Erroneous communication between the innate and adaptive immune systems through cytokines results in exaggerated or attenuated immune response. It is not known whether the pathologic immune response in inflammatory bowel disease has its origin in a dysbalance of pro- and anti-inflammatory cytokine release or whether it is secondary in subsequence of a defective intestinal barrier or the destructive power of aggressive microbiota in the gut lumen.

Cytokines in inflammatory bowel disease

Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.

/pdf/the-dna-sequence-of-human-chromosome-22-1sz455fnn8.pdf

The DNA sequence of human chromosome 22

The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease.

Gene map of the extended human MHC

Long-read, single-molecule real-time (SMRT) sequencing is routinely used to finish microbial genomes, but available assembly methods have not scaled well to larger genomes. We introduce the MinHash Alignment Process (MHAP) for overlapping noisy, long reads using probabilistic, locality-sensitive hashing. Integrating MHAP with the Celera Assembler enabled reference-grade de novo assemblies of Saccharomyces cerevisiae, Arabidopsis thaliana, Drosophila melanogaster and a human hydatidiform mole cell line (CHM1) from SMRT sequencing. The resulting assemblies are highly continuous, include fully resolved chromosome arms and close persistent gaps in these reference genomes. Our assembly of D. melanogaster revealed previously unknown heterochromatic and telomeric transition sequences, and we assembled low-complexity sequences from CHM1 that fill gaps in the human GRCh38 reference. Using MHAP and the Celera Assembler, single-molecule sequencing can produce de novo near-complete eukaryotic assemblies that are 99.99% accurate when compared with available reference genomes.

/pdf/assembling-large-genomes-with-single-molecule-sequencing-and-3owcjv6cvc.pdf

Assembling large genomes with single-molecule sequencing and locality-sensitive hashing

The major histocompatibility complex (MHC) has become a paradigm for how selection can act to maintain adaptively important genetic diversity in natural populations. Here, we review the contribution of studies on the MHC in non-model species to our understanding of how selection affects MHC diversity, emphasising how ecological and ethological processes influence the tempo and mode of evolution at the MHC, and conversely, how variability at the MHC affects individual fitness, population dynamics and viability. We focus on three main areas: the types of information that have been used to detect the action of selection on MHC genes; the relative contributions of parasite-mediated and sexual selection on the maintenance of MHC diversity; and possible future lines of research that may help resolve some of the unanswered issues associated with MHC evolution.

/pdf/the-evolutionary-ecology-of-the-major-histocompatibility-20e94rlsvi.pdf

The evolutionary ecology of the major histocompatibility complex.

Here we report the first complete sequence and gene map of a human major histocompatibility complex (MHC), a region on chromosome 6 which is essential to the immune system (reviewed in ref. 1). When it was discovered over 50 years ago the region was thought to specify histocompatibility genes, but their nature has been resolved only in the last two decades. Although many of the 224 identified gene loci (128 predicted to be expressed) are still of unknown function, we estimate that about 40% of the expressed genes have immune system function. Over 50% of the MHC has been sequenced twice, in different haplotypes, giving insight into the extraordinary polymorphism and evolution of this region. Several genes, particularly of the MHC class II and III regions, can be traced by sequence similarity and synteny to over 700 million years ago, dearly predating the emergence of the adaptive immune system some 400 million years ago. The sequence is expected to be invaluable for the identification of many common disease loci. In the past, the search for these loci has been hampered by the complexity of high gene density and linkage disequilibrium.

G Ribas-Despuig

Papers

Complete sequence and gene map of a human major histocompatibility complex