Systematic review of genome-wide expression studies in multiple sclerosis

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High divergence in primate-specific duplicated regions: Human and chimpanzee Chorionic Gonadotropin Beta genes

<p>Abstract</p> <p>Background</p> <p>Low nucleotide divergence between human and chimpanzee does not sufficiently explain the species-specific morphological, physiological and behavioral traits. As gene duplication is a major prerequisite for the emergence of new genes and novel biological processes, comparative studies of human and chimpanzee duplicated genes may assist in understanding the mechanisms behind primate evolution. We addressed the divergence between human and chimpanzee duplicated genomic regions by using Luteinizing Hormone Beta (<it>LHB</it>)/Chorionic Gonadotropin Beta (<it>CGB</it>) gene cluster as a model. The placental <it>CGB </it>genes that are essential for implantation have evolved from an ancestral pituitary <it>LHB </it>gene by duplications in the primate lineage.</p> <p>Results</p> <p>We shotgun sequenced and compared the human (45,165 bp) and chimpanzee (39,876 bp) <it>LHB/CGB </it>regions and hereby present evidence for structural variation resulting in discordant number of <it>CGB </it>genes (6 in human, 5 in chimpanzee). The scenario of species-specific parallel duplications was supported (i) as the most parsimonious solution requiring the least rearrangement events to explain the interspecies structural differences; (ii) by the phylogenetic trees constructed with fragments of intergenic regions; (iii) by the sequence similarity calculations. Across the orthologous regions of <it>LHB/CGB </it>cluster, substitutions and indels contributed approximately equally to the interspecies divergence and the distribution of nucleotide identity was correlated with the regional repeat content. Intraspecies gene conversion may have shaped the <it>LHB/CGB </it>gene cluster. The substitution divergence (1.8–2.59%) exceeded two-three fold the estimates for single-copy loci and the fraction of transversional mutations was increased compared to the unique sequences (43% versus ~30%). Despite the high sequence identity among <it>LHB/CGB </it>genes, there are signs of functional differentiation among the gene copies. Estimates for d_n/d_srate ratio suggested a purifying selection on <it>LHB </it>and <it>CGB8</it>, and a positive evolution of <it>CGB1</it>.</p> <p>Conclusion</p> <p>If generalized, our data suggests that in addition to species-specific deletions and duplications, parallel duplication events may have contributed to genetic differences separating humans from their closest relatives. Compared to unique genomic segments, duplicated regions are characterized by high divergence promoted by intraspecies gene conversion and species-specific chromosomal rearrangements, including the alterations in gene copy number.</p

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Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

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Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

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Genetic Association and Altered Gene Expression of CYBB in Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS and experimental autoimmune encephalomyelitis, the murine model of the disease. On the other hand, reduced ROS levels can increase susceptibility to autoimmunity. In this work, we screened for association with MS 11 single nucleotide polymorphisms (SNPs) and two microsatellite markers in the five genes (NCF1, NCF2, NCF4, CYBA, and CYBB) of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) system, the enzymatic pathway producing ROS in the brain and neural tissues, in 347 Finnish patients with MS and 714 unaffected family members. This analysis showed suggestive association signals for NCF1 and CYBB (lowest p = 0.038 and p = 0.013, respectively). Functional relevance for disease predisposition was further supported for the CYBB gene, by microarray analysis in CD4+/− mononuclear cells of 21 individuals from five Finnish multiplex MS families, as well as by real-time RT-PCRs performed on RNA extracted from peripheral blood mononuclear cells of an Italian replication cohort of 21 MS cases and 21 controls. Our results showed a sex-specific differential expression of CYBB, suggesting that this gene, and more in general the NOX2 system, deserve to be further investigated for their possible role in MS.Peer reviewe