- Manchester, Manchester, United Kingdom
Martin Yuille
The University of Manchester, CIGMR, Faculty Member
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This socio-economic study is based on the widely held view that there is an inadequate supply of human biological samples that is hampering biomedical research development and innovation (RDI). The potential value of samples and the... more
This socio-economic study is based on the widely held view that there is an inadequate supply of human biological samples that is hampering biomedical research development and innovation (RDI). The potential value of samples and the associated data are thus not being realized. We aimed to examine whether the financing of biobanks contributes to this problem and then to propose a national solution. We combined three methods: a qualitative case study; literature analysis; and informal consultations with experts. The case study enabled an examination of the complex institutional arrangements for biobanks, with a particular focus on cost models. For the purposes of comparison, a typology for biobanks was developed using the three methods. We found that it is not possible to apply a standard cost model across the diversity of biobanks, and there is a deficit in coordination and sustainability and an excess of complexity. We propose that coordination across this diversity requires dedicated resources for a national biobanking distributed research infrastructure. A coordination center would establish and improve standards and support a national portal for access. This should be financed centrally by public funds, possibly supplemented by industrial funding. We propose that: a) sample acquisition continues to be costed into projects and project proposals to ensure biobanking is driven by research needs; b) core biobanking activities and facilities be supported by central public funds distributed directly to host public institutions; and c) marginal costs for access be paid for by the user.
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In order to improve understanding of how HIV-1 infection down-modulates cell surface membrane expression of CD4, we have measured several parameters of CD4 expression in the human tumor T-cell lines CEM and MOLT-4 at different times after... more
In order to improve understanding of how HIV-1 infection down-modulates cell surface membrane expression of CD4, we have measured several parameters of CD4 expression in the human tumor T-cell lines CEM and MOLT-4 at different times after infection. Three independent HIV-1 isolates were used including one that encodes a truncated nef protein and another that appeared to be noncytolytic against CEM. The level of CD4 mRNA, the rate of biosynthesis of CD4 protein, and the percentage of CD4-positive cells were measured. With each viral isolate it was found that infection led to a specific and almost complete inhibition of CD4 protein biosynthesis. This substantially exceeded, at every time point after infection, a concomitant reduction in CD4 mRNA. Hence an inhibition of translation probably accounts for much of the decline in the rate of CD4 biosynthesis. This implicates a novel selective translational inhibition of host gene expression by HIV-1 as a factor in the disappearance of surface membrane CD4 from infected cultures.
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Yuille M. Advanced biobanking and good management. In “Zukunft der Biobanken-Forschung in Deutschland: Vernetzung, Kollaborationen und Strukturaufbau” eds M. Hummel, T. Illig, R. Jahns, M. Kiehntopf, M. Krawczak, P. Schirmacher, S.C. Semler. Pp 73-96. Akademische Verlagsgesellschaft AKA GmbH, Ber...more
This paper has three main propositions. First, the success of translational research requires changes in practice and culture by universities, hospitals and industry. Second, biobanking networks are one of the most effective ways of... more
This paper has three main propositions. First, the success of translational research requires changes in practice and culture by universities, hospitals and industry. Second, biobanking networks are one of the most effective ways of enabling those changes – if the networks have standards that can reach across universities, hospitals and industry. Third, a network quality management system based on ISO9001 requirements can be an effective tool to drive the changes required for a biobanking network to function. The goal of academic biomedical research has been to serve a scientific good: to understand the human organism in health and disease. The goal of clinical and industrial research has been to serve a public good: to develop and innovate for the alleviation of human disease and ill-health. Today, in the rapidly changing landscape of biomedical research, academic researchers are capable of and are being encouraged by society to address both goals. To address two goals in place of ...
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To investigate the genetics of chronic lymphocytic leukemia (CLL). In 56 (7%) out of 800 CLL patients with concomitant malignant hematological disease, 51 families and 141 cases were ascertained. 106 cases (75%) of CLL, 27 cases (19%) of... more
To investigate the genetics of chronic lymphocytic leukemia (CLL). In 56 (7%) out of 800 CLL patients with concomitant malignant hematological disease, 51 families and 141 cases were ascertained. 106 cases (75%) of CLL, 27 cases (19%) of nonCLL and 8 cases (6%) of myeloproliferative disorders. Paternal disease was transmitted primarily to the youngest sons in the sibship while maternal disease was transmitted equally to all sibs, demonstrated by means of matrix conjugation and confirmed with Cox regression on parity and birth order (maternal-offspring combination: relative risk (RR), 95% confidence interval (CI)=1.47 (0.89 - 2.43), p=0.12, compared with paternal-offspring combination: RR=3.25, 95% CI=(1.57-6.72), p<0.001). The B-cell expression in familial and sporadic CLL was indistinguishable. Parental genomic imprinting is pointed out as one possible mechanism behind this non-Mendelian genomic output.
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Chromosome 11q23 is frequently a site of chromosomal translocation in both acute leukemias and chronic lymphoproliferative disorders. In the former, an 8 kb region within the MLL gene is consistently involved, whereas in the latter... more
Chromosome 11q23 is frequently a site of chromosomal translocation in both acute leukemias and chronic lymphoproliferative disorders. In the former, an 8 kb region within the MLL gene is consistently involved, whereas in the latter breakpoints appear to be heterogeneous. In a B cell acute leukemia cell line with t(14;18)(q32.3;q21.3) we have previously demonstrated a reciprocal translocation between the LAZ3/BCL6 gene at 3q27 and the B cell specific transcriptional coactivator gene BOB-1 at 11q23.1, implicating BOB-1 as a potential proto-oncogene. To confirm the chromosomal localization of BOB-1 we have mapped it by FISH to 11q23.1. It lay immediately telomeric of the ATM gene. We have also investigated the frequency of BOB-1 rearrangements in a panel of 32 cell lines and 71 patient samples. In one case of T cell prolymphocytic leukemia-a disease where 11q23 abnormalities are observed-a chromosomal rearrangement was identified 3.3-0.9 kb centromeric of the 3' end of the gene. Th...
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Chronic lymphocytic leukemia (CLL) shows evidence of familial aggregation, but the genetic basis is poorly understood. The existence of a linkage between HLA and Hodgkin lymphoma, another B-cell disorder, coupled with the fact that CLL is... more
Chronic lymphocytic leukemia (CLL) shows evidence of familial aggregation, but the genetic basis is poorly understood. The existence of a linkage between HLA and Hodgkin lymphoma, another B-cell disorder, coupled with the fact that CLL is frequently associated with autoimmune disease, led to the question of whether the major histocompatibility complex (MHC) region is involved in familial cases of CLL. To examine this proposition, 5 microsatellite markers on chromosome 6p21.3 were typed in 28 families with CLL, 4 families with CLL in association with other lymphoproliferative disorders, and 1 family with splenic lymphoma with villous lymphocytes. There was no evidence of linkage in these families to chromosome 6p21.3. The best estimates of the proportions of sibling pairs with CLL that share 0, 1, or 2 MHC haplotypes were not significantly different from the null expectation. This implies that genes within the MHC region are unlikely to be the major determinants of familial CLL. (Blo...
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A calculation grid developed by an international expert group was tested across biobanks in six countries to evaluate costs for collections of various types of biospecimens. The assessment yielded a tool for setting specimen-access prices... more
A calculation grid developed by an international expert group was tested across biobanks in six countries to evaluate costs for collections of various types of biospecimens. The assessment yielded a tool for setting specimen-access prices that were transparently related to biobank costs, and the tool was applied across three models of collaborative partnership.
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The ataxia telangiectasia (A-T) gene, ATM, predisposes affected homozygotes to a wide range of malignancies. It has been suggested that this is a consequence of the genomic instability associated with the syndrome. The elevated risk of... more
The ataxia telangiectasia (A-T) gene, ATM, predisposes affected homozygotes to a wide range of malignancies. It has been suggested that this is a consequence of the genomic instability associated with the syndrome. The elevated risk of malignancy is not, however, observed among A-T heterozygotes (except, apparently, regarding breast cancer). In this report we describe results from the study of the rare sporadic disease, T cell prolymphocytic leukaemia (T-PLL). In all individuals tested, we observed that at least one ATM allele was disrupted by rearrangement, that in many cases both alleles were disrupted and that there were additional mutations, predominantly missense, that clustered toward the 3' end of the gene corresponding to the protein's phosphatidylinositol 3-kinase (PIK)-related domain. We conclude that the ATM gene can act as a tumour suppressor in the development of sporadic T-PLL. Our finding of a surfeit of mutations within ATM may reflect the involvement of the ...
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In biobank networks, accrual, aggregation, and retrieval of samples and data are impeded if minimal standards are not agreed in advance by the network members. The critical requirement is that outputs be standardized between biobanks. To... more
In biobank networks, accrual, aggregation, and retrieval of samples and data are impeded if minimal standards are not agreed in advance by the network members. The critical requirement is that outputs be standardized between biobanks. To start to address this problem of minimal standards, we undertook a pilot study and now report a follow-up study with 79 centers to identify sources of variability in a common measurement-the estimation of DNA concentration. Our main findings include confirmation of the results of the pilot study on overall variability between centers; fluorescence spectroscopy yields lower estimates of concentration and has less accuracy than absorption spectroscopy; and the 2 technologies differ in their sensitivity to mixing of the samples before measurement. We found that more recent servicing of liquid handling devices contributes to accuracy (at least when deploying absorption spectroscopy). We conclude that, while further study is required, there is a need to promote the development of complete Standard Operating Procedures in academic and commercial laboratories with the implementation of management systems that ensure full adherence to those procedures. There also needs to be a consensus on how much variability in measurements is acceptable for each downstream platform for technologies, including genotyping, sequencing, and epigenetics.
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Research Interests: Genetics, Polymorphism, British, Apoptosis, Nature, and 17 moreCell Division, HUMAN PAPILLOMAVIRUS, Adipose tissue, Humans, Protein Kinases, Female, Polymerase Chain Reaction, Squamous Cell Carcinoma, DNA methylation, Oral Squamous Cell Carcinoma (OSCC), Adult, Cancer cells, Amino Acid Substitution Rates, CpG island, Cancers, Transcription Start Site, and Nucleotides
The UK DNA Banking Network (UDBN) undertakes biobanking for genetic epidemiology research projects. A task assigned to it is the addition of scientific value to the resources under its management. This task is implemented by enabling... more
The UK DNA Banking Network (UDBN) undertakes biobanking for genetic epidemiology research projects. A task assigned to it is the addition of scientific value to the resources under its management. This task is implemented by enabling appropriate access to the resources. We reasoned that access requires not only a fair access policy but also a quality policy implemented via a Quality Management System (QMS). UDBN decided to achieve consistency in sample management by identifying and implementing a suitable QMS with external certification. UDBN selected ISO9001 as a QMS. It was soon recognized that the QMS needed to encompass not only UDBN but also the academic department in which UDBN sits. An external certification body was selected and a post was dedicated to the role of QMS-Management Representative. Specialized software was acquired. A Quality Manual, individual training files and Standard Operating Procedures (SOPs) were prepared. QMS training was provided. These actions led to the approval of the ISO9001:2000 standard. This is the first report of an academic genetic epidemiology research laboratory receiving approval of the ISO9001 standard to validate the consistency of its operations. ISO9001 was selected because of its greater breadth of scope compared with other QMSs. We found that while laboratory protocols are transferable between labs, QMS SOPs are not transferable. This has consequences for efforts to ensure consistency across a biobank network: joint adoption of one multiparty QMS is probably required. We found that it was not possible to implement a QMS for biobanking in isolation: its host university department needed to be included. We have found that ISO9001 helps enable longitudinal accrual of data on the use of biobanking methods. Thus ISO9001 is not only a management tool to improve access to a biobanking research infrastructure but also a research tool for research infrastructure development.
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The UK DNA Banking Network (UDBN) is a secondary biobank: it aggregates and manages resources (samples and data) originated by others. The network comprises, on the one hand, investigator groups led by clinicians each with a distinct... more
The UK DNA Banking Network (UDBN) is a secondary biobank: it aggregates and manages resources (samples and data) originated by others. The network comprises, on the one hand, investigator groups led by clinicians each with a distinct disease specialism and, on the other hand, a research infrastructure to manage samples and data. The infrastructure addresses the problem of providing secure quality-assured accrual, storage, replenishment and distribution capacities for samples and of facilitating access to DNA aliquots and data for new peer-reviewed studies in genetic epidemiology. 'Fair access' principles and practices have been pragmatically developed that, unlike open access policies in this area, are not cumbersome but, rather, are fit for the purpose of expediting new study designs and their implementation. UDBN has so far distributed >60,000 samples for major genotyping studies yielding…
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Research Interests: Adolescent, Humans, Child, Mutation, Female, and 17 moreOncogene, Male, Clinical Sciences, Aged, Middle Aged, Adult, Genetic Recombination, Amino Acid Sequence, Base Sequence, Cell Cycle Proteins, Cell Surface Markers, DNA binding proteins, Immunoglobulin, Ataxia Telangiectasia, Acute Lymphoblastic Leukemia, Somatic Hypermutation, and Molecular Sequence Data
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Research Interests: Biological Sciences, Humans, Sequence alignment, Mutation, Mice, and 12 moreAnimals, Polymerase Chain Reaction, Proteins, Risk factors, Risk Factors, Amino Acid Sequence, Base Sequence, Cell Cycle Proteins, DNA binding proteins, Ataxia Telangiectasia, Protein Biosynthesis, and Molecular Sequence Data
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Anticipation--earlier onset and more severe disease in the offspring generation--is a well documented feature of familial chronic lymphocytic leukaemia (CLL). In a number of Mendelian diseases, anticipation is caused by expansion of... more
Anticipation--earlier onset and more severe disease in the offspring generation--is a well documented feature of familial chronic lymphocytic leukaemia (CLL). In a number of Mendelian diseases, anticipation is caused by expansion of contiguous triplets of nucleotides. The severity of disease expression and penetrance is related to the extent of the triplet expansion. To investigate whether repeat nucleotide repeat expansion is a feature of CLL, the repeat expansion detection (RED) technique was applied to samples from 17 patients with familial disease and 32 patients with early-onset CLL disease. No potentially pathological CAG expansions were detected. We conclude that unstable CAG repeat expansion is not a feature of CLL and that other processes are likely to be involved in generating anticipation in familial forms of the disease.
Research Interests: Leukemia, Humans, Female, Male, Clinical Sciences, and 5 moreAged, Middle Aged, Adult, Age of Onset, and DNA mutational analysis
Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Around 10-15% of individuals with recessively inherited Fanconi anaemia (FA) develop AML. FA is one of a group of recessive syndromes characterized by excessive... more
Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Around 10-15% of individuals with recessively inherited Fanconi anaemia (FA) develop AML. FA is one of a group of recessive syndromes characterized by excessive spontaneous chromosomal breakage in which heterozygote carriers appear to display an increased risk of cancer and there is some indirect evidence that FA carriers may also be at increased risk of AML. This suggests that FA genes may play a role in the development of AML in the wider context. To examine this proposition, further, we have screened samples from 79 AML patients for mutations in the major FA gene, FANCA. No truncating FANCA mutations were detected. One missense mutation previously designated as pathogenic and five novel missense mutations causing non-conservative amino acid substitutions were detected. The data suggests that while FANCA mutations are rare, FANCA mutations may contribute to the development of the disease in a subset of AML.
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... Sir Tatjana Stankovic and colleagues (Jan 2, p 26)1 provide evidence that carriers of ataxia telangiectasia gene (ATM) mutations are at an increased risk of B-cell chronic lymphocytic leukaemia (B-CLL). We have investigated the... more
... Sir Tatjana Stankovic and colleagues (Jan 2, p 26)1 provide evidence that carriers of ataxia telangiectasia gene (ATM) mutations are at an increased risk of B-cell chronic lymphocytic leukaemia (B-CLL). We have investigated the possible role of the ATM gene in CLL by linkage. ...
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Natural killer (NK) activity in peripheral blood mononuclear cells is augmented by products released by two different strains of streptococci. This property is due at least in part to an erythrogenic toxin (ET). A preparation of... more
Natural killer (NK) activity in peripheral blood mononuclear cells is augmented by products released by two different strains of streptococci. This property is due at least in part to an erythrogenic toxin (ET). A preparation of physiologically active ET from strain NY5 group A beta-hemolytic streptococci and streptococcal products (SP) derived from the culture supernatants of ATCC strain 19165 group A streptococci were both potent inducers of NK activity. An anti-serum to ET reacted with two polypeptides in SP, one of which comigrated with ET when analyzed by SDS-PAGE. Using an affinity column with an antiserum to ET known to neutralize its mitogenic properties, the NK-enhancing activity of ET and SP was partly absorbed and was recovered upon elution. These findings suggest that immunologically related ETs in different streptococcal strains play a role in the activation of NK cells. This novel property of streptococci may feature in the pathogenesis of streptococcal infections and their protean manifestations.
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While screening for germline CHK2 mutations in cancer cases by heteroduplex CSGE, we observed that additional PCR fragments were generated from the... more
While screening for germline CHK2 mutations in cancer cases by heteroduplex CSGE, we observed that additional PCR fragments were generated from the 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; end region of the gene that includes exons 11-14. Direct sequencing of these fragments suggested that homologous loci (possibly pseudogenes) were concomitantly being amplified. Searches of public sequence databases showed that a number of areas of the genome show a high degree of homology to exons 10-14 of the CHK2 gene. The presence of these homologous regions means that standard screening methods for detecting mutations in CHK2, based on PCR of genomic DNA, are prone to error. To circumvent this problem, we have developed a strategy, based on long-range PCR, to screen the functional copy of CHK2. Using this approach it is possible to carry out a comprehensive mutational analysis of CHK2 from genomic DNA.
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... Increasing evidence that germline mutations in CHEK2 do not cause Li-Fraumeni syndrome . Nayanta Sodha 1,* ,; Richard S. Houlston 2 ,; Sarah Bullock 2 ,; Martin A. Yuille 3 ,; Carol Chu 4 ,; Gwen Turner 4 ,; Rosalind A. Eeles 1,2.... more
... Increasing evidence that germline mutations in CHEK2 do not cause Li-Fraumeni syndrome . Nayanta Sodha 1,* ,; Richard S. Houlston 2 ,; Sarah Bullock 2 ,; Martin A. Yuille 3 ,; Carol Chu 4 ,; Gwen Turner 4 ,; Rosalind A. Eeles 1,2. ... 1 Royal Marsden NHS Trust, Sutton, Surrey, UK ...