Bo Johanneson

Sex-biased dispersal in sperm whales: contrasting mitochondrial and nuclear genetic structure of global populations.

The social organization of most mammals is characterized by female philopatry and male dispersal. Such sex–biased dispersal can cause the genetic structure of populations to differ between the maternally inherited mitochondrial DNA (mtDNA) and the bi–parental nuclear genome. Here we report on the global genetic structure of oceanic populations of the sperm whale, one of the most widely distributed mammalian species. Groups of females and juveniles are mainly found at low latitudes, while males reach polar waters, returning to tropical and subtropical waters to breed. In comparisons between oceans, we did not find significant heterogeneity in allele frequencies of microsatellite loci (exact test; p = 0.23). Estimates of GST = 0.001 and RST = 0.005 also indicated negligible if any nuclear DNA differentiation. We have previously reported significant differentiation between oceans in mtDNA sequences. These contrasting patterns suggest that interoceanic movements have been more prevalent among males than among females, consistent with observations of females being the philopatric sex and having a more limited latitudinal distribution than males. Consequently, the typical mammalian pattern may have operated on a global scale in sperm whales.

A Major Susceptibility Locus for Systemic Lupus Erythemathosus Maps to Chromosome 1q31

A set of 87 multicase families with systemic lupus erythemathosus (SLE) from European (Iceland, Sweden, England, Norway, Italy, and Greece) and recently admixed (Mexico, Colombia, and the United States) populations were genotyped and analyzed for 62 microsatellite markers on chromosome 1. By parametric two-point linkage analysis, six regions (1p36, 1p21, 1q23, 1q25, 1q31, and 1q43) were identified that have LOD scores of Z>or=1.50, with different contributions, depending on the population of origin of the families (European or admixed American). All of the regions have been described previously and have therefore been confirmed in this analysis. The locus at 1q31 showed a significant three-point LOD score of Z=3.79 and was contributed by families from all populations, with several markers and under the same parametric model. Analysis of a known mutation in the CD45 gene did not support the role that this mutation plays in disease. We conclude that the locus at 1q31 contains a major susceptibility gene, important to SLE in general populations.

Both risk alleles for Fc|[gamma]|RIIA and Fc|[gamma]|RIIIA are susceptibility factors for SLE: a unifying hypothesis

The aim of this study was to analyze in families with SLE for the presence of linkage and the structure and transmission of haplotypes containing alleles for the low-affinity Fcγ receptors. The Fcγ receptor polymorphisms FcγRIIA-131R/H, FcγRIIIA-176F/V and FcγRIIIB-NA1/2 and a polymorphism in the FcγRIIB gene were genotyped with RFLP, allele-specific PCR or pyrosequencing. Individual SNPs and haplotypes were tested for linkage in multicase families and for association using contingency tables, transmission disequilibrium test and affected family-based control groups in Swedish and Mexican single-case families. No linkage or association could be detected using the FcγR polymorphisms in the multicase families. However, an association was found for both FcγRIIA-131R and IIIA-176F alleles in the single-case families, but not for IIIB or IIB. Allelic association to SLE was found for a haplotype that included both risk alleles, but not in haplotypes where only one or the other was present. We propose that FcγRIIA-131R and FcγRIIIA-176F are both risk alleles for SLE transmitted primarily, but not exclusively on a single major haplotype that behaves functionally in a situation similar to that of compound heterozygozity.

Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus.

A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1–q15 and 20p11–q13.13 (P-value=0.0056 and P-value=0.0044, respectively) and a region with P-value<0.01 on 16p13–q12.2.The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.

Association analysis with microsatellite and SNP markers does not support the involvement of BCL-2 in systemic lupus erythematosus in Mexican and Swedish patients and their families

We have described suggestive linkage between microsatellite markers within the cytogenetic region 18q21–23 and SLE, a region where linkage with other autoimmune diseases has also been detected. The Bcl-2 gene located within this region, is a candidate gene because of its role in apoptosis, a physiological mechanism that could be deregulated in autoimmune disease. Furthermore, several studies have found abnormalities of Bcl-2 expression in SLE patients. We therefore sought to determine if the Bcl-2 gene is involved in SLE by studying members of a large cohort of Mexican SLE patients (n = 378) and 112 Swedish simplex families. Using a microsatellite marker and two single nucleotide polymorphisms located within the gene, we were unable to detect association between Bcl-2 and SLE in either population. We also tested whether combinations of alleles of the Bcl-2 and IL-10.G microsatellites would increase the risk for SLE. Our results do not support such hypothesis. Our findings suggest that linkage between SLE and the 18q21–23 region is due to a gene other than Bcl-2.

IgG Fc receptor polymorphisms and association with autoimmune disease

The aim of this study was to investigate whether a genetic polymorphism of FcγRIII exists in mice, which could explain the different susceptibility to pathogenic IgG anti‐collagen type II (CII) antibodies in mice carrying the collagen‐induced arthritis (CIA)‐susceptible H‐2q haplotype. The gene for FcγRIII was sequenced in 11 common mouse strains, and the results revealed three different haplotypes of mouse FcγRIII: FcγRIII:V, FcγRIII:H and FcγRIII:T. To study the consequences of this polymorphism, we generated mice carrying the FcγRIII:H haplotype from the CIA‐susceptible, H‐2q‐positive DBA/1 mouse or the FcγRIII:V haplotype from the CIA‐resistant, H‐2q‐positive SWR mouse. After CII immunization or transfer of IgG anti‐CII antibodies, FcγRIII:H‐expressing mice, but not FcγRIII:V‐expressing mice, developed progressively severe arthritis. We also investigated if C5, in addition to FcγRIII polymorphism, could affect the susceptibility to the pathogenic IgG anti‐CII antibodies in H‐2q‐positive mice. Here we show that SWR mice, naturally deficient in C5, can develop CIA when supplemented with C5 and that anti‐C5 antibody treatment of FcγRIII:H‐expressing mice inhibits arthritis development. These data demonstrate for the first time a genetic polymorphism of FcγRIII in mice that may, together with C5, regulate induction of autoimmune disease.

Systematic validation of hypothesis-driven candidate genes for cervical cancer in a genome-wide association study

A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but most studies have not included an independent replication or the results have been inconsistent between studies. In order to independently validate these associations, we reexamined 58 candidate gene/regions previously reported to be associated with cervical cancer using the gene-based Adaptive Rank Truncated Product test in a genome-wide association study (GWAS) of 1034 cervical cancer patients and 3948 controls from the Swedish population. Of the 58 gene/regions, 8 had a nominal P value < 0.05 [tumor necrosis factor (TNF), P = 5.0 × 10(-4); DEAD (Asp-Glu-Ala-Asp) box helicase 1 [DDX1], P = 2.2 × 10(-3); exonuclease 1 [EXO1], P = 4.7 × 10(-3); excision repair cross-complementing rodent repair deficiency, complementation group 1 [ERCC1], P = 0.020; transmembrane channel-like 6 and 8 genes [TMC6-TMC8], P = 0.023; secreted phosphoprotein 1 [SPP1], P = 0.028; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2], P = 0.033 and chloride channel, voltage-sensitive 7 [CLCN7], P = 0.047). After correction for multiple testing, only TNF remained statistically significant (P = 0.028). Two single-nucleotide polymorphisms that are in nearly perfect linkage disequilibrium (rs2857602 and rs2844484) contributed most to the association with TNF. However, they are not independent from the previously reported associations within the MHC region. The very low number of previously reported associations with cervical cancer that replicate in the Swedish population underscore the need to apply more stringent criteria when reporting associations, including the prerequisite of replicating the association as part of the original study.