Discovery Of Alleles Research Articles

Identification of Quantitative Trait Loci That Affect Aggressive Behavior in Mice

Despite the previous development of single-gene knock-out mice that exhibit alterations in aggressive behavior, very little progress has been made toward identifying the natural gene variants (alleles) that contribute to individual or strain differences in aggression. Whereas most inbred mouse strains show an intermediate level of inter-male aggression in the resident-intruder or dangler behavioral tests, NZB/B1NJ mice are extremely aggressive and A/J mice are extremely unaggressive. We took advantage of the large phenotypic difference between these strains and used an outcross-backcross breeding protocol and a genome-wide scan to identify aggression quantitative trait loci (QTLs) on distal chromosome 10 (Aggr1; p = 6 x 10(-7)) and proximal chromosome X (Aggr2; p = 2.14 x 10(-5)). Candidate genes for Aggr1 and Aggr2, respectively, include the diacylglycerol kinase alpha subunit gene (Dagk1) and the glutamate receptor subunit AMPA3 gene (Gria3). This is the first report of significant aggression QTLs established through a genome-wide scan in any mammal. The mapping of these QTLs is a step toward the definitive identification of mouse alleles that affect aggression and may lead, ultimately, to the discovery of homologous alleles that affect individual differences in aggression within other mammalian species.

Trends in transplantation of hematopoietic stem cells from unrelated donors.

Transplants of hematopoietic stem cells from unrelated donors have become feasible for patients with a growing variety of hematologic disorders. The probability of finding a suitable donor has increased because of the expansion of the network of registries containing more than seven million HLA-typed donors worldwide. The selection of compatible donors has become more effective, thanks to the discovery of new HLA alleles and the development of precise and efficient HLA typing methods using DNA technology. Improved methods for transplantation may provide the opportunity to further decrease treatment-related toxicity and improve survival.

Non-conservative substitutions distinguish previously uncharacterized HLA-A molecules.

The extent of class I HLA polymorphism is not yet realized, and to provide a glimpse of the HLA-A polymorphism which remains undetected, we have analyzed approximately 3,700 National Marrow Donor Program (NMDP) Donor/Recipient Pair Retrospective Study Samples with HLA-A DNA sequence-based typing (SBT). Seventeen new HLA-A alleles were detected, with a total of 19 nucleotide substitutions distinguishing these new alleles from their closest HLA-A relatives. Nearly all of the new alleles differ by single nucleotide substitutions; a majority of these substitutions can be explained by gene conversion events but 6 alleles likely originated by point mutation. Fifteen of the 19 nucleotide substitutions translate into amino acid differences in the molecule. Structurally, the inferred amino acid alterations were non-conservative in terms of chemical property, and most substitutions were positioned in 1 or more of the specificity pockets which determine peptide binding. Although these new alleles were identified in a primarily Caucasian sample population, 9 of the 17 new HLA-A alleles were found in samples of non-Caucasoid origin. A new allele detection rate of 1 in approximately 200 individuals in our data set would, therefore, be higher in a non-Caucasoid sample population. In summary, the single nucleotide substitutions that distinguish undetected HLA-A alleles translate into functionally distinct HLA-A molecules. Further studies of the role of HLA-A in transplantation, in disease association, and in evolution must therefore accommodate the discovery of new alleles differing by single nucleotides.

Improving availability and safety of unrelated donor transplants.

Transplants of hematopoietic stem cells from unrelated donors have become feasible for a growing population of patients with hematologic malignancy. More than 2,000 patients with acute and chronic leukemia, lymphoma, myeloma, and myelodysplasia are transplanted each year worldwide using marrow or blood stem cells from unrelated volunteers. Many patients have achieved complete immunologic tolerance and have become long-term survivors. The probability of finding a suitable donor has increased, because of the expansion of the network of registries containing more than 5 million HLA-typed donors worldwide. The selection of compatible donors has become more effective, thanks to the discovery of new HLA alleles and the development of precise and efficient HLA typing methods using DNA technology. Prophylaxis of viral and fungal infections has decreased morbidity and improved survival. The availability of more selective immunosuppressive agents provides the opportunity to decrease treatment-related toxicity and graft-versus-host disease.

Advanced backcross QTL analysis: a method for the simultaneous discovery and transfer of valuable QTLs from unadapted germplasm into elite breeding lines

Advanced backcross QTL analysis is proposed as a method of combining QTL analysis with variety development. It is tailored for the discovery and transfer of valuable QTL alleles from unadapted donor lines (e.g., land races, wild species) into established elite inbred lines. Following this strategy, QTL analysis is delayed until the BC2 or BC3 generation and, during the development of these populations, negative selection is exercised to reduce the frequency of deleterious donor alleles. Simulations suggest that advanced backcross QTL analysis will be effective in detecting additive, dominant, partially dominant, or overdominant QTLs. Epistatic QTLs or QTLs with gene actions ranging from recessive to additive will be detected with less power than in selfing generations. QTL-NILs can be derived from advanced backcross populations in one or two additional generations and utilized to verify QTL activity. These same QTL-NILs also represent commercial inbreds improved (over the original recurrent inbred line) for one or more quantitative traits. The time lapse from QTL discovery to construction and testing of improved QTL-NILs is minimal (1-2 years). If successfully employed, advanced backcross QTL analysis can open the door to exploiting unadapted and exotic germplasm for the quantitative trait improvement of a number of crop plants.

Allozymes of A WildAgaricus BisporusPopulation: New Alleles, New Genotypes

Eighteen field-collected isolates ofAgaricus bisporus from coastal central California and two extra? limital field isolates were subjected to allozyme analysis via PAGE, and were genotypically scored at six polymorphic loci. This population sample carries previously unreported alleles at three of five loci for which a large culture collection (PSUMCC), composed primarily of cultivar lines, had previously been screened. Only one allele known from the PSUMCC collection was not found in the wild popu? lation. Novel combinations of previously known alleles were also found. With one exception, each field isolate was genetically unique within the field sample. The wild population of A. bisporus thus contains a large number of novel genotypes that are not represented in cultivar lines. These facts strongly suggest that A. bisporus is indigenous to North America. Our observations, particularly the discovery of several new alleles, also indicate that the wild population of this species represents a significant reservoir of genetic information presently unexploited by the commercial mushroom industry. In contrast, four of the field-collected isolates could be assigned to genotypic classes known from the PSUMCC collection or other cultivars. These findings support the widely-held belief that cultivars of A. bisporus do escape from commercial cultivation and can reproduce under natural conditions.

Allozymes of a Wild Agaricus bisporus Population: New Alleles, New Genotypes

Eighteen field-collected isolates of Agaricus bisporus from coastal central California and two extralimital field isolates were subjected to allozyme analysis via PAGE, and were genotypically scored at six polymorphic loci. This population sample carries previously unreported alleles at three of five loci for which a large culture collection (PSUMCC), composed primarily of cultivar lines, had previously been screened. Only one allele known from the PSUMCC collection was not found in the wild population. Novel combinations of previously known alleles were also found. With one exception, each field isolate was genetically unique within the field sample. The wild population of A. bisporus thus contains a large number of novel genotypes that are not represented in cultivar lines. These facts strongly suggest that A. bisporus is indigenous to North America. Our observations, particularly the discovery of several new alleles, also indicate that the wild population of this species represents a significant reservoir of genetic information presently unexploited by the commercial mushroom industry. In contrast, four of the field-collected isolates could be assigned to genotypic classes known from the PSUMCC collection or other cultivars. These findings support the widely-held belief that cultivars of A. bisporus do escape from commercial cultivation and can reproduce under natural conditions.