De novo mutations producing unstable Hbs or Hbs M.

Summary Cases of unstable hemoglobin and hemoglobin M disease that have appeared as de novo mutants over a span of approximately 50 years were used in derivingminimal, direct estimates of mutation rates per nucleotide per generation in man. The estimates are based upon analysis of data related to 40 cases of unstable Hbs and 15 of Hbs M that arose in 13 countries. The estimated rate calculated using all de novo -gene mutants is 7.4×10^-9 per nucleotide per generation; that derived using de novo -gene mutants is 10.0×10^-9. Subsequent calculations of mutation rates per - and -chain gene and extrapolation of these rates to a hypothetical gene of 1000 nucleotides yield an estimated mutation rate of 8.6×10^-6 per 1000 nucleotides per generation. Even though some instances of false paternity may have biased these estimates in an upward direction, underreporting of Hb M cases, and particularly of unstable hemoglobins, makes it likely that the cited values are minimal estimates of mutation rates at the molecular level.     

HIPPI: highly accurate protein family classification with ensembles of HMMs

Background

Given a new biological sequence, detecting membership in a known family is a basic step in many bioinformatics analyses, with applications to protein structure and function prediction and metagenomic taxon identification and abundance profiling, among others. Yet family identification of sequences that are distantly related to sequences in public databases or that are fragmentary remains one of the more difficult analytical problems in bioinformatics.

Results

We present a new technique for family identification called HIPPI (Hierarchical Profile Hidden Markov Models for Protein family Identification). HIPPI uses a novel technique to represent a multiple sequence alignment for a given protein family or superfamily by an ensemble of profile hidden Markov models computed using HMMER. An evaluation of HIPPI on the Pfam database shows that HIPPI has better overall precision and recall than blastp, HMMER, and pipelines based on HHsearch, and maintains good accuracy even for fragmentary query sequences and for protein families with low average pairwise sequence identity, both conditions where other methods degrade in accuracy.

Conclusion

HIPPI provides accurate protein family identification and is robust to difficult model conditions. Our results, combined with observations from previous studies, show that ensembles of profile Hidden Markov models can better represent multiple sequence alignments than a single profile Hidden Markov model, and thus can improve downstream analyses for various bioinformatic tasks. Further research is needed to determine the best practices for building the ensemble of profile Hidden Markov models. HIPPI is available on GitHub at https://github.com/smirarab/sepp.

     

Hemoglobin alpha-chain variation in macaques:primary structures of the alpha 1 and alpha II chains from the adult hemoglobins of Malaysian Macaca nemestrina.

The complete primary structures of each of the two α chains commonly found in the adult hemoglobins of Malaysian Macaca nemestrina (pig-tailed macaques) were obtained from the intact chains and five fragments produced by two nonenzymatic and three enzymatic cleavage reactions. The two chains differ at a single site, the α^I chains having a glutaminyl residue and the α^II chains having a histidinyl residue in position 78. Both chains differ from their human counterpart at five positions, the extent of divergence being similar to that observed for most of the α chains from other species of Macaca that have been analyzed to date. Elucidation of the structural difference between the α^I and α^II chains demonstrates that the high degree of heterogeneity observed among the hemoglobin phenotypes of M. nemestrina is a consequence of underlying genetic variability and not a result of postsynthetic modification of genetically identical proteins. Comparisons with the hemoglobin phenotypes found in other species of Macaca support the contention that chromosomes bearing linked α^I and α^II genes, as well as those bearing single α^I and α^II alleles, combine in zygotes to produce the phenotypic variation observed in members of Malaysian populations of M. nemestrina.     

Multiple fetal and adult hemoglobins in Malaysian Macaca nemestrina: consequences of a-chain variation

The hemoglobins of fetal and adult Macaca nemestrina were investigated electrophoretically and chromatographically. Standard electrophoretic techniques failed to reveal variation in either fetal or adult hemoglobins beyond that previously attributed to the presence of the duplicate γ-chain loci characteristic of this species. However, column chromatography of whole hemolysates on CM-Sephadex or of globin chains on CM-cellulose in 8 M urea revealed that some fetuses had four major hemoglobins and some adults had two major hemoglobin components. All animals examined were of Malaysian origin; the variation described is a consequence of variation in α-chain structure in Malaysian populations of this species, and of the interaction of different α chains with the products of the duplicate γ-chain loci.     

Amino acid compositions of the tryptic peptides comprising the beta-hemoglobin chain of Macaca nemestrina

The tryptic peptides comprising the aminoethylated β-hemoglobin chain of Macaca nemestrina were isolated by paper electrophoresis and chromatography. The results of stains for specific amino acids, comparison of peptide maps with those produced by aminoethlated β chains from human hemoglobin A, and amino acid analyses of all peptides in the macaque β chain support the conclusion that the primary structure of the β chain of M. nemestrina is identical to that of the corresponding chains of M. fuscata fuscata and M. fascicularis. The apparent evolutionary conservatism of macaque β chains is discussed in relation to the wide degree of structural variation previously observed among the α-hemoglobin chains of several species of Macaca.