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PubMed2021

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.

IMPORTANCE: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome. OBJECTIVE: To examine the results of genetic testing for early-onset AF. DESIGN, SETTING, AND PARTICIPANTS: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021. EXPOSURES: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. MAIN OUTCOMES AND MEASURES: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders. RESULTS: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8). CONCLUSIONS AND RELEVANCE: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.

Adult↗

PubMed2002

Plant defensins.

Plant defensins are small, basic peptides that have a characteristic three-dimensional folding pattern that is stabilized by eight disulfide-linked cysteines. They are termed plant defensins because they are structurally related to defensins found in other types of organism, including humans. To date, sequences of more than 80 different plant defensin genes from different plant species are available. In Arabidopsis thaliana, at least 13 putative plant defensin genes (PDF) are present, encoding 11 different plant defensins. Two additional genes appear to encode plant defensin fusions. Plant defensins inhibit the growth of a broad range of fungi but seem nontoxic to either mammalian or plant cells. Antifungal activity of defensins appears to require specific binding to membrane targets. This review focuses on the classification of plant defensins in general and in Arabidopsis specifically, and on the mode of action of plant defensins against fungal pathogens.

Amino Acid Sequence↗

PubMed2001

Dynamic models of gene expression and classification.

Powerful new methods, like expression profiles using cDNA arrays, have been used to monitor changes in gene expression levels as a result of a variety of metabolic, xenobiotic or pathogenic challenges. This potentially vast quantity of data enables, in principle, the dissection of the complex genetic networks that control the patterns and rhythms of gene expression in the cell. Here we present a general approach to developing dynamic models for analyzing time series of whole genome expression. In this approach, a self-consistent calculation is performed that involves both linear and non-linear response terms for interrelating gene expression levels. This calculation uses singular value decomposition (SVD) not as a statistical tool but as a means of inverting noisy and near-singular matrices. The linear transition matrix that is determined from this calculation can be used to calculate the underlying network reflected in the data. This suggests a direct method of classifying genes according to their place in the resulting network. In addition to providing a means to model such a large multivariate system this approach can be used to reduce the dimensionality of the problem in a rational and consistent way, and suppress the strong noise amplification effects often encountered with expression profile data. Non-linear and higher-order Markov behavior of the network are also determined in this self-consistent method. In data sets from yeast, we calculate the Markov matrix and the gene classes based on the linear-Markov network. These results compare favorably with previously used methods like cluster analysis. Our dynamic method appears to give a broad and general framework for data analysis and modeling of gene expression arrays.

Animals↗

PubMed2006

Psoriatic arthritis: one or more diseases?

Psoriatic arthritis (PsA) is a common, debilitating auto-immune disease with diverse clinical features. In this paper, published evidence is examined, which addresses the issues that (a) PsA exists; and (b) PsA can or cannot be viewed as a distinct rheumatic disease from other spondyloarthritides. Evidence derived from epidemiological, clinical, genetic and immunohistological studies is included. Summarizing the evidence, it is clear that PsA does indeed exist, with the prevalence of rheumatic disease in patients with psoriasis (Ps) higher than would be expected. Certain clinical features also occur more commonly in PsA, although none can differentiate consistently from other arthropathies. Both genetic and immunohistological studies suggest that PsA, both oligo- and polyarticular disease, can be clearly separated from rheumatoid arthritis and that it belongs to the family of spondyloarthritides. The presence of Ps may confer a more severe clinical phenotype with poor radiological outcome. It may be that, with time, a specific genetic marker or diagnostic feature will emerge; additional, more detailed pathogenic studies are required. In the meanwhile, particularly with new treatments being evaluated, it is important to continue to develop specific classification or diagnostic criteria and to define both clinical and laboratory-based outcome measures.

Arthritis, Psoriatic↗

PubMed1996

Presence of Salmonella spp. and Campylobacter spp. in shellfish.

Bivalve molluscs, (cockles, mussels, scallops and oysters) were examined according to EC shellfish bed classification regulations for faecal coliforms, Escherichia coli and salmonella, and for coliforms and campylobacter which are not specified by these regulations. Salmonella serotypes were detected in 8% of 433 molluscs. Seven salmonella isolations (2%) were made from category A beds, nominally suitable for immediate consumption according to E. coli counts. A higher percentage of salmonella isolates (6%) was detected in shellfish which require relaying or depuration prior to eating. In another survey, thermophilic Campylobacter spp. were found in 42% of 380 shellfish. These findings show bed classification on the basis of indicator organisms alone is not sufficient to assure the absence of bacterial, and no doubt viral, pathogens. Depuration and end product specifications which require the absence of salmonellae are an essential part of these regulations. Microbiologists may wish to consider whether tests for pathogens such as salmonella and campylobacter should be included when determining the suitability of shellfish for human consumption.

Campylobacter↗

PubMed1997

Outcomes of single organism peritonitis in peritoneal dialysis: gram negatives versus gram positives in the Network 9 Peritonitis Study.

The use of the "peritonitis rate" in the management of patients undergoing peritoneal dialysis is assuming importance in comparing the prowess of facilities, care givers and new innovations. For this to be a meaningful outcome measure, the type of infection (causative pathogen) must have less clinical significance than the number of infections during a time interval. The natural history of Staphylococcus aureus, pseudomonas, and fungal peritonitis would not support that the outcome of an episode of peritonitis is independent of the causative pathogen. Could this concern be extended to other more frequently occurring pathogens? To address this, the Network 9 Peritonitis Study identified 530 episodes of single organism peritonitis caused by a gram positive organism and 136 episodes caused by a single non-pseudomonal gram negative (NPGN) pathogen. Coincidental soft tissue infections (exit site or tunnel) occurred equally in both groups. Outcomes of peritonitis were analyzed by organism classification and by presence or absence of a soft tissue infection. NPGN peritonitis was associated with significantly more frequent catheter loss, hospitalization, and technique failure and was less likely to resolve regardless of the presence or absence of a soft tissue infection. Hospitalization and death tended to occur more frequently with enterococcal peritonitis than with other gram positive peritonitis. The outcomes in the NPGN peritonitis group were significantly worse (resolution, catheter loss, hospitalization, technique failure) compared to coagulase negative staphylococcal or S. aureus peritonitis, regardless of the presence or absence of a coincidental soft tissue infection. Furthermore, for the first time, the poor outcomes of gram negative peritonitis are shown to be independent of pseudomonas or polymicrobial involvement or soft tissue infections. The gram negative organism appears to be the important factor. In addition, the outcome of peritonitis caused by S. aureus is worse than that of other staphylococci. Thus, it is clear that all peritonitis episodes cannot be considered equivalent in terms of outcome. The concept of peritonitis rate is only meaningful when specific organisms are considered.

Aged↗

PubMed2005

Influence of feeding ratio and size on susceptibility to microsporidial gill disease caused by Loma salmonae in rainbow trout, Oncorhynchus mykiss (Walbaum).

Two trials were designed to quantify the effect of feeding ratio and fish size on the cohabitation transmission of Loma salmonae, the causative agent of microsporidial gill disease (MGD) in salmonids, Oncorhynchus spp. To evaluate the effect of feeding ratio on disease onset, groups of 45 rainbow trout, O. mykiss (Walbaum) (RBT), were fed daily at 1% (low), 2% (medium) or 4% (high) of the fish biomass in the tank. There were three tanks at each feeding level: two tanks were exposed to the pathogen and one was a control. For the second objective, 300 RBT were separated into seven tanks so that the weight classifications were small (17-23 g), medium (32-38 g) and large (57-63 g). Each size class was done in duplicate with one control tank containing medium-sized fish. Separately for each trial, on day 0 post-exposure (PE) five highly infectious RBT were added to each tank (not including the control tanks) to begin the cohabitation exposure period. Beginning on day 21 PE and continuing biweekly until days 70 and 77 PE for the feeding and fish size trials, respectively, each fish was evaluated for visible branchial xenomas to determine disease onset time. Using survival analysis, the survival curves for the low, medium and high feedings were not significantly different from each other. However, there were significant differences amongst the small, medium and large weight classes in the size trial. The median numbers of days to the development of branchial xenomas was 31, 38 and 42 for small, medium and large size fish, respectively. On any given day, a medium or large sized fish had a hazard ratio for developing branchial xenomas of 0.66 and 0.63, respectively, compared with a small fish. In addition to host species and host strain differences, fish size is now considered a host risk factor for the development of MGD.

Animal Nutritional Physiological Phenomena↗

PubMed1980

Biochemical aspects of immune complex formation and immune complex diseases.

Formation of immune complexes is a normal part of the immune defence against soluble antigens. Immune complexes may nevertheless play a pathogenic role of their own. The present review discusses antigen antibody interactions with special regard to immune complex formation. A new classification of antigen antibody interactions is proposed, based on the antigenic valence. Oligovalent antigens and bivalent antibodies form genuine immune complexes. Experimental observations and theoretical considerations indicate that although a vast variety of complexes is possible genuine immune complex formation is a self-limiting process, so it is typical that the smallest possible complexes are formed in the largest amounts. Formation of immune complexes differs in mechanism from most other biological ligand binding reactions, and the extent to which immune complex formation follows its own laws is discussed. To explain the mechanism of precipitin reactions, a two-stage model is proposed. The outcome of antigen antibody interactions is further complicated because antibody preparations are typically heterogeneous, and the impact of antibody heterogeneity is also discussed.

Animals↗

PubMed2005

Multiple genetically distinct groups revealed among clinical isolates identified as atypical Aspergillus fumigatus.

To investigate whether genetic variants of A. fumigatus are found among clinical isolates, four isolates that were originally identified as poorly sporulating strains of Aspergillus fumigatus were subjected to molecular analysis. DNA sequence analysis of the alkaline protease genes of these isolates showed that each is genetically distinct and each shows substantial variation (7 to 11%) from the A. fumigatus nucleotide sequence. Subsequent morphological examination suggested that all of the isolates could be classified as Aspergillus viridinutans. To clarify the taxonomic status of these four clinical isolates and of two previously identified as atypical A. fumigatus isolates, partial beta-tubulin and 18S rRNA gene sequences were determined. Each of the six atypical strains had a unique beta-tubulin sequence, whereas the sequences of three standard isolates of A. fumigatus, which were included as controls, were identical to the published A. fumigatus beta-tubulin sequence. The very low level of DNA sequence variation detected in standard isolates of A. fumigatus compared with other isolates from members of Aspergillus section Fumigati suggests that it may be a relatively recently evolved species. The 18S rRNA gene of two of the atypical isolates differed from that of A. fumigatus at a single nucleotide position. Phylogenetic analyses do not support the classification of all of these isolates as A. viridinutans. Thus, some of these isolates represent new species which are potential opportunistic pathogens.

Animals↗

PubMed2006

Thermophilic-anaerobic digestion to produce class A biosolids: initial full-scale studies at Hyperion Treatment Plant.

The highest quality of biosolids is called exceptional quality. To qualify for this classification, biosolids must comply with three criteria: (1) metal concentrations, (2) vector-attraction reduction, and (3) the Class A pathogen-density requirements. The City of Los Angeles Bureau of Sanitation Hyperion Treatment Plant (HTP) (Playa del Rey, California) meets the first two requirements. Thus, the objective of this study was to ensure that HTP's biosolids production would meet the Class A pathogen-reduction requirements following the time-temperature regimen for batch processing (U.S. EPA, 1993; Subsection 32, Alternative 1). Because regulations require the pathogen limits to be met at the last point of plant control, biosolids sampling was not limited to immediately after the digesters, i.e., the digester outflows. The sampling extended to several locations in HTP's postdigestion train, in particular, the last points of plant control, i.e., the truck loading facility and the farm for land application. A two-stage, thermophilic-continuous-batch process, consisting of a battery of six egg-shaped digesters, was established in late 2001 for phase I of this study and modified in early 2002 for phase II. As the biosolids were discharged from the second-stage digesters, the Salmonella sp. (pathogen) and fecal-coliform (indicator) densities were well below the limits for Class A biosolids, even though the second-stage-digester temperatures were a few degrees below the temperature required by Alternative 1. Salmonella sp. densities remained below the Class A limit at all postdigestion sampling locations. Fecal-coliform densities were also below the Class A limit at postdigestion-sampling locations, except the truck-loading facility (phases I and II) and the farm for final use of the biosolids (phase II). Although federal regulations require one of the limits for either fecal coliforms or Salmonella sp. to be met, local regulations in Kern County, California, where the biosolids are land-applied, require compliance with both bacterial limits. Additional work identified dewatering, cooling of biosolids after the dewatering centrifuges, and contamination as possible factors in the rise in density of fecal coliforms. These results provided the basis for the full conversion of HTP to the Los Angeles continuous-batch, thermophilic-anaerobic-digestion process. During later phases of testing, this process was demonstrated to produce fully disinfected biosolids at the farm for land application.

Anaerobiosis↗

PubMed1990

[Immunochemical differences in the surface polysaccharides obtained from Entamoeba histolytica strain HM1:IMSS and its virulent (C-A) and non-virulent (L-6) clones].

There probably exist many different surface molecular polysaccharides with different compositions of their constituent sugars, in the different zymodemes. This fact might have a repercussion upon the resistance to the lysis of the complement. Seeking to prove this hypothesis, the ideal would be to obtain polysaccharide molecules of type LPFG of pathogenic and non-pathogenic zymodemes, demonstrating that there is a difference in the chemical composition of their polysaccharides. If this were true, a serologic classification, of the different zymodemes, would be possible in a fashion similar to gram-negative bacteria. Our results suggest the existence of structural differences between the polysaccharides of a virulent clone (C-A) and a non-virulent one (L-6).

Animals↗

PubMed1994

Acute gastroenteritis in Latin America.

In Latin America, acute gastroenteritis remains to be an important cause of morbidity in adults and a major cause of morbidity and mortality in children. A child under 5 years of age belonging to a low income segment of the Latin American population will develop 5 to 10 bouts of diarrhea every year. The bacterial and viral enteropathogens associated with acute diarrhea are reviewed in this article. Updated information on epidemiologic, clinical, and pathogenic aspects for the relevant enteropathogens is discussed with special emphasis on regional data when available. The current diarrheogenic E. coli classification is particularly discussed. A diagnostic approach to acute gastroenteritis for both the clinical and research laboratories in Latin America as well as guidelines for treatment are proposed.

Acute Disease↗

PubMed2003

Classification of Brucella strains isolated from marine mammals by infrequent restriction site-PCR and development of specific PCR identification tests.

Brucella strains have been isolated since the 1990s from a wide variety of marine mammals and represent potential zoonotic pathogens. They have distinctive phenotypic and molecular characteristics from the terrestrial mammal Brucella species, and two new species names have been previously proposed based on DNA polymorphism at the omp2 locus and their preferential host, i.e. Brucella cetaceae for cetacean isolates and Brucella pinnipediae for pinniped isolates. The results presented in this study on characterization of these strains by infrequent restriction site-PCR (IRS-PCR), taking into account the higher number of IS711 elements in their genome compared to terrestrial mammal Brucella species, supports this classification. The nucleotide sequences of specific DNA fragments detected by IRS-PCR were determined and used to develop PCR identification tests for either B. cetaceae or B. pinnipediae.

Animals↗

PubMed2004

Microtechnique for identification of lactic acid bacteria.

Certain gut species are pathogens, but a number of other resident bacteria may be of some benefit to host health. Examples include enterococci, lactobacilli, propionibacteria, and bifidobacteria, which are present in the colon in significant numbers. Identification and classification are not identical. A group can be identified only after it has been classified, based on a pattern of properties shown by all the members of the group that other groups do not possess. The properties used in identification are often different from those used in classification. Biochemical, nutritional, and physiological characterization tests (usually carried out in bottles and tubes of solid and liquid media and on plates) have been developed and modified since the earliest days of bacteriology. Generally, the characteristics chosen for an identification plan should be easily determinable, whereas those used for classification (such as DNA homology) may be quite difficult to determine. Genera and species identification might not be based on only a few tests, but rather on the pattern given by a whole battery of tests. The members of the family Lactobacillaceae represent one example of this. Some probiotic strains can be selected for their benefical properties as active antimicrobial agents against pathogenic microorganisms, hydrophobic ability, presence of substances with a capacity for adherence to epithelium, and so on. After isolation, identification is an important step before selecting probiotic strains. These identifications can be facilitated through microtechniques. To alleviate the need to inoculate large numbers of tubes with media (conventional test), some rapid multitest systems have been devised and are commercially available (such as the API or Biolog systems). Although they are expensive for large studies and not always sufficiently versatile, these kits do offer the advantages of convenience, miniaturization, rapidity, and, above all, strict standardization. Other methods such as ribotyping or randomly amplified polymorphic DNA do not take into account the phenotypic characteristics (biotyping). In this chapter, we describe a simple, rapid, and economical microplates technique to identify lactic acid bacteria and enterobacteria based on general metabolic characteristics, adapted for routine study of a large number of strains.

Bacteriological Techniques↗

PubMed2000

Comparative genomic hybridization: uses and limitations.

Comparative genomic hybridization (CGH) has contributed significantly to the current knowledge of genomic alterations in hematologic malignancies. Characteristic patterns of genomic imbalances not only have confirmed recent classification schemes in non-Hodgkin's lymphoma, but they provide a basis for the successful identification of genes with previously unrecognized pathogenic roles in the development of different lymphomas. Based on its technical limitations, there is little reason to apply CGH to chromosomes of metaphase cells in routine diagnostic settings. However, the new approach of CGH to DNA microarrays, a procedure termed matrix-CGH, overcomes most of the limitations and opens new approaches for diagnostics and identification of genetically defined leukemia and lymphoma subgroups. Current efforts to develop leukemia specific matrix-CGH DNA chips, which are designed to meet the clinical needs, are presented and discussed.

Hematologic Neoplasms↗

PubMed1997

Systematics of gastrointestinal nematodes of domestic ruminants: advances between 1992 and 1995 and proposals for future research.

The systematics of trichostrongyloid nematodes of ruminants provides a foundation for diagnostics and responds to the need to identify eggs in feces, free-living larvae from pastures or fecal cultures and larval or adult nematodes collected from hosts. These needs are associated with diagnostic problems or research projects. Difficulties in identifying all developmental stages of trichostrongyloid nematodes of domestic ruminants still severely limit the effective diagnosis and control of these parasites. Phylogenetic hypotheses as the basis for predictive classifications have been developed only for the subfamilies of the Trichostrongylidae. This report briefly describes recent progress in the development of improved tools for identification, phylogenetic analyses and predictive classifications. It also describes future research needed on the identification and classification of trichostrongyloid nematode parasites of domestic ruminants. Nematodes included are species of the super-family Trichostrongyloidea known to be important pathogens of domestic ruminants. The information summarized is presented by nematode developmental stage and by taxonomic groups. Eggs: While eggs of some trichostrongyloid nematode parasites of ruminants can be readily identified to their genus (Nematodirus), and some to species (e.g. Nematodirus battus), most of the important pathogens (including the Ostertagiinae and Haemonchinae) cannot be identified morphologically or morphometrically even to family level. However, DNA technology has been developed for determining not only the presence of specific pathogens in eggs from fecal samples, but also for estimating the percentage of the total eggs that each pathogen comprises. This new method will make possible a rapid determination of which individual animals in a herd should be treated. Larvae: The most commonly-used method for identifying infective larvae is time-consuming (several weeks), unreliable for estimating intensities of individual species as components of mixed populations and requires highly trained specialists. Available identification keys for larvae are not well illustrated and need to be augmented. Adults: Recent advances in the identification of adult trichostrongyloids and their systematics are organized by taxonomic group. Genera included are Ostertagia, Haemonchus, Cooperia, Trichostrongylus and Nematodirus. Recently, the first phylogenetic analysis of the Trichostrongylidae family established monophyly for the family. A similar analysis of the Molineidae is needed. Ostertagia: Several studies of polymorphism summarized the phenomenon and listed 19 polymorphic species in five genera. Two studies of DNA differences within and among polymorphic species of Ostertagiinae supported earlier hypotheses that the species pairs represent polymorphic species. A phylogenetic analysis of the Ostertagiinae and generic concepts are needed. Haemonchus: A key to three species of Haemonchus provides, for the first time, morphological characteristics for the microscopical identification to species of individual adult nematodes of either sex. The Food and Drug Administration is now requiring that results of drug trials include identification of Haemonchus to species. Cooperia: Studies using random amplified polymorphic DNA methods showed a high degree of variation within and among C. oncophora/C. surnabada, but supported a polymorphic relationship for the species pair. A phylogenetic analysis of the Cooperiinae is needed. Trichostrongylus: Restriction Fragment Length Polymorphisms (RFLPs) of genomic DNA of two strains of T. colubriformis indicated a high degree of intra- and inter-strain DNA polymorphism. However, other studies demonstrated expected species level differences between T. colubriformis and T. vitrinus using Random Amplified Polymorphic DNA (RAPD) methods. Sequences of the second Internal Transcribed Spacer Region (ITS-2) ribosomal repeat showed sequence differences of 1.3-7.6% among five

Animals↗

PubMed2001

Biopersistence of synthetic mineral fibers as a predictor of chronic inhalation toxicity in rats.

In December 1997 the European Commission (EC) adopted Directive 97/69/EC (O.J. L 343/19 of 13 December 1997) in which criteria were established for the classification and labeling of synthetic mineral fibers. This directive was derived based upon an extensive program evaluating current scientific knowledge on fiber pathogenicity and its relationship to the biopersistence of long fibers. Within this context, the biopersistence of fibers longer than 20 microm was found to be a good predictor of the lung burden and early pathological changes in chronic inhalation studies with fibers as well as of the tumor response in chronic intraperitoneal studies with fibers. The analysis that provided the scientific basis for the relationship of biopersistence to the chronic inhalation results is presented in detail. Proportional odds regression techniques were used to determine the relationship between both inhalation and intratracheal instillation biopersistence clearance half-times and the collagen deposition at the broncho-alveolar junction as determined following 24 mo in chronic inhalation toxicity studies. The results indicate all the indicators of biopersistence considered are equally good predictors of the early long-term change that occurs in the lung in response to more durable fibers. This change, the collagen deposition at the broncho-alveolar junction, is a precursor of interstitial fibrosis, which has been shown to be associated with tumor response in fiber-exposed animals. The results show that the clearance half-times set in the EC directive are within the baseline for this parameter.

Administration, Inhalation↗

PubMed2000

Phylogenetic network of the mtDNA haplogroup U in Northern Finland based on sequence analysis of the complete coding region by conformation-sensitive gel electrophoresis.

Mutations in mtDNA have accumulated sequentially, and maternal lineages have diverged to form population-specific genotypes. Classification of the genotypes has been made based on differences found in restriction fragment analysis of the coding region or in the sequence of the hypervariable segment I. Both methods have shortcomings, as the former may not detect all the important polymorphisms and the latter makes use of a segment containing hypervariable nucleotide positions. Here, we have used conformation-sensitive gel electrophoresis (CSGE) to detect polymorphisms within the coding region of mtDNA from 22 Finns belonging to haplogroup U. Sixty-three overlapping PCR fragments covering the entire coding region were analyzed by CSGE, and the fragments that differed in their migration pattern were sequenced. CSGE proved to be a sensitive and specific method for identifying mtDNA substitutions. The phylogenetic network of the 22 coding-region sequences constituted a perfect tree, free of homoplasy, and provided several previously unidentified common polymorphisms characterizing subgroups of U. After contrasting this data with that of hypervariable segment I, we concluded that position 16192 seems to be prone to recurrent mutations and that position 16270 has experienced a back mutation. Interestingly, all 22 samples were found to belong to subcluster U5, suggesting that this subcluster is more frequent in Finns than in other European populations. Complete sequence data of the mtDNA yield a more reliable phylogenetic network and a more accurate classification of the haplogroups than previous ones. In medical genetics, such networks may help to decide between a rare polymorphism and a pathogenic mutation; in population genetics, the networks may enable more detailed analyses of population history and mtDNA evolution.

Codon↗