Y H Edwards

University College London, Londinium, England, United Kingdom

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Publications (130)634.16 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: SummaryA 317-bp segment of DNA from the 3′ region of the human phosphoglucomutase-1 (PGMl) gene has been examined by a non-radioactive technique for the occurrence of single-strand conformation polymorphism (SSCP), Eight phenotypes were detected and attributed to the presence of four alleles. Genetic analysis of 75 unrelated individuals and six CEPH families whose PGMl protein phenotypes were known revealed strong association between the PGMl ‘+’ and ‘−’ isozyme phenotypes and the variation detected in this region, but no association with the PGMl 1 and PGMl 2 isozyme phenotypes. DNA sequence analysis demonstrated the presence of three nucleotide substitutions underlying the alleles, which were located in the untranslated region of the PGMl gene. There was complete correlation between the nucleotide sequence and the phenotype detected by SSCP analysis. This study provides support for the model that the PGMl isozyme polymorphism is determined at two distinct sites in the coding sequence, one coding for the ‘1’ and ‘2’ alleles and the other coding for the ‘+’ and ‘−’ alleles, separated by a region where intragenic recombination occurs.
    Annals of Human Genetics 09/2007; 57(1):1 - 8. · 2.22 Impact Factor
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    ABSTRACT: Screening a testis cDNA selection library for Y-linked genes yielded 79 cDNAs. Of these, 9 matched the 3' region of the dynamin 1 gene (DNM1) on chromosome 9q34 with >90% identity. Fluoresence in situ hybridisation and PCR amplification were used to localise a large number of DNM1-like sequences to human chromosomes 15 and Y. PCR amplification of overlapping Y-linked YACs allowed a more accurate mapping of the Y-linked DNM1-like cDNAs to a euchromatic locus in close proximity to heterochromatin at Yq11.23. A search of the genome database identified 64 highly homologous copies of the DNM1 fragment. Most of these copies were localised to chromosomes 15 and Y, but others mapped to chromosomes 5, 8, 10, 12, 19 and 22. These sequences exhibit all the major features of a duplicon and have been designated DNM1DN (DNM1 duplicon). Evolutionary studies using fluorescence in situ hybridisation indicate that transposition of the DNM1DN sequence to chromosome 15 took place earlier in primate evolution than the transposition to the Y chromosome. The translocation to the Y took place at a time following the divergence of a common ancestor from gorilla, approximately 4-7 million years ago.
    Annals of Human Genetics 03/2004; 68(Pt 2):85-92. · 2.22 Impact Factor
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    ABSTRACT: Utrophin can functionally replace dystrophin in dystrophin-deficient muscle and may have a role in a therapeutic strategy for Duchenne muscular dystrophy. This has resulted in many investigations of the full-length muscle form of utrophin; however, the short utrophins and non-muscle forms have been relatively neglected, partly because they are difficult to analyze in the presence of the full-length form. Our study circumvents this problem by using mice deficient for the full-length form (UKOex6 mice) to study the translation and distribution of short utrophins. Four tissues were examined-kidney, testis, fetal hands/feet, and brain-and three novel short isoforms were identified, including Up120, which appears to be specific to kidney glomeruli, and Up 109, expressed in the fetal dermis. A third form, Up103, was found in testis but at extremely low levels. A cDNA for Up109 has been isolated and shown to have a unique NH2-terminal sequence. In addition, the first exons of Up109 and another short form, G-utrophin, have both been located within intron 55, 56 kb apart. Our immunological studies show that G-utrophin protein accumulates only in neural tissue, in line with its similarly restricted RNA distribution. Our study of testis expression shows, for the first time, that full-length utrophin is expressed at high levels in Leydig cells, raising the possibility that this protein is involved in testosterone secretion. We note that translation of the short utrophins, especially Up140 and Up71, is relatively inefficient and discuss the significance of this observation.
    Mammalian Genome 02/2003; 14(1):47-60. · 2.42 Impact Factor
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    ABSTRACT: We describe the construction of a dog embryonic head/neck cDNA library and the isolation of the dog homolog of the Treacher Collins Syndrome gene, TCOF1. The protein shows a similar three-domain structure to that described for human TCOF1, but the dog gene lacks exon 10 and contains two exons not present in the human sequence. In addition, exon 19 is differentially spliced in the dog. How these structural differences relate to TCOF1 phosphorylation is discussed. Isolation of a genomic clone allowed the exon/intron boundaries to be characterized and the dog TCOF1 gene to be mapped to CF Chr 4q31, a region syntenic to human Chr 5. Genetic analysis of DNA of dogs from 13 different breeds identified nine DNA sequence variants, three of which gave rise to amino acid substitutions. Grouping dogs according to head type showed that a C396T variant, leading to a Pro117Ser substitution, is associated with skull/face shape in our dog panel. The numbers are small, but the association between the T allele and brachycephaly, broad skull/short face, was highly significant (p= 0.000024). The short period of time during which the domestic dog breeds have been established suggests that this mutation has arisen only once in the history of dog domestication.
    Mammalian Genome 07/2001; 12(8):622-629. · 2.42 Impact Factor
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    ABSTRACT: Genes involved in human male sex determination and spermatogenesis are likely to be located on the Y chromosome. In an effort to identify Y-linked, testis-expressed genes, a cDNA selection library was generated by selecting testis cDNA with Y-cosmid clones. Resultant clones containing repetitive or vector material were eliminated, and 79 of the remaining clones were sequenced. Nineteen cDNAs showed homology with the TTY2 gene, and indicated that TTY2 is part of a large gene family. Screening of a panel of Y-linked cosmids revealed that the TTY2 gene family includes at least 26 members organized in 14 subfamilies. Further investigation revealed that TTY2 genes are arranged in tandemly arrayed clusters on both arms of the Y chromosome, and each gene comprises a series of tandemly arranged repeats. RT-PCR studies for two of these genes revealed that they are expressed in adult and fetal testis, as well as in the adult kidney. None of the genes investigated in detail contain an open reading frame. We conclude that the TTY2 gene family is composed of multiple copies, some of which may function as noncoding RNA transcripts and some may be pseudogenes.
    Genome Research 07/2001; 11(6):935-45. · 14.40 Impact Factor
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    ABSTRACT: Domestic dog breeds show a wide variety of morphologies and offer excellent opportunities to study the molecular genetics of phenotypic traits. We are interested in exploring this potential and have begun by investigating the genetic basis of a short-tail trait. Our focus has been on the T gene, which encodes a T-box transcription factor important for normal posterior mesoderm development. Haploinsufficiency of T protein underlies a short-tail phenotype in mice that is inherited in an autosomal dominant fashion. We have cloned the dog homolog of T and mapped the locus to canine Chromosome (Chr) 1q23. Full sequence analysis of the T gene from a number of different dog breeds identified several polymorphisms and a unique missense mutation in a bob-tailed dog and its bob-tailed descendants. This mutation is situated in a highly conserved region of the T-box domain and alters the ability of the T protein to bind to its consensus DNA target. Analysis of offspring from several independent bobtail x bobtail crosses indicates that the homozygous phenotype is embryonic lethal.
    Mammalian Genome 04/2001; 12(3):212-8. · 2.42 Impact Factor
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    ABSTRACT: The MSX2 gene encodes a homeodomain transcription factor important for normal head and face morphogenesis. MSX2 is expressed in key craniofacial structures during development and mutations in the human gene give rise to various craniofacial abnormalities. We are interested in the genetic basis of non-pathogenic variation in skull and face shape. As part of this study we have analysed DNA from a panel of different dog breeds, selected for the differences they show in these traits and investigated MSX2 as a candidate gene. In this paper we describe the cloning of the canine homologue of MSX2, the determination of its structure, sequence and localization of the gene to dog chromosome 4q23. The DNAs from 11 individual domestic dogs belonging to 10 different breeds were sequenced in a search for genetic variation. Our studies show that variation in MSX2 does not contribute to the diversity of face shape observed in these domestic dogs and that the MSX2 sequence is strongly conserved between different dog breeds. The proximal promoter shows a high level of interspecies sequence conservation and several conserved transcription factor binding motifs have been identified and their significance discussed.
    Animal Genetics 03/2001; 32(1):32-6. · 2.58 Impact Factor
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    ABSTRACT: Accumulation of mutations in tumour suppressor genes and oncogenes has been proposed to underlie the initiation and progression of sporadic colorectal cancer (CRC). Evidence is accumulating to suggest that the caudal homeobox gene CDX2 is implicated in the pathogenesis of CRC. The CDX2 transcription factor is expressed in intestinal epithelium and is markedly down-regulated in colon tumours. Furthermore, Cdx2 heterozygous null mice develop multiple intestinal tumours. In this present study, we have investigated CDX2 as a potential candidate gene for sporadic CRC by a thorough search of all exons and exon/intron boundaries for DNA polymorphisms and rare variants in a panel of CRC tumours. 6 polymorphisms were identified and the haplotypes determined. In addition two rare variants were found, one of which was only identified in DNA from a CRC case. Loss of heterozygosity was observed in 3 out of 28 informative CRC cases. A possible association between particular haplotypes and tumour progression was also suggested by the data. In addition a preliminary analysis of the relative expression of CDX2 alleles in tumour/normal tissue suggested some variation in the levels, however further analysis is required before any conclusions can be drawn. While CDX2 mutations predisposing to sporadic CRC have not been identified, this study has established that loss of CDX2 contributes towards the progression of some sporadic CRC tumours.
    British Journal of Cancer 02/2001; 84(2):218-25. · 5.08 Impact Factor
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    ABSTRACT: A multiple copy gene family on the human Y chromosome has been shown to be transcribed but not translated.
    Genome Research - GENOME RES. 01/2001; 11(8).
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    ABSTRACT: A region of minimal deletion in B-cell non-Hodgkin's lymphoma (B-NHL) has recently been defined between D6S186 and D6S227 spanning 5-9 Mb at 6q26-q27, predicting the presence of at least one tumor suppressor gene (TSG) at this locus. During the construction of a deletion map in the B-NHL tumor panel, we report the identification of a Burkitt's lymphoma cell line, BL74, having an apparent homozygous deletion at the D6S347 locus, internal to the critical region. Since this case may facilitate the localization of the target TSG, a detailed structural molecular characterization and search for candidate genes were undertaken at this locus. While BL74 underwent a loss of heterozygosity at 6q26-q27, D6S347 was also likely subjected to a somatic interlocus gene conversion-like event between two homologous but distinct loci, resulting in the homozygous replacement of a 1860- to 2067-bp segment of one locus with the corresponding segment copied from the other locus. Two genes at this locus were identified, but their lack of expression in B-cell lineages tentatively excludes them as candidate TSGs. Another still unidentified gene at this locus may be disrupted by the gene conversion-like event, which would represent a novel mechanism of TSG inactivation.
    DNA Research 09/2000; 7(4):261-72. · 4.43 Impact Factor
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    ABSTRACT: The human T developmental gene has been implicated in the etiology of neural tube defects (NTDs) on the basis both of mouse studies of its homologue, T (Brachyury), and of allelic association in a Caucasian population. We have investigated the frequency of the T allelic variant TIVS7-2 in 218 Irish NTD case-parent triads. This population showed the same trend as previously reported, with an excess of the TIVS7-2 allele among cases. Log-linear modeling of case and maternal genotypic effects within families indicated that TIVS7-2 was elevated in cases (relative risk, RR = 1.36) but not in mothers (RR = 0.91). The TIVS7-2 allele is markedly associated with cases born before 1980 (RR = 2.09; CI = 1.23-3.55; corrected p = 0.030), but not with more recent cases (RR = 0.92). Cases carrying a TIVS7-2 allele did not show any increased tendency to be homozygous for the thermolabile variant of the folate-dependent enzyme 5,10-methylene tetrahydrofolate reductase, which is an established genetic risk factor for NTDs. Since the incidence of NTDs has declined markedly in Ireland over the last few decades, we suggest that the T-associated risk is potentiated by nutritional or environmental risk factor(s), the impact of which have been diminishing over time.
    American Journal of Medical Genetics 06/2000; 92(3):206-11.
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    ABSTRACT: The HLXB9 homeobox gene was recently identified as a locus for autosomal dominant Currarino syndrome, also known as hereditary sacral agenesis (HSA). This gene specifies a 403-amino acid protein containing a homeodomain preceded by a very highly conserved 82-amino acid domain of unknown function; the remainder of the protein is not well conserved. Here we report an extensive mutation survey that has identified mutations in the HLXB9 gene in 20 of 21 patients tested with familial Currarino syndrome. Mutations were also detected in two of seven sporadic Currarino syndrome patients; the remainder could be explained by undetected mosaicism for an HLXB9 mutation or by genetic heterogeneity in the sporadic patients. Of the mutations identified in the 22 index patients, 19 were intragenic and included 11 mutations that could lead to the introduction of a premature termination codon. The other eight mutations were missense mutations that were significantly clustered in the homeodomain, resulting, in each patient, in nonconservative substitution of a highly conserved amino acid. All of the intragenic mutations were associated with comparable phenotypes. The only genotype-phenotype correlation appeared to be the occurrence of developmental delay in the case of three patients with microdeletions. HLXB9 expression was analyzed during early human development in a period spanning Carnegie stages 12-21. Signal was detected in the basal plate of the spinal cord and hindbrain and in the pharynx, esophagus, stomach, and pancreas. Significant spatial and temporal expression differences were evident when compared with expression of the mouse Hlxb9 gene, which may partly explain the significant human-mouse differences in mutant phenotype.
    The American Journal of Human Genetics 06/2000; 66(5):1504-15. · 11.20 Impact Factor
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    ABSTRACT: The human T developmental gene has been implicated in the etiology of neural tube defects (NTDs) on the basis both of mouse studies of its homologue, T (Brachyury), and of allelic association in a Caucasian population. We have investigated the frequency of the T allelic variant TIVS7-2 in 218 Irish NTD case-parent triads. This population showed the same trend as previously reported, with an excess of the TIVS7-2 allele among cases. Log-linear modeling of case and maternal genotypic effects within families indicated that TIVS7-2 was elevated in cases (relative risk, RR = 1.36) but not in mothers (RR = 0.91). The TIVS7-2 allele is markedly associated with cases born before 1980 (RR = 2.09; CI = 1.23–3.55; corrected p = 0.030), but not with more recent cases (RR = 0.92). Cases carrying a TIVS7-2 allele did not show any increased tendency to be homozygous for the thermolabile variant of the folate-dependent enzyme 5,10-methylene tetrahydrofolate reductase, which is an established genetic risk factor for NTDs. Since the incidence of NTDs has declined markedly in Ireland over the last few decades, we suggest that the T-associated risk is potentiated by nutritional or environmental risk factor(s), the impact of which have been diminishing over time. Am. J. Med. Genet. 92:206–211, 2000. © 2000 Wiley-Liss, Inc.
    American Journal of Medical Genetics 05/2000; 92(3):206 - 211.
  • Y Edwards, F Drummond, J Sowden
    EXS 02/2000;
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    ABSTRACT: The ability to carry out gene targeting in somatic stem cells while maintaining their stem cell characteristics would have important implications for gene therapy and for the analysis of gene function. Using mouse myoblasts, we have explored this possibility by attempting to alter the promoter of a myosin heavy chain gene (MyHCIIB) characteristic of physiologically "fast" muscle so as to force its unscheduled expression in physiologically "slow" muscle fibers. Conditionally immortalized muscle precursor cells were transfected with a gene targeting construct designed to replace the MyHCIIB promoter with that for the carbonic anhydrase III gene (CAIII), which is highly expressed in slow muscle. A potentially targeted clone was isolated and differentiated in culture to form myotubes which expressed MyHCIIB. Cells from the same clone were injected into both slow and fast muscle of host mice, where they contributed to fiber formation. In slow muscle, the fibers derived from this clone did not express MyHCIIB; this may reflect an instability of the targeted MyHCIIB locus and/or a failure of the hybrid promoter to function in slow fibers in vivo. Nonetheless, we have demonstrated that a "promoter knock-in" gene targeting procedure can be used to generate unique MyHCIIB-expressing myotubes in culture and that conditionally immortalized myoblasts can be subjected to extensive passaging and genetic manipulation without losing their ability to form fibers in culture and in vivo.
    Experimental Cell Research 01/2000; 253(2):523-32. · 3.56 Impact Factor
  • American Journal of Medical Genetics - AMER J MED GENET. 01/2000; 92(3):206-211.
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    J Wilson, W Putt, C Jimenez, Y H Edwards
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    ABSTRACT: Utrophin is a large protein which accumulates at the neuromuscular synapse and myotendinous junctions in adult skeletal muscle, and is widely expressed in several non-skeletal muscle tissues. Evidence from a variety of sources suggests that a successful strategy for treatment of Duchenne muscular dystrophy patients will be to increase expression of utrophin in muscle. There is still much to be learnt about utrophin gene regulation, in particular regarding alternative isoforms, their promoters and role in muscle and non-muscle tissues. Using 5"-RACE we have identified two novel transcripts of utrophin, Up71 and Up140, with unique first exons and promoters located in intron 62 and intron 44, respectively. These transcripts appear to be structural homologues of the short dystrophin transcripts, Dp140 and Dp71, emphasizing the high degree of structural conservation between the utrophin and dystrophin genes. RT-PCR shows that Up71 and Up140 are widely expressed in both human and mouse tissues, including skeletal muscle. We present evidence for transcript-specific differential mRNA splicing of exon 71, in both Up71 and Up140, similar to that described for dystrophin. No evidence for splicing of exon 78 of utrophin was found. This is in contrast to dystrophin and may reflect a subtle functional difference in patterns of phosphorylation between the two proteins.
    Human Molecular Genetics 08/1999; 8(7):1271-8. · 7.69 Impact Factor
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    ABSTRACT: Sacral agenesis is a heterogeneous group of congenital anomalies in which most cases are sporadic but rare familial forms also occur. Although one gene has been mapped to chromosome 7q36 in families with hemisacrum, associated with anorectal atresia and presacral mass, it is clear that the genetic aetiology of these disorders is complex and other genes remain to be discovered. Some years ago, the idea of T (Brachyury) as a candidate gene for sacral agenesis was raised, because tail abnormalities associated with T and the t complex, on mouse chromosome 17, resemble spinal defects seen in man. The recent cloning and mapping of the human T gene prompted us to re-evaluate this idea. T is a transcription factor essential for the normal development of posterior mesodermal structures. Although the sequence and function of T are highly conserved in evolution, our genetic study shows that the coding region of the human gene is highly polymorphic. Three common variable amino acid sites in known functional domains have been identified: Gly356Ser, Asn369Ser, and Gly177Asp. For the latter variant, functional studies have shown that the presence of Asp at residue 177 reduces the stability of T dimer formation. A search for rare mutation of T in 28 selected patients with sacral agenesis/anorectal atresia identified a novel, rare variant in one patient and her mother. This mutation leads to an amino acid change within a conserved activation domain. While the functional significance of this single mutation requires further investigation, we can conclude from our studies that if T has a role in the aetiology of sacral agenesis, its contribution is small in this particular set of patients. However, we cannot exclude a more major role in other forms of sacral defect.
    Journal of Medical Genetics 04/1999; 36(3):208-13. · 5.70 Impact Factor
  • C Papapetrou, W Putt, M Fox, Y H Edwards
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    ABSTRACT: Tbx6 is a member of the T-box family of proteins, which share a region of homology corresponding to the DNA-binding domain of the transcription factor T. Previous expression studies and knockout experiments in mice indicate that Tbx6 is important for specification of paraxial mesoderm structures. We have isolated and characterized the human orthologue, TBX6. Sequence comparisons show that overall the nucleotide homology between human and mouse TBX6/Tbx6 is 84%; within the T-box there is 89% nucleotide homology and 96% amino acid identity. TBX6 maps to chromosome 16 p11.2, a region syntenic with mouse chromosome 7, at 61 cM, the map position of mouse Tbx6. RT-PCR studies of RNA distribution indicate that this gene is expressed not only during gastrulation but has a second phase of expression in some adult tissues including testis. DNA/protein-binding studies demonstrate that Tbx6 binds to the same target DNA as T protein and can form a dimeric complex with DNA. We could find no evidence that Tbx6 forms a heterodimer with T.
    Genomics 02/1999; 55(2):238-41. · 3.01 Impact Factor
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    ABSTRACT: Clues regarding candidate genes which influence susceptibility to spina bifida and anencephaly come from the identification of folate-associated risk factors and from studies of mouse mutants showing neural tube anomalies. On this basis we selected five candidate genes; CBS, MS, MTHFR, T (Brachyury) and BRCA1 for genetic analysis in 31 Dutch and 48 British NTD families. Ten polymorphisms, two for each gene, were used in transmission tests for disequilibrium (TDT). In six instances more than 50 transmissions from heterozygous parents could be examined. Using TDT we find evidence for an association between an allele at the T gene and liability to NTD in the embryo. Data from British and Dutch populations showed the same trend and in combination gave a chi 2TDT = 4.89, P = 0.03 (OR 2.39, CI 95% 1.02-5.61). No association, in either population group, was found for CBS, MS and MTHFR, the enzymes most directly associated with the known risk factors in folate metabolism. The possibility of complex genetic interactions was explored; the data show that a Gly919 MS variant occurs more frequently in combination with the MTHFR thermolabile variant in mothers of NTD offspring (OR 3.94, CI 95% 1.0-16.3).
    Annals of Human Genetics 10/1998; 62(Pt 5):379-96. · 2.22 Impact Factor

Publication Stats

3k Citations
634.16 Total Impact Points

Institutions

  • 1971–2007
    • University College London
      Londinium, England, United Kingdom
  • 2000
    • Columbia University
      • Department of Genetics and Development
      New York City, New York, United States
  • 1987–1995
    • Oxford University Hospitals NHS Trust
      • Molecular Genetics Group
      Oxford, England, United Kingdom
  • 1979–1988
    • St. George's School
      • Department of Child Health
      Middletown, Rhode Island, United States
  • 1985
    • The University of Manchester
      Manchester, England, United Kingdom