Fellow travellers: a concordance of colonization patterns between mice and men in the North Atlantic region.

BACKGROUND: House mice (Mus musculus) are commensals of humans and therefore their phylogeography can reflect human colonization and settlement patterns. Previous studies have linked the distribution of house mouse mitochondrial (mt) DNA clades to areas formerly occupied by the Norwegian Vikings in Norway and the British Isles. Norwegian Viking activity also extended further westwards in the North Atlantic with the settlement of Iceland, short-lived colonies in Greenland and a fleeting colony in Newfoundland in 1000 AD. Here we investigate whether house mouse mtDNA sequences reflect human history in these other regions as well. RESULTS: House mice samples from Iceland, whether from archaeological Viking Age material or from modern-day specimens, had an identical mtDNA haplotype to the clade previously linked with Norwegian Vikings. From mtDNA and microsatellite data, the modern-day Icelandic mice also share the low genetic diversity shown by their human hosts on Iceland. Viking Age mice from Greenland had an mtDNA haplotype deriving from the Icelandic haplotype, but the modern-day Greenlandic mice belong to an entirely different mtDNA clade. We found no genetic association between modern Newfoundland mice and the Icelandic/ancient Greenlandic mice (no ancient Newfoundland mice were available). The modern day Icelandic and Newfoundland mice belong to the subspecies M. m. domesticus, the Greenlandic mice to M. m. musculus. CONCLUSIONS: In the North Atlantic region, human settlement history over a thousand years is reflected remarkably by the mtDNA phylogeny of house mice. In Iceland, the mtDNA data show the arrival and continuity of the house mouse population to the present day, while in Greenland the data suggest the arrival, subsequent extinction and recolonization of house mice--in both places mirroring the history of the European human host populations. If house mice arrived in Newfoundland with the Viking settlers at all, then, like the humans, their presence was also fleeting and left no genetic trace. The continuity of mtDNA haplotype in Iceland over 1000 years illustrates that mtDNA can retain the signature of the ancestral house mouse founders. We also show that, in terms of genetic variability, house mouse populations may also track their host human populations.

The mouse major histocompatibility complex: some assembly required.

We have assembled a contig of 81 yeast artificial chromosome clones that spans 8 Mb and contains the entire major histocompatibility complex (Mhc) from mouse strain C57BL/6 (H2b), and we are in the process of assembling an Mhc contig of bacterial artificial chromosome (BAC) clones from strain 129 (H2bc), which differs from C57BL/6 in the H2-Q and H2-T regions. The current BAC contig extends from Tapasin to D17Leh89 with gaps in the class II, H2-Q, and distal H2-M regions. Only four BAC clones were required to link the class I genes of the H2-Q and H2-T regions, and no new class I gene was found in the previous gap. The proximal 1 Mb of the H2-M region has been analyzed in detail and is ready for sequencing; it includes 21 class I genes or fragments, at least 14 olfactory receptor-like genes, and a number of non-class I genes that clearly establish a conserved synteny with the class I regions of the human and rat Mhc.

Mhc class I and non-class I gene organization in the proximal H2-M region of the mouse.

A bacterial artificial chromosome (BAC) contig was constructed across the proximal part of the H2-M region from the major histocompatibility complex (Mhc) of mouse strain 129 (H2bc). The contig is composed of 28 clones that span approximately 1 megabasepair (Mb), from H2-T1 to Mog, and contains three H2-T genes and 18 H2-M genes. We report the fine mapping of the H2-M class I gene cluster, which includes the previously reported M4-M6, the M1 family, the M10 family, and four additional class I genes. All but two of the H2-M class I genes are conserved among haplotypes H2k, H2b, and H2bc, and only two genes are found in polymorphic HindIII fragments. Six evolutionarily conserved non-class I genes were mapped to a 180 kilobase interval in the distal part of the class I region in mouse, and their order Znf173-Rfb30-Tctex5-Tctex6- Tctex4-Mog was found conserved between human and mouse. In this Znf173-Mog interval, three mouse class I genes, M6, M4, and M5, which are conserved among haplotypes, occupy the same map position as the human HLA-A class I cluster, which varies among haplotypes and is diverged in sequence from the mouse genes. These results further support the view that class I gene diverge and evolve independently between species.

Mitochondrial DNA rearrangements associated with mF plasmid integration and plasmodial longevity in Physarum polycephalum.

Plasmodial cultures of Physarum polycephalum have defined life spans and undergo a reproducible decline (senescence) before losing the ability to be subcultured. Studies of the mtDNA of a long-lived Physarum strain, which does not undergo senescence, revealed a 7. 9-kb insertion in its mtDNA. This insertion is derived from a mitochondrial plasmid which enhances mitochondrial fusion and mtDNA recombination. Four different recombination events are required to convert the parental mtDNA to the form found in the long-lived strain. An additional recombination event, which deletes a 2.4-kb region of the insert from the long-lived strain, has been identified in the mtDNA of a normally senescing strain. These observations imply a mitochondrial involvement in the process of plasmodial senescence and implicate a region of the DNA derived from the mitochondrial plasmid as being necessary for plasmodial longevity.

BAC clones and STS markers near the distal breakpoint of the fourth t-inversion, In(17)4d, in the H2-M region on mouse chromosome 17.

The H2-M region is the most distal part of the mouse major histocompatibility complex (Mhc) and is likely to include the distal breakpoint of the fourth t-inversion, In(17)4d. The conserved synteny breakpoint between mouse and human is located in the H2-M region between D17Leh89, a putative olfactory receptor gene, and Pgk2 (phosphoglycerate kinase 2). To analyze the H2-M region, we screened a mouse bacterial artificial chromosome (BAC) library, using the D17Mit64, D17Tu49, D17Leh89, D17Leh467, and Pgk2 markers. Thirty-eight BAC clones were obtained and mapped in five clusters, and 25 sequence-tagged site (STS) markers were newly developed. The regions surrounding D17Tu49 and D17Leh467 are abundant in L1 repeat sequences and may, therefore, be candidates for the breakpoints of conserved synteny and t-inversion. D17Leh89 was linked to D17Mit64 by two contiguous BAC clones. The Aeg1 (acidic epididymal glycoprotein 1) and Aeg2 genes were mapped close to Pgk2, on the same BAC clones. The genetic length between D17Leh89-D17Mit64 and Pgk2-Aeg can be estimated as 0.5-0.7 centiMorgan (cM), and the most distal class I gene, H2-M2, can be placed 0.3-1.0 cM proximal to the t-inversion breakpoint. A recombinational hotspot is suggested to be located between Aeg and Tpxl in an interspecific cross of (C57BL/6J x Mus spretus).

BAC/YAC contigs from the H2-M region of mouse Chr 17 define gene order as Znf173-Tctex5-mog-D17Tu42-M3-M2.

A yeast artificial chromosome (YAC) contig from the C57BL/6 (H2(b)) mouse was created from the major histocompatibility complex (Mhc, H2 in mouse) class Ib subregion, H2-M. It spans approximately 1.2 megabase (Mb) pairs and unites the previous >1.5-Mb YAC contigs (Jones et al. 1995) into a single contig, which includes 21 Mhc class I genes distal to H2-T1. A bacterial artificial chromosome (BAC) contig from the 129 (H2(bc)) mouse, spanning approximately 600 kilobases, was also built from Znf173 (Afp, a gene for acid finger protein), through Tctex5 (t-complex testis expressed-5) and Mog (myelin oligodendrocyte glycoprotein), to H2-M2. Twenty-four sequence-tagged site (STS) markers were newly developed, and 35 markers were mapped in the YAC/BAC contigs, which define the marker order as Cen - Znf173 - Tctex5 - Mog - D17Tu42 - D17Mit232 - H2-M3 - D17Leh525 - H2-M2 - Tel. The gene order of Znf173 - Tctex5 - Mog - D17Tu42 is conserved between mouse and human, showing that the middle H2-M region corresponds to the subregion of the human Mhc surrounding HLA-A.

Characterization of two class I genes from the H2-M region: evidence for a new subfamily.

We cloned, sequenced, and mapped two divergent major histocompatibility class Ib genes from BALB/c mice. M9d and M10d both have the potential to encode full-length class I molecules, but transcripts were not readily detectable. M9 is 86% similar to M1 in its nucleotide sequence and maps next to it on YAC clones. M9 is only 64% similar to M10 and 60% to H2-K k. Probes from M10 define a new subfamily of eight class I genes in C3H mice; five cluster directly distal to H2-T1, and three are located between M9-1-7-8 and M6-4-5 in the H2-M region.

Genomic evolution of the distal Mhc class I region on mouse Chr 17.

A 5-Mb YAC contig, partly supplemented with BAC contigs, was created from the distal Mhc class I region on mouse Chr 17. The gene order of Znf173-Tctex5-Mog-D17Tu42-D17Leh 89 is conserved between mouse and human but not the physical distance, supporting the independent expansion of Mhc class I genes in the so-called accordion model of Mhc evolution. The distal H2-M region includes the breakpoint of conserved synteny between mouse and human as well as the In(17)4 t-inversion. The H2-M region is rich in L1 repeats, implying that the insertion of L1 repeats may be associated with the evolutionary flexibility to break a chromosome.

H2-M3, a full-service class Ib histocompatibility antigen.

H2-M3 is an MHC class Ib molecule of the mouse with a unique preference for N-formylated peptides, which may come from the N-termini of endogenous, mitochondrial proteins or foreign, bacterial proteins. The crystal structure of M3 revealed a hydrophobic peptide-binding groove with an occluded A pocket and the peptide shifted one residue relative to class Ia structures. The formyl group is held by a novel hydrogen bonding network, involving His9 on the bottom of the groove, and the side chain of the P1 methionine is lodged in the B pocket. M3 is a full-service histocompatibility (H) antigen, i.e. self-M3 can present endogenous peptides as minor H antigens and foreign, bacterial antigens in a defensive immune response to infection; and foreign M3 complexed with endogenous self-peptides.

MHC class I gene organization in > 1.5-Mb YAC contigs from the H2-M region.

Sixteen yeast artificial chromosome (YAC) clones have been mapped to the H2-M region at the distal end of the mouse major histocompatibility complex (MHC) on chromosome 17. Analysis of the YACs with single- and multicopy probes yielded a proximal contig spanning a minimum of 800 kb and a distal contig of 700 kb. A probe for the conserved fourth exon of MHC class I genes detected 19 restriction fragments, including 6 of the 8 previously characterized H2-M class I genes, in the proximal contig. This contig spans the gap from the M to the T region and includes the T1 gene. By contrast, only two class I genes, M2 and M3, were found in the distal contig. These two genes, which are both expressed, may mark the end of the MHC. The order among nine class I genes and seven other markers was determined in the cloned DNA from the centromere as T1, Tu32A, (M1-M7-M8), Tu32B, B30, M6, M4, M5, Mog, Tu42A parallel M2, Leh525, M3, Tu42B, where the orientation with respect to the centromere is unknown for M1-M7-M8.

Physical mapping of the human and mouse MOG gene at the distal end of the MHC class Ib region.

Myelin/oligodendrocyte glycoprotein (MOG) is expressed specifically in the central nervous system (CNS) by myelinating glial cells, the oligodendrocytes. The external location of MOG on myelin sheaths and its late expression during myelinogenesis argue for a role of MOG in the completion of myelin and maintenance of its integrity. MOG is a target autoantigen in demyelinating diseases, such as experimental autoimmune encephalomyelitis (EAE) in animals and multiple sclerosis (MS) in humans. We previously located the gene encoding MOG to the major histocompatibility complex (MHC), both in human, by cytogenetics, and in mouse, by analysis of recombinants. To refine the position, we have now selected yeast artificial chromosome clones (YAC) which contain the MOG gene. Physical mapping of the human MOG and the mouse Mog genes by characterization of these YAC clones indicated that the gene is located at the distal end of the major histocompatibility complex (MHC) class Ib region in both species. The human MOG gene lies 60 kilobases (kb) telomeric to HLA-F in a head-to-head orientation; the mouse Mog gene lies 25 (kb) telomeric to H2-M5 in a tail-to-head orientation. These orthologous genes provide markers for comparative analysis of the evolution of the MHC in the two species. The physical mapping of MOG should facilitate analysis of its role in hereditary neurological diseases, and the YAC clones identified here will permit the identification of new genes in the region.

Mitochondrial DNA of Physarum polycephalum: physical mapping, cloning and transcription mapping.

Mitochondrial DNA (mtDNA) has been isolated from four strains of Physarum polycephalum and a restriction site map has been determined using nine restriction enzymes. The restriction site maps of the four strains are similar but each strain is distinguished by insertions, deletions and restriction enzyme site polymorphisms. The sum of the restriction fragments gives mitochondrial genome sizes which vary from about 56 kb to 62 kb. In all four strains the composite map of the restriction enzyme sites for the mtDNA is circular. Knowledge of the restriction enzyme map has enabled cloning of mtDNA fragments representing the entire mtDNA of strain M3. The cloned fragments have been used to create a transcription map of the mtDNA.

Pancreatic somatostatinoma: presentation with recurrent episodes of severe hyperglycaemia and ketoacidosis.

A 47-year-old woman was admitted on four occasions over a four-year period with severe hyperglycaemia associated with marked ketoacidosis. She had weight loss with hepatomegaly and ultrasonography indicated a pancreatic tumour which was shown to be a somatostatinoma. Resection resulted in prolonged survival. The biochemical and morphological features of this rare tumour are presented, and an explanation for the unusual presentation of a somatostatinoma with episodes of ketoacidosis is given.

Major lower intestinal haemorrhage. Angiographic localisation and current management.

Thirty-four patients with major lower intestinal bleeding underwent emergency selective mesenteric angiography during a 6-year period. Angiography identified a bleeding site in 16 patients (47%). Diverticulosis, found in 22 patients (65%), and angiodysplasia, found in 4 (12%), were the most common causes of major colonic bleeding and originated more frequently from the right colon. Eight patients (24%) bled from less common sources. Radiological control of bleeding was unreliable with a significant complication rate. Fourteen of 16 patients with positive angiograms and 6 of 18 patients with negative angiograms required surgery for persistent major bleeding. Angiographic localisation of colonic bleeding allowed limited resection in 9 of 11 patients with control of haemorrhage in 8 (89%). Fourteen of 34 patients were managed non-operatively; of these 2 had minor recurrent bleeding. The overall mortality rate was 29%, the operative mortality rate 40% and the non-operative mortality rate 14%. A rational diagnostic approach is presented, emphasising the role of selective mesenteric angiography in the management and surgical strategy of major lower intestinal bleeding.

Non-invasive assessment of lower limb ischaemia by blood velocity wave-form analysis.

Clinical examination combined with angiography is conventionally used to assess lower limb arterial disease. The shape of the blood velocity wave form in the common femoral artery varies with the extent of proximal arterial disease, suggesting that wave-form analysis may provide additional haemodynamic information of potential value in surgical decision-making. This paper studies the use of two methods of wave-form analysis, pulsatility index and Laplace transform analysis, to assess lower limb arterial disease. The blood velocity wave form was measured non-invasively at the common femoral artery using a locally developed mean frequency processor and a commercial 9.5 MHz bidirectional Doppler ultrasound unit. Wave forms from 70 limbs (35 patients) with suspected atherosclerotic arterial disease and from 20 normal limbs with no history or signs of disease were studied. Both methods of wave-form analysis provided a statistically significant separation between patients with severe and moderate disease as assessed angiographically (P less than 0.001). These results suggest that significant aorto-iliac disease can be virtually excluded by a normal common femoral wave form. Furthermore, wave-form analysis may have an important role in the follow-up of patients after bypass grafting or iliac angioplasty and in the detection of presymptomatic aorto-iliac disease.

Giant hepatic hemangiomas: diagnostic and therapeutic dilemmas.

This report describes four cases of surgically treated giant hepatic hemangiomas which illustrate some diagnostic and therapeutic difficulties encountered in the management of this condition. An important diagnostic triad has emerged, which should alert the physician to the possibility of a complicated hepatic hemangioma: the clinical signs of an acute inflammatory liver process contrasted with a normal white blood cell count and liver function tests. Hemangiomas of the left lobe were either missed or poorly demonstrated on selective hepatic angiographic examination, and in two patients the diagnosis was made only at the time of laparotomy. Hepatic resection was successfully performed in all patients; there was minimal morbidity and none of the patients died. In two patients with multiple hemangiomas, only symptomatic or easily resectable lesions were removed. All patients are alive and well; three have been followed up for more than 5 years. We conclude that resection in asymptomatic cases should be carried out only in those cases that require a diagnostic laparotomy and in those where the lesion is easily resectable. The majority of patients with symptomatic and complicated tumors should undergo resection, but even in these patients continued conservative treatment is appropriate when the risk of major resection outweighs the small risk of live-threatening bleeding.

Primary sclerosing cholangitis: biliary drainage and duct dilatation.

A further extension of the U-tube technique is described in the treatment of six patients with primary sclerosing cholangitis who developed progressive jaundice and recurrent biliary sepsis. All six patients had operative intrahepatic duct dilatation and U-tube placement. Three patients in addition had a Roux-en-Y hepaticojejunal anastomosis. Five patients are improved and are well after a median follow-up period of 56 months. Two patients have had the U-tube removed electively. Three patients with progressive disease required further percutaneous catheter dilatation of intrahepatic strictures via the U-tube tract. Application of the technique permits evaluation of the biliary system by tube cholangiography and provides access in complex cases for repeated therapeutic intrahepatic stricture dilatation.