Cordula Haas

In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend toward smaller genetic distances resulting from larger numbers of markers became apparent.

MRL/lpr mice develop lymphoproliferation and accelerated autoimmune glomerulonephritis from which they ultimately die. To investigate the role of IFN-gamma in the manifestation of the disease, we generated MRL/lpr mice lacking the IFN-gamma receptor (MRL/lpr gammaR -/-). The absence of IFN-gamma signaling had no effect on generalized lymphoproliferation, expansion of CD4- CD8- double-negative T cells, or hypergammaglobulinemia. By contrast, glomerulonephritis as detected by proteinuria and histology was absent in MRL/lpr gammaR -/- mice. While serum IgG1 anti-dsDNA Abs were increased in all three strains of MRL/lpr mice (gammaR +/+, +/-, -/-), those of the IgG2a and IgG3 isotypes were low in MRL/lpr gammaR -/- mice. Immune complexes and C3 deposition were dramatically reduced in the glomerular capillaries of MRL/lpr gammaR -/- mice compared with MRL/lpr gammaR +/+ and +/- mice. Therefore, IFN-gamma plays a key regulatory role in the development of nephritis in MRL/lpr mice. Low levels of IFN-gamma-dependent IgG2a and IgG3 autoantibodies in MRL/lpr gammaR -/- mice might protect them from the pathogenic features of IgG3 cryoglobulins and complement-activating IgG2a and IgG3.

(NZB x NZW)F1 female (BW) mice spontaneously develop an autoimmune disease, characterized by the production of autoantibodies (autoAbs) and glomerulonephritis, which can be delayed by neutralizing IFN-gamma Abs and accelerated by IFN-gamma injections. To define the role of IFN-gamma in the pathogenesis of glomerulonephritis, we established a population of BW mice deficient in IFN-gammaR (BWgammaR[-/-]) by repeated crossing; these mice were compared with BWgammaR(+/+) and +/- littermates. Of the BWgammaR(+/+) and +/- mice, 50% showed immune complex glomerulonephritis with heavy proteinuria at 8 mo of age, while only 10% of the BWgammaR(-/-) mice were affected at 14 mo. The serum concentration of anti-dsDNA and anti-histone Abs was dramatically reduced in BWgammaR(-/-) mice. The role of IFN-gamma in promoting class switch to IgG2a and IgG3 could not fully account for the impaired production of anti-dsDNA in BWgammaR(-/-) animals since, IgM and IgG1 levels were also reduced. There was a high incidence of B cell lymphoma in the BWgammaR(-/-) mice, which might be related to the suppression of autoAb production. Thus, the absence of glomerulonephritis in BWgammaR(-/-) mice is likely due to a dramatic yet unexplained effect of the inactivation of IFN-gamma signaling on autoAb production.

Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, >99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836-0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father-son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RM Y-STRs in identifying and separating unrelated and related males and provides a reference database.