SCL/TAL1 in Hematopoiesis and Cellular Reprogramming.

SCL, a transcription factor of the basic helix-loop-helix family, is a master regulator of hematopoiesis. Scl specifies lateral plate mesoderm to a hematopoietic fate and establishes boundaries by inhibiting the cardiac lineage. A combinatorial interaction between Scl and Vegfa/Flk1 sets in motion the first wave of primitive hematopoiesis. Subsequently, definitive hematopoietic stem cells (HSCs) emerge from the embryo proper via an endothelial-to-hematopoietic transition controlled by Runx1, acting with Scl and Gata2. Past this stage, Scl in steady state HSCs is redundant with Lyl1, a highly homologous factor. However, Scl is haploinsufficient in stress response, when a rare subpopulation of HSCs with very long term repopulating capacity is called into action. SCL activates transcription by recruiting a core complex on DNA that necessarily includes E2A/HEB, GATA1-3, LIM-only proteins LMO1/2, LDB1, and an extended complex comprising ETO2, RUNX1, ERG, or FLI1. These interactions confer multifunctionality to a complex that can control cell proliferation in erythroid progenitors or commitment to terminal differentiation through variations in single component. Ectopic SCL and LMO1/2 expression in immature thymocytes activates of a stem cell gene network and reprogram cells with a finite lifespan into self-renewing preleukemic stem cells (pre-LSCs), an initiating event in T-cell acute lymphoblastic leukemias. Interestingly, fate conversion of fibroblasts to hematoendothelial cells requires not only Scl and Lmo2 but also Gata2, Runx1, and Erg, indicating a necessary collaboration between these transcription factors for hematopoietic reprogramming. Nonetheless, full reprogramming into self-renewing multipotent HSCs may require additional factors and most likely, a permissive microenvironment.

Evaluation and presentation of forensic DNA evidence in European laboratories.

The first part of this article describes Bayes' theorem and its practical application to scientific evidence. Secondly, statements proposed by European DNA laboratories are presented, analysed and commented upon. Finally, the authors reiterate their proposal of adopting a likelihood ratio framework justified by the usefulness of the approach in practical context of DNA cases. Note that this framework underlines the main questions the experts have to answer at trial: to what degree does the evidence support the prosecutor's hypothesis? and to what degree does the evidence support the defence's hypothesis?

Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families.

The BRCA2 8765delAG mutation was previously reported in hereditary breast cancer families of French Canadian and Yemenite Jewish descent. Haplotype analysis, using six microsatellite markers that span BRCA2 and two intragenic polymorphisms, was performed on 8765delAG mutation carriers to determine if there was evidence that the mutations were identical by descent. The alleles of the microsatellite markers most closely flanking BRCA2 (D13S1697 and D13S1701) were found to be identical in state in all the mutation carriers. However, the disease-associated allele of one of the intragenic markers differed between the Yemenite Jews and French Canadian families, indicating that the 8765delAG mutation has independent origins in these two geographically and ethnically distinct populations.

Founder BRCA1 and BRCA2 mutations in early-onset French Canadian breast cancer cases unselected for family history.

Recently, founder BRCA1 and BRCA2 mutations were identified in Canadian breast cancer and breast-ovarian cancer families of French ancestry. The presence of a breast cancer case diagnosed at younger than 36 years of age was strongly predictive of the presence of any founder mutation screened. Here we report the occurrence of founder BRCA1 and BRCA2 mutations in a series of 61 French Canadian women with invasive breast cancer diagnosed at age 40 or younger, unselected for family history of breast and ovarian cancer. Germline mutations in BRCA1 (n = 4) and BRCA2 (n = 4) were identified in 8 of 61 (13%) cases. All BRCA1 mutations were found in invasive ductal carcinomas, the most common histologic type of tumor in this series. In contrast, the BRCA2 mutations were found in tumors of various histologic types: two ductal carcinomas, a tumor containing both ductal and lobular histologic types and an invasive lobular carcinoma. Of the 37 women with at least one first-, second- or third-degree relative with breast or ovarian cancer and the 24 women with no history of these cancers, 7 (19%) and 1 (4%), respectively, were mutation carriers. The seven mutation carriers with a family history of cancer had at least one first-, second- or third-degree relative with a breast cancer diagnosis at less than 51 years of age. The identification of founder BRCA1 and BRCA2 mutations in young-onset breast cancer cases unselected for family history can facilitate carrier detection when the expected yield of a comprehensive screen may be low.

The impact of the principles of evidence interpretation on the structure and content of statements.

The Forensic Science Service (FSS) has devoted appreciable effort to developing the application of the principles of evidence interpretation. Much of the work has been reported in previous papers in this journal, in particular those that develop a model for Case Assessment and Interpretation (CAI). The principles of interpretation are restated and the implications for structure and content of statements are described.

Genetic differentiation within and between four UK ethnic groups.

In previous papers [L.A. Foreman, J.A. Lambert, I.W. Evett, Regional genetic variation in Caucasians, Forensic Sci. Int. 95 (1998) 27-37; L.A. Foreman, Analyses to investigate appropriate measures of differentiation between European Caucasian populations using short tandem repeat (STR) data, FSS Research Report FSS-RR-804 (1999)], we have carried out detailed investigations of the level of regional and national variation in STR characteristics exhibited within white Caucasian populations. The studies described here extend our earlier work to the black African/Caribbean and Asian (Indo-Pakistani) populations of the UK, routinely considered in casework calculations at the Forensic Science Service (FSS). In addition, estimation of allele distributions and database comparisons are carried out for two further populations, i.e. those classified as containing individuals of Oriental and Arabic appearance.

More on the hierarchy of propositions: exploring the distinction between explanations and propositions.

Interpretation of the weight of scientific evidence depends upon the framing of at least two competing propositions to weigh against each other. It is the stage of framing propositions that is the most difficult aspect of evidence interpretation. The logical structure for case assessment and interpretation has been described by the authors in three previous papers [Cook R, et al. A model for case assessment and interpretation. Science & Justice 1998; 38: 151-156. Cook R, et al. A hierarchy of propositions: deciding which level to address in casework. Science & Justice 1998; 38: 231-239. Cook R, et al. Case pre-assessment and review in a two-way transfer case. Science & Justice 1999; 39: 103-111]. This paper considers the framing of propositions in greater detail, in particular the intermediate stage of exploring less formal explanations. All of the discussion is based on experiences encountered in workshops with caseworking forensic scientists.

A model for case assessment and interpretation.

The authors describe a new approach to decision-making in an operational forensic science organization based on a model, embodying the principles of Bayesian inference, which has been developed through workshops run within the Forensic Science Service for forensic science practitioners. Issues which arise from the idea of pre-assessment of cases are explored by means of a case example.

Regional genetic variation in Caucasians.

When evaluating DNA evidence, the necessary calculations are often carried out using databases drawn from broad populations; for example, the Forensic Science Service (FSS) maintains genetic databases for the 3 major racial groups of England and Wales--Caucasian, Afro-Caribbean and Asian (from the Indian subcontinent). The resulting figures may be challenged in court on the premise that they are not based on data from the population of most relevance in the particular case under consideration. One important factor might be the location of the crime. Since the recent establishment of a National DNA Intelligence Database, data have been made available from a wide range of geographical regions in England and Wales. This paper gives details of analyses conducted to measure the differentiation between white caucasian populations from these regions and from other areas of the UK and abroad using a Bayesian approach.

Using a tree diagram to interpret a mixed DNA profile.

A recent case is described where the evidence of bloodstaining on a knife suggested that it was a mixture from the two victims. Interpretation of the evidence in this problem necessitated the formulation of several sets of multiple hypotheses which were analyzed by means of a tree diagram. The problem was then greatly simplified to one of comparing the two alternative hypotheses of most interest. It was found that results were robust to variation in the expert's judgment regarding the possibility that a mixture of blood was present on the knife.

Taking account of peak areas when interpreting mixed DNA profiles.

This paper establishes a logical framework for taking account of peak areas when interpreting mixed DNA STR profiles. The principles apply wherever such data are available but they are illustrated here by means of data which have been collected from made up mixtures of known concentrations analyzed at short tandem repeat loci. The data have led to some modeling assumptions which are used for numerical examples. In actual casework the proportions of the various components will not be known and there is a discussion of whether they should be allowed for by integrating over a prior distribution. This is a conceptual paper, rather than a prescription for casework, and the scope for further work is outlined.

Statistical analysis of data for three British ethnic groups from a new STR multiplex.

Data have been collected from 602 Caucasians, 190 Afro-Caribbeans and 257 Asians of Indo/Pakistani descent who have been profiled using a new six locus short tandem repeat (STR) multiplex. The data have been analysed by conventional significance testing methods: the exact test, homozygosity, and conventional goodness of fit to Hardy-Weinberg proportions. Frequency tables are given and the expected performance in British forensic casework is discussed.

Statistical analysis of data for three British ethnic groups from a new STR multiplex

Data have been collected from 602 Caucasians, 190 Afro-Caribbeans and 257 Asians of Indo/Pakistani descent who have been profiled using a new six locus short tandem repeat (STR) multiplex. The data have been analysed by conventional significance testing methods: the exact test, homozygosity, and conventional goodness of fit to Hardy-Weinberg proportions. Frequency tables are given and the expected performance in British forensic casework is discussed.(AU)

A study of independence between STR and conventional blood type loci.

Blood samples from approximately 200 Scottish Caucasian individuals were typed at conventional loci (PGM, Gc and EAP) and also with a four locus STR multiplex. Tests of the data are described which demonstrate that the assumptions of between locus independence are robust for use in forensic casework.

Validation of a frequency database for four STR loci for use in casework in the Strathclyde Police Forensic Science Laboratory.

Data for four STR loci have been collected from 400 samples taken from complainers and suspects encountered in casework at the Strathclyde Police Forensic Science Laboratory (SPFSL). This paper describes statistical testing which demonstrates that its use will provide operationally robust procedures. Comparisons made with data collected from other British samples confirmed no practical differences between the different frequency distributions. This work provides further confirmation of the reliability of the so-called "product rule' in estimating the frequency of multilocus genotypes in British forensic casework.

Statistical analysis of a large file of data from STR profiles of British Caucasians to support forensic casework.

Data from nearly 2500 British Caucasians, profiled using an STR quadruplex, have been analysed. The data came from several laboratories and represent samples from different geographical distributions. Analysis of the combined files shows that previous reports of failed independence tests were the results of sampling effects. A further convincing proof is given of the robustness of the statistical methods used to estimate evidential value in casework. Comparisons between different samples show that regional effects between Scotland and the South of England have no importance from the forensic viewpoint.

Large scale database experiments to assess the significance of matching DNA profiles.

Over 5,700 three-probe VNTR DNA profiles collected by several United Kingdom (UK) laboratories have been compared to examine the probability of randomly matching 2 samples from different individuals. In over 16 million comparisons, using a matching rule corresponding to the matching guideline employed by the UK Forensic Science Service, no profiles were found to match at the 3 loci D1S7 (MS1), D7S21(MS31) and D12S11 (MS43a). The frequency of occurrence of a set of Caucasian profiles have been estimated with 6 reference databases. The results show that there were greater differences in the frequency estimates when using a database of Afro-Caribbean or Asian profiles, rather than a different Caucasian database. The results further demonstrate the power and robustness of the VNTR DNA profiling technique for forensic casework.

Inhibition of theophylline metabolism by interferon.

1 day after a single intramuscular injection of recombinant human interferon alpha A in 5 patients with stable chronic active hepatitis B and 4 healthy controls theophylline clearance was significantly reduced and theophylline elimination half-life was significantly increased. There was a clear relation between pre-treatment and post-treatment theophylline clearance rates, indicating that the greatest effect of interferon was in subjects who were fast metabolisers of theophylline. These observations support the contention that the actions of endogenous interferon may account for the effects of immunisations and viral infections on hepatic drug metabolism. Moreover, treatment with interferon may cause clinically important drug interactions.