Linkage between late onset,dominant spinocerebellar ataxia and HLA

Summary Three families with at least three generations of family members affected with spino-cerebellar ataxia transmitted in a dominant fashion were studied. In each family every available member, above the lowest age at onset observed in that family, was subject to a thorough clinical investigation and blood was sampled for HLA,A,B and C-typing. In all three families the affected members had signs which were characteristic for cerebellar ataxia, without spasticity or dementia. In two families the mean age at onset was in accordance with the literature, viz. in the fourth and fifth decade, while in the third family mean age at onset was over 50 years. In the two pedigrees with the usual age at onset there was evidence of linkage between the disease and the HLA-system with a combined lod score of 1.499 at a recombination fraction of 0.05 for males. The third pedigree gave negative lod scores for linkage between HLA and the disease locus for both males and females but in this family also the high age at onset was indicative of genetic heterogeneity.     

Biogeography of Mesozoic leptosporangiate ferns related to extant ferns

The paleobiogeography of the extant leptosporangiate fern families present in the Mesozoic is reviewed based mainly on data from megafossils that possess enough characters to be assigned to a family. Times of first appearances are discussed for each family, followed by their distribution throughout the Mesozoic. Paleolatitudes and climatic conditions indicate that first appearances of many fern families occur about or above 30° and in conditions of higher moisture. Much of fern distribution in the past was likely due to long-distance dispersal.     

中国单轴霉分类的研究——Ⅰ.寄生在唇形科和苋科植物上的新种

本文描述了单轴霉属(Plasmopara)霜霉菌的二个新种。它们是:寄生于唇形科植物香薷(Elsholtzia ciliata(Thunb.)Hyland)上的香薷单轴霉(Plasmopara elsholtziae spnov.)及苋科植物牛膝(Achyranthes bidentata Bl.)上的牛膝单轴霉(Plasmopara achyranthis sp. nov.)。牛膝单轴霉是本属真菌寄生于苋科植物的首次记录。上述二新种都有拉丁文及汉文描述,还分别讨论了新种与其同科或不同科寄主上的近似种之间的区别。     

The matK gene: sequence variation and application in plant systematics

Although the matK gene has been used in addressing systematic questions in four families, its potential application to plant systematics above the family level has not been investigated. This paper examines the rates, patterns, and types of nucleotide substitutions in the gene and addresses its utility in constructing phylogenies above the family level. Eleven complete sequences from the GenBank representing seed plants and liverworts and nine partial sequences generated for genera representing the monocot families Poaceae, Joinvilleaceae, Cyperaceae, and Smilacaceae were analyzed. The study underscored the high rate of substitution in the gene and the presence of mutationally conserved sectors. The use of different sectors of the gene and the cumulative inclusion of informative sites showed that the 3' region was most useful in resolving phylogeny, and that the topology and robustness of the tree reached a plateau after the inclusion of 100 informative sites from that region for the taxa used. The impact of using partial sequencing on sample size is addressed. The presence of a relatively conserved 3' region and the less conserved 5' region provides two sets of characters that can be used at different taxonomic levels from the tribal to the division levels.     

Membrane topology prediction by hydropathy profile alignment: membrane topology of the Na(+)-glutamate transporter GltS

Structural classification of families of membrane proteins by bioinformatics techniques has become a critical aspect of membrane protein research. We have proposed hydropathy profile alignment to identify structural homology between families of membrane proteins. Here, we demonstrate experimentally that two families of secondary transporters, the ESS and 2HCT families, indeed share similar folds. Members of the two families show highly similar hydropathy profiles but cannot be shown to be homologous by sequence similarity. A structural model was predicted for the ESS family transporters based upon an existing model of the 2HCT family transporters. In the model, the transporters fold into two domains containing five transmembrane segments and a reentrant or pore-loop each. The two pore-loops enter the membrane embedded part of the proteins from opposite sides of the membrane. The model was verified by accessibility studies of cysteine residues in single-Cys mutants of the Na+-glutamate transporter GltS of Escherichia coli, a member of the ESS family. Cysteine residues positioned in predicted periplasmic loops were accessible from the periplasm by a bulky, membrane-impermeable thiol reagent, while cysteine residues in cytoplasmic loops were not. Furthermore, two cysteine residues in the predicted pore-loop entering the membrane from the cytoplasmic side were shown to be accessible for small, membrane-impermeable thiol reagents from the periplasm, as was demonstrated before for the Na+-citrate transporter CitS of Klebsiella pneumoniae, a member of the 2HCT family. The data strongly suggests that GltS of the ESS family and CitS of the 2HCT family share the same fold as was predicted by comparing the averaged hydropathy profiles of the two families.     

Isolation and characterization of two families of satellite DNA with repetitive units of 135 bp and 2.5 kb in the ant Monomorium subopacum (Hymenoptera, Formicidae)

Analyzing the satellite DNA in the ant species Monomorium subopacum we found two unrelated families of satellite DNA. Because these satellite DNA families were isolated using the two enzymes HaeIII and EcoRI we called the two families HaeIII and EcoRI family, respectively. The HaeIII family proved to be organized in a 135-bp basic unit repeat, the EcoRI family in a 2.5-kb basic unit repeat. The latter represents perhaps the longest satellite DNA isolated up to now in insects. The HaeIII family apparently comprises about 10% of the total genomic DNA whereas the EcoRI family represents only about 1-2%. A comparative analysis of the two satellite DNA sequences showed no homology between the two families although both sequences possessed long A and T stretches. Eight of the 34 chromosomes showed hybridization with the HaeIII family and hybridization signals are visible in six chromosomes with the EcoRI family. Analysis of the electrophoretic mobility of satellite DNA on non-denaturing polyacrylamide showed that the HaeIII family is only slightly curved. However, the unit of the EcoRI satellite DNA family has curvature, especially the first 1000 bp of the monomeric repeat, in which this DNA is AT rich and has numerous A and T stretches. There are also internal inverted subrepeats in each family. The sequences of satellite DNA families found in Monomorium subopacum are different from the sequences of other satellite DNAs cloned in insects, including other species of ants.     

Integration of related sequences with protein three-dimensional structural families in an updated version of PALI database

The database of Phylogeny and ALIgnment of homologous protein structures (PALI) contains three-dimensional (3-D) structure-dependent sequence alignments as well as structure-based phylogenetic trees of protein domains in various families. The latest updated version (Release 2.1) comprises of 844 families of homologous proteins involving 3863 protein domain structures with each of these families having at least two members. Each member in a family has been structurally aligned with every other member in the same family using two proteins at a time. In addition, an alignment of multiple structures has also been performed using all the members in a family. Every family with at least three members is associated with two dendrograms, one based on a structural dissimilarity metric and the other based on similarity of topologically equivalenced residues for every pairwise alignment. Apart from these multi-member families, there are 817 single member families in the updated version of PALI. A new feature in the current release of PALI is the integration, with 3-D structural families, of sequences of homologues from the sequence databases. Alignments between homologous proteins of known 3-D structure and those without an experimentally derived structure are also provided for every family in the enhanced version of PALI. The database with several web interfaced utilities can be accessed at: http://pauling.mbu.iisc.ernet.in/~pali.     

Recognizing very distant sequence relationships among proteins by family profile analysis.

Family profile analysis (FPA), described in this paper, compares all available homologous amino acid sequences of a target family with the profile of a probe family while conventional sequence profile analysis (Gribskov M, Lüthy R, Eisenberg D. Meth Enzymol 1990;183:146-159) considers only a single target sequence in comparison with the probe family. The increased input of sequence information in FPA expands the range for sequence-based recognition of structural relationships. In the FPA algorithm, Zscores of each of the target sequences, obtained from a probe profile search over all known amino acid sequences, are averaged and then compared with the scores for sequences of 100 reference families in the same probe family search. The resulting F-Zscore of the target family, expressed in "effective standard deviations" of the mean Zscores of the reference families, with value above a threshold of 3.5 indicates a statistically significant evolutionary relationship between the target and probe families. The sensitivity of FPA to sequence information was tested with several protein families where distant relationships have been verified from known tertiary protein architectures, which included vitamin B6-dependent enzymes, (beta/alpha)8-barrel proteins, beta-trefoil proteins, and globins. In comparison to other methods, FPA proved to be significantly more sensitive, finding numerous new homologies. The FPA technique is not only useful to test a suspected relationship between probe and target families but also identifies possible target families in profile searches over all known primary structures.     

Sequence of archaealMethanococcus jannaschii α-amylase contains features of families 13 and 57 of glycosyl hydrolases: A trace of their common ancestor?

Two sequentially different, seemingly unrelated α-amylase families exist, known as family-13 and family-57 glycosyl hydrolases. Despite the common enzyme activity, it has as yet been impossible to detect any sequence similarity between the two families. The detailed analysis of the recently determined sequence of the α-amylase from methanogenic archaeonMethanococcus jannaschii using the sensitiveHydrophobic Cluster Analysis method revealed that this α-amylase contains features of both families of α-amylases. Thus theM. jannaschii α-amylase is similar to thePyrococcus furiosus α-amylase from family 57 while it obviously contains most of the sequence fingerprints characteristic for α-amylase family 13. Importantly, a glutamic acid residue equivalent with the family-13 catalytic glutamate positioned in the β5-strand segment was identified in members of family 57. The results presented in this report indicate that the two families, 13 and 57, are either the products of a very distant common ancestor or have evolved from each other, although at present they can represent two different α-amylase families with evolved different catalytic mechanisms, catalytic machinery and folds.     

Oxidation of amines by flavoproteins

Many flavoproteins catalyze the oxidation of primary and secondary amines, with the transfer of a hydride equivalent from a carbon-nitrogen bond to the flavin cofactor. Most of these amine oxidases can be classified into two structural families, the D-amino acid oxidase/sarcosine oxidase family and the monoamine oxidase family. This review discusses the present understanding of the mechanisms of amine and amino acid oxidation by flavoproteins, focusing on these two structural families.     

Mapping and analysis of quantitative trait loci for grain oil content and agronomic traits using AFLP and SSR in sunflower ( Helianthus annuus L.)

Crosses were made between two inbred lines of sunflower. Parents and 118 F(3) families were planted in the field in a randomized complete block design in two replications. Genetic control for some agronomical traits: grain weight by plant (GWP), 1,000-grain weight (TGW), percentage of oil in grain (POG) and sowing to flowering date (STF) was investigated in F(3) families and their parents. Genetic variability was observed among the 118 F(3) families for all the traits studied. Genetic gain was obtained when the best F(3) family, or the mean of 10% of the selected families was compared with the best parent for GWP, TWG and POG. Heritability was 0.23 for GWP, 0.55 for TGW, 0.57 for POG and 0.32 for STF. A set of 244 F(3) families from the same cross, including the above 118 mentioned families and their two parents, were screened with 276 AFLP and microsatellite markers and a linkage map was constructed based on 170 markers. Two putative QTLs for the GWP trait ( gmp), one QTL for TGW ( tgw), six QTLs for POG ( pog) and two for STF ( stf) were detected. The percentage of phenotypic variance explained by each QTL ranged from 2.6% to 70.9%. The percentage of total phenotypic variance explained was 50.7% for GWP, 5.4% for TGW, 90.4% for POG and 89.3% for STF. Although these regions need to be more-precisely mapped, the information obtained should help in marker-assisted selection.     

Eleven MRL-lpr/lpr anti-DNA autoantibodies are encoded by genes from four VH gene families: a potentially biased usage of VH genes

The genes encoding 11 independently derived anti-DNA autoantibodies from the lupus-prone mouse strain, MRL-lpr/lpr, were examined with VH, D, and JH gene probes. These autoantibodies do not define new VH gene families, since all of the autoantibodies were encoded by VH genes from four of the nine known gene families. A minimum of nine different VH genes encoded this panel of 11 anti-DNA autoantibodies. These results are consistent with the stochastic use of the VH gene repertoire and the expression of multiple VH genes. However, the data is also consistent with a biased usage of the VH gene repertoire. First, two pairs of autoantibodies, one from the J558 family and one from the 7183 family, appear to express identical or closely related VH genes as determined by the position of two restriction enzyme sites 5' of the expressed VH genes. In addition, three autoantibodies that appear to be sister clones might define a third VH gene that is used repeatedly. Secondly, about 45% of the panel is encoded by the Q52 and 7183 families, which are the 3' most families. These families have been shown to be preferentially rearranged early in B cell ontogeny. This suggests that some anti-DNA autoantibodies might originate from a population of B cells that predominate early in ontogeny. An alternative hypothesis is that the potential bias in VH gene and gene family usage could be due to antigen selection. All four JH genes are expressed, although the JH1 gene appears to be underutilized in both expressed and unexpressed rearrangements. Two members of the panel that bind double-stranded DNA were encoded by two different VH gene families, the S107 family and the J558 family.     

Clinical and molecular studies in two families with Fraser syndrome: a new FRAS1 gene mutation, prenatal ultrasound findings and implications for genetic counselling

Fraser syndrome is a rare autosomal recessive genetic disorder characterized by cryptophthalmus, variable expression of cutaneous syndactyly of fingers and toes, genital ambiguity and renal agenesis/dysgenesis. We present here molecular and clinical findings of four fetuses with FS from two families. Molecular genetic studies in the two families revealed mutations in FRAS1 gene allowing better genetic counselling and subsequent prenatal diagnosis in one of the two families. In family one, a nonsense mutation (c.3730C>T, p.R1244X) previously described in a Polish patient was found. In family two a novel nonsense mutation previously not known was detected (c.370C>T, p.R124X). PGD is planned for family 1.     

Mapping of bovine ovulation rate QTL; an analytical approach for three generation pedigrees

Interval mapping was conducted for ovulation rate quantitative trait loci (QTL) using data from two related families from the United States Department of Agriculture, US Meat Animal Research Center twinning cattle herd. Both families are extended, three generation pedigrees from which records of sons, daughters and granddaughters were analysed. Both a method of analysis and results from that analysis are reported herein. Results from one of the two families (839802) were previously reported, but reanalysis here including the second, related family (839803) and a revised statistical model lessens support for the previously reported QTL. Results from interval mapping provided evidence for QTL in regions corresponding to those previously suggested for chromosomes 7 (chromosome-wise P < 0.05) and 19 (chromosome-wise P < 0.01) in the 839802 family, although statistical significance was reduced. In contrast to the previous report, evidence for a chromosome 5 QTL in the same family was greatly reduced while support for a QTL on chromosome 10 increased (chromosome-wise P < 0.01). Analysis of data from the related 839803 family failed to replicate evidence of QTL observed on either chromosome 7 or chromosome 19 in the 839802 family.     

Presence of large deletions in kindreds with autism

Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb. In one family, a deletion at marker D7S630 was complex, with two segments deleted (37 kb and 18 kb) and two retained (2,836 bp and 38 bp). Three families had deletions at D7S517, with each family having a different deletion (96 kb, 183 kb, and >69 kb). Another three families had deletions at D8S264, again with each family having a different deletion, ranging in size from <5.9 kb to >260 kb. At a fourth marker, D8S272, a 192-kb deletion was found in five families. Unrelated subjects and additional families without autism were screened for deletions at these four sites. Families screened included 40 families from Centre d'Etude du Polymorphisme Humaine and 28 families affected with learning disabilities. Unrelated samples were 299 elderly control subjects, 121 younger control subjects, and 248 subjects with Alzheimer disease. The deletion allele at D8S272 was found in all populations screened. For the other three sites, no additional deletions were identified in any of the groups without autism. Thus, these deletions appear to be specific to autism kindreds and are potential autism-susceptibility alleles. An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis.     

A new family of tandem repetitive early histone genes in the sea urchin Lytechinus pictus: evidence for concerted evolution within tandem arrays.

We have isolated and characterized a third nonallelic tandemly arrayed histone cluster (LpE) from the sea urchin Lytechinus pictus. Although this tandem array is not intermingled with the other two early histone gene families also found in the L. pictus genome, the order and polarity of the five histone coding sequences in this family are the same as every other well characterized sea urchin early histone gene family. Heteroduplex analysis and restriction endonuclease mapping experiments indicate that the LpE family is more closely related to the B-C than the A-D family of early histone genes. Examination of several individual sperm DNA samples has revealed considerable polymorphism in each of the three tandem repeat families. Within an individual, however, each family is remarkably homogeneous. Thus, our results indicate that rapid fixation of variants acts to homogenize the members of a single tandem array at a considerably faster rate within a family than between families. However, at least some exchange of sequences between families is evident based on the conservation of many restriction endonuclease recognition sites and from analysis of a a cosmid clone in which the A-D and E tandem repeats are found adjacent to one another. These differences in the rate of fixation of variants within and between these families are likely to be responsible for the maintenance of diversity between the different families.     

Phylogenetic relationships among families of Gadiformes (Teleostei, Paracanthopterygii) based on nuclear and mitochondrial data

Phylogenetic hypotheses among Gadiformes fishes at the suborder, family, and subfamily levels are controversial. To address this problem, we analyze nuclear and mitochondrial DNA (mtDNA) sequences for the most extensive taxonomic sampling compiled to date, representing all of the recognized families and subfamilies in the order (except the monotypic family Lyconidae). Our study sampled 117 species from 46 genera, comprising around 20% of the species described for the order (more than 60% of all genera in the order) and produced 2740 bp of DNA sequence data for each species. Our analysis was successful in confirming the monophyly of Gadiformes and most of the proposed families for the order, but alternative hypotheses of sister-group relationships among families were poorly resolved. Our results are consistent with dividing Gadiformes into 12 families in three suborders, Muraenolepidoidei, Macrouroidei, and Gadoidei. Muraenolepidoidei contains the single family Muraenolepididae. The suborder Macrouroidei includes at least three families: Macrouridae, Macruronidae and Steindachneriidae. Macrouridae is deeply divided into two well-supported subfamilies: Macrourinae and Bathygadinae, suggesting that Bathygadinae may be ranked at the family level. The suborder Gadoidei includes the families: Merlucciidae, Melanonidae, Euclichthyidae, Gadidae, Ranicipitidae, and Bregmacerotidae. Additionally, Trachyrincinae could be ranked at family level including two subfamilies: Trachyrincinae and Macrouroidinae within Gadoidei. Further taxonomic sampling and sequencing efforts are needed in order to corroborate these relationships.     

Germ-line mosaicism in tuberous sclerosis: how common?

Two-thirds of cases of tuberous sclerosis complex (TSC) are sporadic and usually are attributed to new mutations, but unaffected parents sometimes have more than one affected child. We sought to determine how many of these cases represent germ-line mosaicism, as has been reported for other genetic diseases. In our sample of 120 families with TSC, 7 families had two affected children and clinically unaffected parents. These families were tested for mutations in the TSC1 and TSC2 genes, by Southern blotting and by single-strand conformational analysis. Unique variants were detected in six families. Each variant was present and identical in both affected children of a family but was absent in both parents and the unaffected siblings. Sequencing of the variants yielded two frameshift mutations, one missense mutation, and two nonsense mutations in TSC2 and one nonsense mutation in TSC1. To determine which parent contributed the affected gametes, the families were analyzed for linkage to TSC1 and TSC2, by construction of haplotypes with markers flanking the two genes. Linkage analysis and loss-of-heterozygosity studies indicated maternal origin in three families, paternal origin in one family, and either being possible in two families. To evaluate the possibility of low-level somatic mosaicism for TSC, DNA from lymphocytes of members of the six families were tested by allele-specific PCR. In all the families, the mutant allele was detected only in the known affected individuals. We conclude that germ-line mosaicism was present in five families with mutations in the TSC2 gene and in one family with the causative mutation in the TSC1 gene. The results have implications for genetic counseling of families with seemingly sporadic TSC.     

Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer.

Seven families, selected for breast cancer segregation, have been analyzed for chromosome 17q12-q23 linkage to breast and ovarian cancer. In two of them, linkage is seen with most markers tested, increasing toward the most proximal region, but without informative recombinations above NM23. In the remaining families, no linkage is observed. Families with 17q linkage are not easily distinguished by clinical characteristics such as early onset (mean age at diagnosis < or = 45 years) or organs involved. In fact, the family with the highest lod scores (> or = 2.3) belongs to the "later onset" (> 45 years) category of families. Interestingly, prostatic cancer is the most frequent malignancy, after breast cancer, in the families that we studied (13 cases total, all metastasizing) and is especially prevalent in males presumed to carry the trait. Of 16 paternal carriers, 7 (44%) had developed prostatic cancer. Haplotype analysis in families with 17q linkage reveals two further prostatic cases as potential carriers. We propose that breast cancer genes may predispose to prostatic cancer in male carriers.