Children's Hospital Oakland Research Institute

About: Children's Hospital Oakland Research Institute is a based out in . It is known for research contribution in the topics: Population & Human leukocyte antigen. The organization has 1568 authors who have published 2480 publications receiving 203418 citations.

Insights into hominid evolution from the gorilla genome sequence

Abstract: Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution.

Hyaluronidases: their genomics, structures, and mechanisms of action.

Abstract: 1.1 Overview of the hyaluronidases The hyaluronidases (Hyals) are classes of enzymes that degrade predominantly hyaluronan (HA). The term “hyaluronidase” is somewhat of a misnomer since they have the limited ability to degrade chondroitin (Ch) and chondroitin sulfates (ChS), albeit at a slower rate. It is a common misconception that the bacterial Hyals have absolute specificity for HA. This is incorrect. Both bacterial 1 and vertebrate enzymes degrade Ch and ChS, albeit at a slower rate. The plausible reason for this broader specificity is that chondroitins preceded HA in evolution. For example, the nematode, Caenorhabditis elegans, contains only Ch and no HA, with only one Hyal-like sequence (unpublished observations). This is most likely a chondroitinase. It is plausible, therefore, that the vertebrate Hyals evolved originally from pre-existing chondroitinases 1. This may explain why Hyals, recognizing their ancestral substrate, retain limited ability to also degrade Ch and ChS. The Hyals from bacteria have been well characterized, and much information is available (for representative publications see 2–5). The Hyals in vertebrate tissues, on the other-hand, have not been studied extensively, however, due to the lack of structural information. Such studies were more difficult and, therefore, more limited. In addition, vertebrate Hyals are present at exceedingly low concentrations. In human serum, e.g., Hyal1 is present at 60 ng/ml 6. They have high specific activities that are unstable during the course of purification, requiring the constant presence of detergents and protease inhibitors for their isolation. Many of such difficulties have been overcome, and a great deal of information is now available, facilitated in part by the Human Genome Project 7. Six Hyal sequences occur in the human genome, constituting a newly recognized family of enzymes. They have similar catalytic mechanisms that contrast markedly with the bacterial Hyals. There is growing interest in these enzymes as their HA substrate is achieving much attention. An outstanding review of the hyaluronidases was published 50 years ago by Karl Meyer, who was also the first to describe the chemical structure of HA 8. Interestingly, a chapter on mucopolysaccharidases, the former name for the hyaluronidases, was included in Volume 1 of Methods in Enzymology 9. The most recent overview of all of the Hyals appeared in 1971 10. Since that time, no comprehensive review has appeared. Karl Meyer classified the Hyals into three distinct classes of enzymes 8, based entirely on the biochemical analyses available at the time. With the advent of sequence and structural data, we can now appreciate how remarkably accurate Karl Meyer’s classification scheme was. No modification of his formulation is necessary. There are three major groups of Hyals, based on their mechanisms of action. Two of the groups are endo-β-N-acetyl-hexosaminidases. One group includes the vertebrate enzymes that utilize substrate hydrolysis 11,12. The second group, which is predominantly bacterial, includes the eliminases that function by β-elimination of the glycosidic linkage with introduction of an unsaturated bond 2–4,13–17. As these enzymes catalyze the breaking of chemical bond by means other than hydrolysis or oxidation, and with the forming a new double bond they are also termed lyases. Both terms, the eliminase (or β-eliminase) and the lyase, are used in the review interchangeably. The third group are the endo-β-glucuronidases. These are found in leeches, which are annelids 18, and in certain crustaceans 19. No sequence data are available, and little is known about this potentially interesting class of enzymes. However, their mechanism of action resembles that of the eukaryotic or vertebrate enzymes more closely than the bacterial enzymes. Sequence data for vertebrate Hyals now provide opportunities to formulate structure-function relationships, to examine probable mechanisms of catalysis, to identify putative substrate binding sites, and to consider the additional non-enzymatic functions of this family of multifunctional enzymes for two of the three groups, for the hydrolase and lyase types of Hyals, respectively 2. Such a review is presented here, documenting some of the common and some of the unusual features that distinguish each of these families of enzymes. The primary objective of this review is to clarify what is known about the structure and mode of action of all the Hyals. Since so little is known of the leech-type of Hyals, the β-endoglucuronidases, the emphasis will, by necessity, be upon two of the three classes of enzymes. Other aspects of these enzymes, such as their physiological activities, their dependence on reaction conditions, their role in cell biology and involvement in metabolism, and their use as reagents or as therapeutics, are not the concern presently. A review of these other aspects of the Hyals will appear separately (Stern and Jedrzejas, in preparation). High levels of HA turnover occur in vertebrate tissues. Tight regulation of catabolism is crucial for modulating steady state levels, important for normal homeostasis, and for embryonic development, wound healing, regeneration, and repair. Under pathological conditions, as in severe stress, shock, septicemia, in burn patients, following major surgery, massive injury, circulating HA levels increases rapidly. HA also increases in association with aggressive malignancies. Determining the mechanism of action of the Hyals is critical for understanding their controls over such a wide range of functions (for reviews, see 20,21).

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk: Analysis of the Type 1 Diabetes Genetics Consortium Families

Abstract: OBJECTIVE— The Type 1 Diabetes Genetics Consortium has collected type 1 diabetic families worldwide for genetic analysis. The major genetic determinants of type 1 diabetes are alleles at the HLA-DRB1 and DQB1 loci, with both susceptible and protective DR-DQ haplotypes present in all human populations. The aim of this study is to estimate the risk conferred by specific DR-DQ haplotypes and genotypes. RESEARCH DESIGN AND METHODS:— Six hundred and seven Caucasian families and 38 Asian families were typed at high resolution for the DRB1, DQA1, and DQB1 loci. The association analysis was performed by comparing the frequency of DR-DQ haplotypes among the chromosomes transmitted to an affected child with the frequency of chromosomes not transmitted to any affected child. RESULTS— A number of susceptible, neutral, and protective DR-DQ haplotypes have been identified, and a statistically significant hierarchy of type 1 diabetes risk has been established. The most susceptible haplotypes are the DRB1\*0301-DQA1\*0501-DQB1*0201 (odds ratio [OR] 3.64) and the DRB1\*0405-DQA1\*0301-DQB1*0302, DRB1\*0401-DQA1\*0301-DQB*0302, and DRB1\*0402-DQA1\*0301-DQB1*0302 haplotypes (ORs 11.37, 8.39, and 3.63), followed by the DRB1\*0404-DQA1\*0301-DQB1*0302 (OR 1.59) and the DRB1\*0801-DQB1\*0401-DQB1*0402 (OR 1.25) haplotypes. The most protective haplotypes are DRB1\*1501-DQA1\*0102-DQB1*0602 (OR 0.03), DRB1\*1401-DQA1\*0101-DQB1*0503 (OR 0.02), and DRB1\*0701-DQA1\*0201-DQB1*0303 (OR 0.02). CONCLUSIONS— Specific combinations of alleles at the DRB1, DQA1, and DQB1 loci determine the extent of haplotypic risk. The comparison of closely related DR-DQ haplotype pairs with different type 1 diabetes risks allowed identification of specific amino acid positions critical in determining disease susceptibility. These data also indicate that the risk associated with specific HLA haplotypes can be influenced by the genotype context and that the trans- complementing heterodimer encoded by DQA1*0501 and DQB1*0302 confers very high risk.

Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel

Abstract: Abstract