea Urchin Genome Project are summarized here. The species chosen was Strongylocentrotus purpuratus , a research model of major importance in developmental and molecular biology. A virtual map of the genome was constructed by sequencing the ends of 76,020 bacterial artificial chromosome (BAC) recombinants (average length, 125 kb). The BAC-end sequence tag connectors (STCs) occur an average of 10 kb apart, and, together with restriction digest patterns recorded for the same BAC clones, they provide immediate access to contigs of several hundred kilobases surrounding any gene of interest. The STCs survey >5% of the genome and provide the estimate that this genome contains ≈27,350 protein-coding genes. The frequency distribution and canonical sequences of all middle and highly repetitive sequence families in the genome were obtained from the STCs as well. The 500-kb Hox gene complex of this species is being sequenced in its entirety. In addition, arrayed cDN...
The main conclusion is that systems biology approaches can indeed advance cancer research, having... more The main conclusion is that systems biology approaches can indeed advance cancer research, having already proved successful in a very wide variety of cancer-related areas, and are likely to prove superior to many current research strategies. Major points include:
The chromosome 21 mapping and sequencing consortium M. Hattori*¶¶, A. Fujiyama*, TD Taylor*, H. W... more The chromosome 21 mapping and sequencing consortium M. Hattori*¶¶, A. Fujiyama*, TD Taylor*, H. Watanabe*, T. Yada*, H.-S. Park*, A. Toyoda*, K. Ishii*, Y. Totoki*, D.-K. Choi*, E. Soeda†, M. Ohki‡, T. Takagi§, Y. Sakaki*§; S. Taudienk¶¶, K. Blechschmidtk, A. Polleyk, ...
Huntington's disease (HD) is one of an increasing number of neurodegenerative disorders caus... more Huntington's disease (HD) is one of an increasing number of neurodegenerative disorders caused by a CAG/polyglutamine repeat expansion. Mice have been generated that are transgenic for the 5′ end of the human gene carrying (CAG)–(CAG) repeat expansions. In three lines, ...
The distal part of human chromosome 21q22.3 is exceptionally gene rich and contains several loci ... more The distal part of human chromosome 21q22.3 is exceptionally gene rich and contains several loci that have been linked to hereditary disorders. In the course of constructing an extensive transcript map for chromosome 21, we have isolated numerous coding segments in 21q22.3 that ...
The region of chromosome 21 between genes CBR and ERG (CBR–ERG region), which spans 2.5 Mb on 21q... more The region of chromosome 21 between genes CBR and ERG (CBR–ERG region), which spans 2.5 Mb on 21q22.2, has been defined by analysis of patients with partial trisomy 21. It contributes significantly to the pathogenesis of many characteristics of Down syndrome, including ...
The quest for the mutation responsible for Huntington's disease (HD) has required an excepti... more The quest for the mutation responsible for Huntington's disease (HD) has required an exceptionally detailed analysis of a large part of 4p16.3 by molecular genetic techniques, making this stretch of 2.2 megabases one of the best characterized regions of the human genome. Here we ...
Angiotensin II (Ang II) is the major vasoactive component of the renin-angiotensin system. Severa... more Angiotensin II (Ang II) is the major vasoactive component of the renin-angiotensin system. Several components of the renin-angiotensin system have been demonstrated in different tissues. Whereas the roles of tissue and renal renin-angiotensin system have been studied in detail, much ...
Huntington's disease (HD) is an inherited neurodegenerative disorder which is characterized ... more Huntington's disease (HD) is an inherited neurodegenerative disorder which is characterized by uncontrolled movements, general motor impairments and dementia (1 ). The mutation responsible for HD has been identified as an expansion ...
The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 gl... more The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human ...
X-linked dominant hypophosphatemic rickets (HYP) is the most common form of hereditary rickets. R... more X-linked dominant hypophosphatemic rickets (HYP) is the most common form of hereditary rickets. Recently we have cloned thePEX gene and shown it to be mutated and deleted in HYP individuals. We have now completely sequenced a 243-kb genomic region containing PEX and have identified all intron–exon boundary sequences. We show that PEX, homologous to members of a neutral endopeptidase family, has an exon organization that is very similar to neprilysin. We have performed an extensive mutation analysis examining all 22 PEX coding exons in 29 familial and 14 sporadic cases of hypophosphatemia. Sequence changes include missense, frameshift, nonsense, and splice site mutations and intragenic deletions. A mutation was found in 25 (86%) of the 29 familial cases and 8 (57%) of the 14 sporadic cases. Our data provide the first evidence that most of the familial and also a large number of the sporadic cases of hypophosphatemia are caused by loss-of-function mutations in PEX.[The sequence data d...
After the completion of a draft human genome sequence, the International Human Genome Sequencing ... more After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evo...
Mutations in the humanAIREgene (hAIRE) result in the development of an autoimmune disease named A... more Mutations in the humanAIREgene (hAIRE) result in the development of an autoimmune disease named APECED (autoimmunepolyendocrinopathycandidiasisectodermaldystrophy; OMIM 240300). Previously, we have cloned hAIREand shown that it codes for a putative transcription-associated factor. Here we report the cloning and characterization ofAire, the murine ortholog of hAIRE. Comparative genomic sequencing revealed that the structure of theAIREgene is highly conserved between human and mouse. The conceptual proteins share 73% homology and feature the same typical functional domains in both species. RT–PCR analysis detected three splice variant isoforms in various mouse tissues, and interestingly one isoform was conserved in human, suggesting potential biological relevance of this product. In situ hybridization on mouse and human histological sections showed that AIRE expression pattern was mainly restricted to a few cells in the thymus, calling for a tissue-specific function of the gene product.
Functional characterization of the mouse genome requires the availability of a comprehensive phys... more Functional characterization of the mouse genome requires the availability of a comprehensive physical map to obtain molecular access to chromosomal regions of interest. Positional cloning remains a crucial way of linking phenotype with particular genes. A key step and frequent stumbling block in positional cloning is making a contig of a genetically defined candidate region. The most efficient first step is isolating YAC (Yeast Artificial Chromosome) clones. A robust, detailed YAC contig map is thus an important tool. Employing Interspersed Repetitive Sequence (IRS)-PCR genomics, we have generated an advanced second-generation YAC contig map of the mouse genome that doubles both the depth of clones and the density of markers available. In addition to the primarily YAC-based map, we located 1942 BAC (Bacterial Artificial Chromosome) clones. This allows us to present for the first time a dense framework of BACs spanning the genome of the mouse, which, for instance, can serve as a nucl...
Proceedings of the National Academy of Sciences, 2000
Results of a first-stage Sea Urchin Genome Project are summarized here. The species chosen was St... more Results of a first-stage Sea Urchin Genome Project are summarized here. The species chosen was Strongylocentrotus purpuratus , a research model of major importance in developmental and molecular biology. A virtual map of the genome was constructed by sequencing the ends of 76,020 bacterial artificial chromosome (BAC) recombinants (average length, 125 kb). The BAC-end sequence tag connectors (STCs) occur an average of 10 kb apart, and, together with restriction digest patterns recorded for the same BAC clones, they provide immediate access to contigs of several hundred kilobases surrounding any gene of interest. The STCs survey >5% of the genome and provide the estimate that this genome contains ≈27,350 protein-coding genes. The frequency distribution and canonical sequences of all middle and highly repetitive sequence families in the genome were obtained from the STCs as well. The 500-kb Hox gene complex of this species is being sequenced in its entirety. In addition, arrayed cDN...
The main conclusion is that systems biology approaches can indeed advance cancer research, having... more The main conclusion is that systems biology approaches can indeed advance cancer research, having already proved successful in a very wide variety of cancer-related areas, and are likely to prove superior to many current research strategies. Major points include:
The chromosome 21 mapping and sequencing consortium M. Hattori*¶¶, A. Fujiyama*, TD Taylor*, H. W... more The chromosome 21 mapping and sequencing consortium M. Hattori*¶¶, A. Fujiyama*, TD Taylor*, H. Watanabe*, T. Yada*, H.-S. Park*, A. Toyoda*, K. Ishii*, Y. Totoki*, D.-K. Choi*, E. Soeda†, M. Ohki‡, T. Takagi§, Y. Sakaki*§; S. Taudienk¶¶, K. Blechschmidtk, A. Polleyk, ...
Huntington's disease (HD) is one of an increasing number of neurodegenerative disorders caus... more Huntington's disease (HD) is one of an increasing number of neurodegenerative disorders caused by a CAG/polyglutamine repeat expansion. Mice have been generated that are transgenic for the 5′ end of the human gene carrying (CAG)–(CAG) repeat expansions. In three lines, ...
The distal part of human chromosome 21q22.3 is exceptionally gene rich and contains several loci ... more The distal part of human chromosome 21q22.3 is exceptionally gene rich and contains several loci that have been linked to hereditary disorders. In the course of constructing an extensive transcript map for chromosome 21, we have isolated numerous coding segments in 21q22.3 that ...
The region of chromosome 21 between genes CBR and ERG (CBR–ERG region), which spans 2.5 Mb on 21q... more The region of chromosome 21 between genes CBR and ERG (CBR–ERG region), which spans 2.5 Mb on 21q22.2, has been defined by analysis of patients with partial trisomy 21. It contributes significantly to the pathogenesis of many characteristics of Down syndrome, including ...
The quest for the mutation responsible for Huntington's disease (HD) has required an excepti... more The quest for the mutation responsible for Huntington's disease (HD) has required an exceptionally detailed analysis of a large part of 4p16.3 by molecular genetic techniques, making this stretch of 2.2 megabases one of the best characterized regions of the human genome. Here we ...
Angiotensin II (Ang II) is the major vasoactive component of the renin-angiotensin system. Severa... more Angiotensin II (Ang II) is the major vasoactive component of the renin-angiotensin system. Several components of the renin-angiotensin system have been demonstrated in different tissues. Whereas the roles of tissue and renal renin-angiotensin system have been studied in detail, much ...
Huntington's disease (HD) is an inherited neurodegenerative disorder which is characterized ... more Huntington's disease (HD) is an inherited neurodegenerative disorder which is characterized by uncontrolled movements, general motor impairments and dementia (1 ). The mutation responsible for HD has been identified as an expansion ...
The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 gl... more The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human ...
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Papers by Hans Lehrach