The (À938C4A) polymorphism in the promoter region of the BCL-2 gene was recently associated with ... more The (À938C4A) polymorphism in the promoter region of the BCL-2 gene was recently associated with inferior time to treatment and overall survival in B-cell chronic lymphocytic leukemia (CLL) patients displaying the À938A/A genotype and may thus serve as an unfavorable genetic marker in CLL. Furthermore, the À938A/A genotype was associated with increased expression of Bcl-2. To investigate this further, we analyzed the À938 genotypes of the BCL-2 gene in 268 CLL patients and correlated data with treatment status, overall survival and known prognostic factors, for example, Binet stage, immunoglobulin heavy-chain variable (IGHV) mutational status and CD38 expression. In contrast to the recent report, the current cohort of CLL patients showed no differences either in time to treatment or overall survival in relation to usage of a particular genotype. In addition, no correlation was evident between the (À938C4A) genotypes and IGHV mutational status, Binet stage or CD38. Furthermore, the polymorphism did not appear to affect the Bcl-2 expression at the RNA level. Taken together, our data do not support the use of the (À938C4A) BCL-2 polymorphism as a prognostic marker in CLL and argue against its postulated role in modulating Bcl-2 levels.
It is often hypothesized that slow inbreeding causes less inbreeding depression than fast inbreed... more It is often hypothesized that slow inbreeding causes less inbreeding depression than fast inbreeding at the same absolute level of inbreeding. Possible explanations for this phenomenon include the more efficient purging of deleterious alleles and more efficient selection for heterozygote individuals during slow, when compared with fast, inbreeding. We studied the impact of inbreeding rate on the loss of heterozygosity and on morphological traits in Drosophila melanogaster. We analysed five noninbred control lines, 10 fast inbred lines and 10 slow inbred lines; the inbred lines all had an expected inbreeding coefficient of approximately 0.25. Forty single nucleotide polymorphisms in DNA coding regions were genotyped, and we measured the size and shape of wings and counted the number of sternopleural bristles on the genotyped individuals. We found a significantly higher level of genetic variation in the slow inbred lines than in the fast inbred lines. This higher genetic variation was resulting from a large contribution from a few loci and a smaller effect from several loci. We attributed the increased heterozygosity in the slow inbred lines to the favouring of heterozygous individuals over homozygous individuals by natural selection, either by associative over-dominance or balancing selection, or a combination of both. Furthermore, we found a significant polynomial correlation between genetic variance and wing size and shape in the fast inbred lines. This was caused by a greater number of homozygous individuals among the fast inbred lines with small, narrow wings, which indicated inbreeding depression. Our results demonstrated that the same amount of inbreeding can have different effects on genetic variance depending on the inbreeding rate, with slow inbreeding leading to higher genetic variance than fast inbreeding. These results increase our understanding of the genetic basis of the common observation that slow inbred lines express less inbreeding depression than fast inbred lines. In addition, this has more general implications for the importance of selection in maintaining genetic variation.
The (À938C4A) polymorphism in the promoter region of the BCL-2 gene was recently associated with ... more The (À938C4A) polymorphism in the promoter region of the BCL-2 gene was recently associated with inferior time to treatment and overall survival in B-cell chronic lymphocytic leukemia (CLL) patients displaying the À938A/A genotype and may thus serve as an unfavorable genetic marker in CLL. Furthermore, the À938A/A genotype was associated with increased expression of Bcl-2. To investigate this further, we analyzed the À938 genotypes of the BCL-2 gene in 268 CLL patients and correlated data with treatment status, overall survival and known prognostic factors, for example, Binet stage, immunoglobulin heavy-chain variable (IGHV) mutational status and CD38 expression. In contrast to the recent report, the current cohort of CLL patients showed no differences either in time to treatment or overall survival in relation to usage of a particular genotype. In addition, no correlation was evident between the (À938C4A) genotypes and IGHV mutational status, Binet stage or CD38. Furthermore, the polymorphism did not appear to affect the Bcl-2 expression at the RNA level. Taken together, our data do not support the use of the (À938C4A) BCL-2 polymorphism as a prognostic marker in CLL and argue against its postulated role in modulating Bcl-2 levels.
It is often hypothesized that slow inbreeding causes less inbreeding depression than fast inbreed... more It is often hypothesized that slow inbreeding causes less inbreeding depression than fast inbreeding at the same absolute level of inbreeding. Possible explanations for this phenomenon include the more efficient purging of deleterious alleles and more efficient selection for heterozygote individuals during slow, when compared with fast, inbreeding. We studied the impact of inbreeding rate on the loss of heterozygosity and on morphological traits in Drosophila melanogaster. We analysed five noninbred control lines, 10 fast inbred lines and 10 slow inbred lines; the inbred lines all had an expected inbreeding coefficient of approximately 0.25. Forty single nucleotide polymorphisms in DNA coding regions were genotyped, and we measured the size and shape of wings and counted the number of sternopleural bristles on the genotyped individuals. We found a significantly higher level of genetic variation in the slow inbred lines than in the fast inbred lines. This higher genetic variation was resulting from a large contribution from a few loci and a smaller effect from several loci. We attributed the increased heterozygosity in the slow inbred lines to the favouring of heterozygous individuals over homozygous individuals by natural selection, either by associative over-dominance or balancing selection, or a combination of both. Furthermore, we found a significant polynomial correlation between genetic variance and wing size and shape in the fast inbred lines. This was caused by a greater number of homozygous individuals among the fast inbred lines with small, narrow wings, which indicated inbreeding depression. Our results demonstrated that the same amount of inbreeding can have different effects on genetic variance depending on the inbreeding rate, with slow inbreeding leading to higher genetic variance than fast inbreeding. These results increase our understanding of the genetic basis of the common observation that slow inbred lines express less inbreeding depression than fast inbred lines. In addition, this has more general implications for the importance of selection in maintaining genetic variation.
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Papers by Tomas Axelsson