Copy number variation in pediatric multiple sclerosis.

BACKGROUND: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. OBJECTIVES AND METHODS: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. RESULTS AND DISCUSSION: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. CONCLUSIONS: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

SNP-based analysis of the HLA locus in Japanese multiple sclerosis patients.

Although several major histocompatibility complex (MHC)-wide single-nucleotide polymorphism (SNP) studies have been performed in populations of European descent, none have been performed in Asian populations. The objective of this study was to identify human leukocyte antigen (HLA) loci associated with multiple sclerosis (MS) in a Japanese population genotyped for 3534 MHC region SNPs. Using a logistic regression model, two SNPs (MHC Class III SNP rs422951 in the NOTCH4 gene and MHC Class II SNP rs3997849, susceptible alleles A and G, respectively) were independently associated with MS susceptibility (204 patients; 280 controls), two (MHC Class II SNP rs660895 and MHC Class I SNP rs2269704 in the NRM gene, susceptible alleles G and G, respectively) with aquaporin-4- (AQP4-) MS susceptibility (149 patients; 280 controls) and a single SNP (MHC Class II SNP rs1694112, susceptible allele G) was significant when contrasting AQP4+ against AQP4- patients. Haplotype analysis revealed a large susceptible association, likely DRB1*04 or a locus included in the DRB1*04 haplotype, with AQP4- MS, which excluded DRB1*15:01. This study is the largest study of the HLA's contribution to MS in Japanese individuals.

Multiple sclerosis genetics.

Multiple sclerosis (MS) clusters with the so-called complex genetic diseases, a group of common disorders characterized by modest disease risk heritability and multifaceted gene-environment interactions. The major histocompatibility complex (MHC) is the only genomic region consistently associated with MS, and susceptible MHC haplotypes have been identified. Although the MHC does not account for all genetic contribution to MS, the other genetic contributors have been elusive. Microarray gene-expression studies, which also have not identified a major MS locus, have, however, been promising in elucidating some of the possible pathways involved in the disease. Yet, microarray studies thus far have been unable to separate the genetic causes of MS from the expression consequences of MS. The use of new methodologies and technologies to refine the phenotype, such as brain spectroscopy, PET and functional magnetic resonance imaging combined with novel computational tools and a better understanding of the human genome architecture, may help resolve the genetic causes of MS.

Identification of trait loci affecting white meat percentage and other growth and carcass traits in commercial broiler chickens.

White meat is the most economically valuable part of a broiler chicken. Increasing white meat relative to overall body size (white meat percentage, WM%) makes a broiler, gram for gram, a more valuable animal. However, accurately measuring WM% requires removing the bird from the breeding flock. Identification of markers for genomic regions associated with WM% would allow direct genetic selection on breeders. The objective of the current study was to identify genomic regions affecting WM% and other growth and carcass traits in an F2 cross between 2 commercial broiler lines that differed in WM%. Two commercial lines were crossed to generate 5 F1 half-sib families of each reciprocal cross type. One male from each family was crossed with 3 females from each of the other families within each reciprocal cross type. Seven F2 half-sib families, totaling 430 F2 individuals, were analyzed. Microsatellite markers (n = 73) on the 11 largest chromosomes were analyzed for associations with various growth and carcass traits by least squares interval mapping using line-cross, half-sib, combined, and parent of origin models. Sixty-eight QTL were identified at the 5% chromosome-wise level, including 6 QTL affecting WM%. Ten QTL reached 5% genome-wise significance, including 1 WM% QTL on Gga 2. The current study identified genomic regions harboring QTL affecting WM% and other carcass and growth traits, which may be useful for direct genetic selection, and also identified putative imprinted QTL in the chicken. The advantage of using multiple statistical models was evident because QTL were identified with the combined and parent of origin models that were not identified with the line-cross or half-sib models.

Microsatellite markers associated with resistance to Marek's disease in commercial layer chickens.

The objective of the current study was to identify QTL conferring resistance to Marek's disease (MD) in commercial layer chickens. To generate the resource population, 2 partially inbred lines that differed in MD-caused mortality were intermated to produce 5 backcross families. Vaccinated chicks were challenged with very virulent plus (vv+) MD virus strain 648A at 6 d and monitored for MD symptoms. A recent field isolate of the MD virus was used because the lines were resistant to commonly used older laboratory strains. Selective genotyping was employed using 81 microsatellites selected based on prior results with selective DNA pooling. Linear regression and Cox proportional hazard models were used to detect associations between marker genotypes and survival. Significance thresholds were validated by simulation. Seven and 6 markers were significant based on proportion of false positive and false discovery rate thresholds less than 0.2, respectively. Seventeen markers were associated with MD survival considering a comparison-wise error rate of 0.10, which is about twice the number expected by chance, indicating that at least some of the associations represent true effects. Thus, the present study shows that loci affecting MD resistance can be mapped in commercial layer lines. More comprehensive studies are under way to confirm and extend these results.