Replication linkage study for prostate cancer susceptibility genes.

BACKGROUND: Since the publication of the first genome screen for prostate cancer (CaP) 5 years ago, over a dozen linkage studies have appeared. Most attention has been directed to chromosome 1, where two separate regions have been identified as harboring a prostate cancer susceptibility locus: HPC1 in the 1q24-25 interval and PCaP in the 1q42.2-43 interval. Linkage analysis of chromosome 16 has also provided evidence of harboring two loci predisposing to CaP. METHODS: We report on a replication linkage study of chromosomes 1 and 16 in 45 new and 4 expanded multiplex CaP families. Multipoint Z-scores were obtained for 30 highly polymorphic short-sequence tandem repeat markers spanning chromosome 1, and 22 markers spanning chromosome 16. RESULTS: The replication sample gave no evidence for a CaP susceptibility locus in the 1q24-25 interval and equivocal evidence for such a locus at 1q42.2-43. With respect to chromosome 16, positive Z-scores were obtained over a contiguous interval covering the entire p arm and the proximal half of the q arm. CONCLUSIONS: The linkage analysis of our replication sample does not support the existence of HPC1, and the evidence for the existence of PCaP remains equivocal. Evidence of a susceptibility locus on 16p remains strong, but the evidence for a susceptibility locus on 16q is weakened.

Genomewide search for type 2 diabetes susceptibility genes in four American populations.

Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association's GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999).

Detection of chromosomal aberrations by a whole-genome microsatellite screen.

Chromosomal aberrations are a common cause of multiple anomaly syndromes that include developmental and growth retardation. Current microscopic techniques are useful for the detection of such aberrations but have a limit of resolution that is above the threshold for phenotypic effect. We hypothesized that a genomewide microsatellite screen could detect chromosomal aberrations that were not detected by standard cytogenetic techniques in a portion of these individuals. To test this hypothesis, we performed a genomewide microsatellite screen of patients, by use of a currently available genetic-marker panel that was originally designed for meiotic mapping of Mendelian traits. We genotyped approximately 400 markers on 17 pairs of parents and their children who had normal karyotypes. By using this approach, we detected and confirmed two cases of segmental aneusomy among 11 children with multiple congenital anomalies. These data demonstrate that a genomewide microsatellite scan can be used to detect chromosomal aberrations that are not detected by microscopic techniques.

Genetic and physical mapping of the McKusick-Kaufman syndrome.

McKusick-Kaufman syndrome is a human developmental anomaly syndrome comprising mesoaxial or postaxial polydactyly, congenital heart disease and hydrometrocolpos. This syndrome is diagnosed most frequently in the Old Order Amish population and is inherited in an autosomal recessive pattern with reduced penetrance and variable expressivity. Homozygosity mapping and linkage analyses were conducted using two pedigrees derived from a larger pedigree published in 1978. The PedHunter software query system was used on the Amish Genealogy Database to correct the previous pedigree, derive a minimal pedigree connecting those affected sibships that are in the database and determine the most recent common ancestors of the affected persons. Whole genome short tandem repeat polymorphism (STRP) screening showed homozygosity in 20p12, between D20S162 and D20S894 , an area that includes the Alagille syndrome critical region. The peak two-point LOD score was 3.33, and the peak three-point LOD score was 5.21. The physical map of this region has been defined, and additional polymorphic markers have been isolated. The region includes several genes and expressed sequence tags (ESTs), including the jagged1 gene that recently has been shown to be haploinsufficient in the Alagille syndrome. Sequencing of jagged1 in two unrelated individuals affected with McKusick-Kaufman syndrome has not revealed any disease-causing mutations.

Effect of the estrogen receptor locus on reproduction and production traits in four commercial pig lines.

We investigated the effect of the estrogen receptor (ESR) gene on growth and reproductive traits in four Large White-based commercial pig lines. A total of 9,015 litter records from 4,262 sows genotyped at the ESR locus were analyzed to determine whether ESR influenced total number born (TNB) or number born alive (NBA). Teat number (TN), test ADG, ADFI, feed:gain ratio (F/G), and ultrasonic backfat (BF) were also analyzed to determine effects of ESR. The TNB and NBA were increased per favorable allele of ESR (P < .01) with additive effects of .42 (.31) and .39 (.31) pigs/litter in the first parity (later parities), respectively. Dominance effects were near zero in parity one, but they were .16 and .14 pigs for TNB and NBA, respectively, in later parities (P < .05). A favorable additive pleiotropic effect was detected for BF (P < .001; -.11 mm per copy of the favorable litter size allele). There were no detectable effects on ADG or F/G (P > .10), although ADF was reduced 18 g/d per copy of the favorable litter size allele (P < .05). Average TN was 13.1 for pigs carrying the favorable litter size allele vs 13.2 for noncarriers (P < .05). Marker-assisted selection using ESR is warranted to increase litter size in the Large White-based lines considered here and will be of considerable economic value to pork producers.

The estrogen receptor locus is associated with a major gene influencing litter size in pigs.

Identification of individual major genes affecting quantitative traits in livestock species has been limited to date. By using a candidate gene approach and a divergent breed cross involving the Chinese Meishan pig, we have shown that a specific allele of the estrogen receptor (ER) locus is associated with increased litter size. Female pigs from synthetic lines with a 50% Meishan background that were homozygous for this beneficial allele produced 2.3 more pigs in first parities and 1.5 more pigs averaged over all parities than females from the same synthetic lines and homozygous for the undesirable allele. This beneficial ER allele was also found in pigs with Large White breed ancestory. Analysis of females with Large White breed background showed an advantage for females homozygous for the beneficial allele as compared to females homozygous for the other allele of more than 1 total pig born. Analyses of growth performance test records detected no significant unfavorable associations of the beneficial allele with growth and developmental traits. Mapping of the ER gene demonstrated that the closest known genes or markers were 3 centimorgans from ER. To our knowledge, one of these, superoxide dismutase gene (SOD2), was mapped for the first time in the pig. Analysis of ER and these linked markers indicated that ER is the best predictor of litter size differences. Introgression of the beneficial allele into commercial pig breeding lines, in which the allele was not present, and marker-assisted selection for the beneficial allele in lines with Meishan and Large White background have begun.

Evidence for an inactive plasma membrane-associated precursor of active cytoplasmic ornithine decarboxylase in developing embryos of Musca domestica.

During embryonic development of Musca domestica inactive ornithine decarboxylase protein appears in the embryos at 6 h postoviposition, increases in concentration and reaches a maximum level at 9 h postoviposition. The inactive enzyme is associated with the plasma membrane and appears to be the precursor for active ornithine decarboxylase, which is associated with the cytosolic fraction just prior to hatching. Both ornithine decarboxylase protein and enzymatic activity disappear during the early larval stage of this insect.