| 1. |
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| 2. |
- Brändström, Helena, et al.
(author)
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A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function
- 2002
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In: Biochemical and Biophysical Research Communications - BBRC. - 0006-291X .- 1090-2104. ; 293:1, s. 13-17
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Journal article (peer-reviewed)abstract
- Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and has previously been shown to regulate bone mass by inhibiting osteoclast differentiation and activation. Recent evidence indicates that OPG also plays a role in the vascular system, since ablation of the OPG gene in mice results in calcification of the aorta and renal arteries, and association has been found between serum levels of OPG and cardiovascular mortality. This study presents a novel single nucleotide polymorphism, a T/C transition located 129 bp upstream the TATA-box of the human OPG gene, detected by sequence analysis. The OPG genotype was determined by restriction fragment length polymorphism in a cohort consisting of 59 healthy subjects. The intima-media thickness (IMT) in the common carotid artery and maximal post-ischemic forearm blood flow (FBF) were investigated. Subjects with the CC genotype showed a significantly increased IMT (p<0.05) and a concommitantly reduced maximal FBF (p<0.01) as compared to those with the T allele. Thus, our results show that the polymorphism in the promoter region of OPG is associated with both vascular morphology and function in apparently healthy subjects.
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| 3. |
- Brändström, Helena, et al.
(author)
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A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients : The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA)
- 2004
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In: Blood Pressure. - : Informa UK Limited. - 0803-7051 .- 1651-1999. ; 13:3, s. 152-157
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Journal article (peer-reviewed)abstract
- Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and in previous studies has been shown to regulate osteoclast activity and differentiation. Ablation of the OPG gene in mice results in calcification of the aorta and renal arteries. We have previously reported an association between a single nucleotide polymorphism in the promoter region of OPG and vascular morphology and function in healthy humans. The objective with this study was to confirm our previous results in a larger population, and in addition, to study subjects with hypertension. The OPG genotype was determined by restriction fragment length and the intima-media thickness (IMT) of the common carotid artery was measured by ultrasound in 100 patients with hypertension and left ventricular hypertrophy, and 75 healthy normotensive control subjects. In the hypertensive group subjects with the CC genotype (n=24) showed a significantly increased IMT compared to those with the TC (n=52, p=0.007) and TT (n=24, p=0.009) genotype, in the hypertensive group only (mean +/- SD for TT=0.88 +/- 0.21 mm, TC=0.90 +/- 0.16 mm, CC=1.05 +/- 0.31 mm). The allele distribution did not differ between hypertensive and control individuals. The present study confirms our previous finding and shows that polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects.
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| 4. |
- Brändström, Helge, et al.
(author)
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Autonomic nerve system responses for normal and slow rewarmers after hand cold provocation : effects of long-term cold climate training
- 2013
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In: International Archives of Occupational and Environmental Health. - : Springer-Verlag New York. - 0340-0131 .- 1432-1246. ; 86:3, s. 357-365
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Journal article (peer-reviewed)abstract
- PURPOSE: Differences among individuals concerning susceptibility to local cold injury following acute cold exposure may be related to function of the autonomic nervous system. We hypothesized that there are differences in heart rate variability (HRV) between individuals with normal or more pronounced vasoconstriction following cold exposure and that there is an adaptation related to prolonged cold exposure in autonomic nervous system response to cold stimuli.METHODS: Seventy-seven young men performed a cold provocation test, where HRV was recorded during cold hand immersion and recovery. Forty-three subjects were re-examined 15 months later, with many months of cold weather training between the tests. Subjects were analyzed as 'slow' and 'normal' rewarmers according to their thermographic rewarming pattern.RESULTS: For the 'pre-training' test, before cold climate exposure, normal rewarmers had higher power for low-frequency (P(LF)) and high-frequency (P(HF)) HRV components during the cold provocation test (ANOVA for groups: p = 0.04 and p = 0.005, respectively). There was an approximately 25 % higher P(HF) at the start in normal rewarmers, in the logarithmic scale. Low frequency-to-high frequency ratio (P(LF)/P(HF)) showed lower levels for normal rewarmers (ANOVA for groups: p = 0.04). During the 'post-training' cold provocation test, both groups lacked the marked increase in heart rate that occurred during cold exposure at the 'pre-training' setting. After cold acclimatization (post-training), normal rewarmers showed lower resting power values for the low-frequency and high-frequency HRV components. After winter training, the slow rewarmers showed reduced low-frequency power for some of the cold provocation measurements but not all (average total P(LF), ANOVA p = 0.05), which was not present before winter training.CONCLUSIONS: These HRV results support the conclusion that cold adaptation occurred in both groups. We conclude that further prospective study is needed to determine whether cold adaptation provides protection to subjects at higher risk for cold injury, that is, slow rewarmers.
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| 5. |
- Brändström, Helge, et al.
(author)
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Hand cold recovery responses before and after 15 months of military training in a cold climate
- 2008
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In: Aviation, Space and Environmental Medicine. - 0095-6562 .- 1943-4448. ; 79:9, s. 904-908
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Journal article (peer-reviewed)abstract
- INTRODUCTION: The ability of fingers to rapidly rewarm following cold exposure is a possible indicator of cold injury protection. We categorized the post-cooling hand-rewarming responses of men before and after participation in 15 mo of military training in a cold environment in northern Sweden to determine: 1) if the initial rewarming category was related to the occurrence of local cold injury during training; and 2) if cold training affected subsequent hand-rewarming responses. METHODS: Immersion of the dominant hand in 10 degrees C water for 10 min was performed pre-training on 77 men. Of those, 45 were available for successful post-training retests. Infrared thermography monitored the dorsal hand during 30 min of recovery. Rewarming was categorized as normal, moderate, or slow based on mean fingertip temperature at the end of 30 min of recovery (TFinger,30) and the percentage of time that fingertips were vasodilated (%VD). RESULTS: Cold injury occurrence during training was disproportionately higher in the slow rewarmers (four of the five injuries). Post-training, baseline fingertip temperatures and cold recovery variables increased significantly in moderate and slow rewarmers: TFinger30 increased from 21.9 +/- 4 to 30.4 +/- 6 degrees C (Moderate), and from 17.4 +/- 0 to 22.3 +/- 7 degrees C (Slow); %VD increased from 27.5 +/- 16 to 65.9 +/- 34% (Moderate), and from 0.7 +/- 2 to 31.7 +/- 44% (Slow). CONCLUSIONS: Results of the cold recovery test were related to the occurrence of local cold injury during long-term cold-weather training. Cold training itself improved baseline and cold recovery in moderate and slow rewarmers.
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| 6. |
- Brändström, Helena
(author)
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Osteoprotegerin in Bone Metabolism
- 2001
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Doctoral thesis (other academic/artistic)abstract
- Bone turnover, remodeling, is a constant process replacing old bone with new. This complex cellular event involves resorption by osteoclasts and formation of new bone by osteoblasts. The balance between osteoblastic and osteoclastic activity is under regulation by several endocrine and paracrine factors. Osteoprotegerin (OPG), a recently discovered protein is an effective inhibitor of osteociast formation and osteoclast activity. In this thesis, the regulation of OPG mRNA expression and protein secretion from human bone cells has been investigated. Also correlation between a single nucleotide polymorphism in the OPG gene and bone mass has been studied. OPG mRNA levels were affected by several endocrine and paracrine factors known to regulate bone resorption, such as prostaglandin E2, TNFs, interleukin-I and glucocorticoid. An ELISA was developed and it was established that human osteoblasts secrete OPG protein and that the secretion is regulated by the above factors. A single nucleotide polymorphism was discovered in the human OPG gene. There was no correlation between the polymorphism and measures of bone mineral density in a cohort of 1044 post-menopausal females. Surprisingly, a correlation between the polymorphism and measures of vascular function and morphology was discovered. The data in the thesis show that OPG is produced in human bone marrow and is regulated by factors affecting the bone remodeling process, suggesting a central role for OPG in human bone turnover. The finding that the polymorphism in the OPG gene correlates with vascular function opens up a new area of research aiming at understanding whether OPG might be involved also in cardiovascular diseases.
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| 7. |
- Brändström, Helena, et al.
(author)
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Regulation of osteoprotegerin mRNA levels by prostaglandin E2 in human bone marrow stroma cells.
- 1998
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In: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 247:2, s. 338-41
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Journal article (peer-reviewed)abstract
- The recently cloned osteoclastogenesis inhibitory factor, or osteoprotegerin (OPG), has been shown to be a potent inhibitor of osteoclast formation. The inhibition is believed to be mediated through specific binding of OPG to a cell surface ligand on osteoblastic stromal cells. In this report we have studied the effect of the bone resorbing agent prostaglandin E2 (PGE2) on OPG mRNA levels in primary cultures of human bone marrow stroma cells (hBMSC). PGE2 dose- and time-dependently down-regulated the mRNA levels of OPG, as measured by RNAse protection assay. After 4 hours of stimulation with 1 microM PGE2, OPG mRNA levels were significantly decreased. The inhibitory effect was seen at and above 1 nM of PGE2. To elucidate whether the OPG mRNA levels are regulated via the proteinkinase A and/or the proteinkinase C pathways we stimulated cells with either forskolin (FSK) or phorbolic ester (PDbu) respectively. FSK (10 microM) decreased OPG mRNA levels to 50 % of control, whereas PE (10 nM) upregulated the mRNA levels to 250 % of control. These data show that PGE2 down-regulates the expression of OPG mRNA in hBMSC, probably via an increase in cAMP. This mechanism might be involved in PGE2-induced bone resorption.
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| 8. |
- Brändström, Helena, et al.
(author)
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Single nucleotide polymorphisms in the human gene for osteoprotegerin are not related to bone mineral density or fracture in elderly women
- 2004
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In: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 74:1, s. 18-24
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Journal article (peer-reviewed)abstract
- Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclast activation and differentiation. In animal models OPG prevents bone loss, and in humans bone resorption can be reduced by injections of OPG. OPG may also play a role in cardiovascular disease since mice lacking the OPG gene display arterial calcification. In a screening effort of the OPG gene, we recently discovered a single nucleotide polymorphism in the promoter region of OPG (T950C), and reported an association with vascular morphology and function in 59 healthy individuals. Due to the pronounced effect of OPG on bone turnover, the present study was conducted to investigate whether OPG polymorphisms are also associated with bone mineral density or with fracture. The relationship between single nucleotide polymorphisms in the promoter region of OPG (T950C) and the first intron (C1217T), and bone mineral density, measured by DXA in the hip or spine or ultrasound of the heel, was investigated in the Malmö OPRA-study of 1044 women, all 75 years old. The possible relation to fracture incidence was also analyzed. Among the 858 and 864 individuals respectively, genotyped, no significant associations between the investigated single nucleotide polymorphisms and bone mineral density measurements (T950C P = 0.50-0.64, C1217T P = 0.51-1.00), quantitative ultrasound measurements of the calcaneus, or fractures (T950C P = 0.61-0.66, C1217T P = 0.14-0.33) were found. Thus, our results show that polymorphisms in the OPG gene, one of which has previously been found to be associated with cardiovascular morphology and function, are not associated with bone mineral density in elderly Swedish women.
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| 9. |
- Brändström, Helena, et al.
(author)
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Tumor necrosis factor-alpha and -beta upregulate the levels of osteoprotegerin mRNA in human osteosarcoma MG-63 cells.
- 1998
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In: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 248:3, s. 454-7
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Journal article (peer-reviewed)abstract
- Osteoprotegerin (OPG) is a recently cloned soluble member of the tumor necrosis factor receptor family. OPG has been shown to inhibit osteoclast recruitment by binding to OPG-ligand, an osteoclast differentiating factor on osteoblastic stromal cells, thereby blocking osteoclastogenesis. In this report we have examined the effect of tumor necrosis factor-alpha (TNF-alpha) and tumor necrosis factor-beta (TNF-beta) on OPG mRNA levels in the human osteosarcoma cell line MG-63. We demonstrate that both TNF-alpha and TNF-beta dose- and time-dependently upregulate the mRNA levels of OPG. The effect is significant at and above 5 pM of TNF-alpha and 1 pM of TNF-beta. The stimulatory effect on OPG mRNA levels in MG-63 cells was detected after 2 hrs of incubation with TNF-alpha or TNF-beta. These data demonstrate that the expression of OPG in osteoblasts, with subsequent effects on osteoclastogenesis, is regulated by TNFs.
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| 10. |
- Bäckström, Gunilla, et al.
(author)
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Genetic variation in the ATP-binding cassette transporter gene ABCG2(BCRP) in a Swedish population
- 2003
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In: European Journal of Pharmaceutical Sciences. - 0928-0987 .- 1879-0720. ; 18:5, s. 359-364
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Journal article (peer-reviewed)abstract
- The ATP-binding cassette transporter ABCG2 (also named breast cancer resistance protein, BCRP) functions as a drug efflux transporter and is expressed at high levels in the human small intestine. The aim of this study was to screen the human ABCG2 gene for genetic variation. The regions of the gene most likely to affect function, namely the coding parts, exon/intron boundaries, 5' untranslated region and 3' untranslated region and the proposed promoter region, were included in the screening. DNA was obtained from 60 Swedish individuals. The screening was performed using a polymerase chain reaction-denaturing high-performance liquid chromatography approach followed by sequence analysis. Eight sites of genetic variation were identified. The sequence variations considered to be most likely to affect transcription level or transport function were a CTCA deletion in the 5' flanking region, a single nucleotide polymorphism (SNP) in a 5' flanking CpG island, two non-synonymous SNPs, changing valine at amino acid position 12 to methionine and glutamine at position 141 to lysine, respectively. Genotyping of these sequence variations revealed linkage between the CTCA deletion and the SNP changing glutamine 141 for lysine. This information forms the basis for future association studies to investigate the genetic basis of differences of drug disposition due to sequence variation in the ABCG2 gene.
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| 11. |
- Frost, Anders, et al.
(author)
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Interleukin-13 inhibits cell proliferation and stimulates interleukin-6 formation in isolated human osteoblasts.
- 1998
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In: The Journal of clinical endocrinology and metabolism. - 0021-972X. ; 83:9, s. 3285-9
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Journal article (peer-reviewed)abstract
- Interleukin-13 (IL-13) is a recently identified cytokine that is secreted by activated T cells and regulates inflammatory responses. We have investigated the effects of IL-13 on isolated human osteoblast-like cells (hOB). IL-13 dose-dependently (1-100 pmol/L) reduced the incorporation rate of [3H]thymidine in hOB cells by more than 50%. Using a cell metabolic assay as well as direct cell counting, we found that treatment with IL-13 lead to a decrease in hOB cell number. The effect was both time and dose dependent, and after 12 days of culture, treatment with IL-13 (0.1 nmol/L) caused a 70% decrease in the number of cells. Also, IL-13 increased the levels of IL-6 messenger ribonucleic acid in hOBs, as measured by ribonuclease protection assay, and stimulated secretion of IL-6 into culture supernatants. In conclusion, IL-13 inhibits cell proliferation and increases IL-6 formation in human osteoblasts. Our findings suggest that IL-13 may cause bone loss due to impaired osteoblastic growth and IL-6-induced osteoclast recruitment.
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| 12. |
- Gerdhem, Paul, et al.
(author)
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Association of the collagen type 1 (COL1A 1) Sp1 binding site polymorphism to femoral neck bone mineral density and wrist fracture in 1044 elderly Swedish women
- 2004
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In: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 74:3, s. 264-269
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Journal article (peer-reviewed)abstract
- Identification of risk factors for osteoporosis has been essential for understanding the development of osteoporosis and related fragility fractures. A polymorphism of the binding site for the transcription factor Sp1 of the collagen I alpha 1 gene (COLIA1) has shown an association to bone mass and fracture, but the findings have not been consistent, which may be related to population differences. The Sp1 polymorphism was determined in 1044 women, all 75 years old, participating in the population-based Osteoporosis Prospective Risk Assessment study in Malmö (OPRA). Bone mineral density, heel ultrasound and all previous fractures were registered. BMD was 2.7% lower in the femoral neck in women carrying at least one copy of the "s" allele ( P = 0.027). There was no difference in bone mass at any other site, weight, BMI or age at menopause. Women with a prevalent wrist fracture (n = 181) had an increased presence of the "s" allele. The odds ratio for prevalent wrist fracture was 2.73 (95% CI 1.1-6.8) for the ss homozygotes and 1.4 (95% CI 1.0-2.0) for the Ss heterozygotes when compared with the SS homozygotes. In conclusion, in this large and homogeneous cohort of 75-year-old Swedish women, there was an association among the Sp1 COLIA1 polymorphism, bone mass, and fracture. The presence of at least one copy of the "s" allele was associated with lower femoral neck BMD and previous wrist fracture and in addition, it was related to an increased risk for wrist fracture.
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| 13. |
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| 14. |
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| 15. |
- Grundberg, Elin, et al.
(author)
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A TA-repeat polymorphism in the gene for the estrogen receptor alpha does not correlate with muscle strength or body composition in young adult Swedish women.
- 2005
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In: Maturitas. - 0378-5122. ; 50:3, s. 153-60
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Journal article (peer-reviewed)abstract
- OBJECTIVES: There are conflicting data in the literature whether estrogens affect muscle strength. Prospective studies with hormone replacement therapy have not been able to convincingly demonstrate a muscular effect and the putative role of estrogen in the development of lean body mass is not established. Both lean mass and fat mass are known to be under strong genetic control and therefore we have investigated the relation between a TA-repeat in the gene for the estrogen receptor alpha (ERalpha) and muscle strength and body composition. METHODS: 175 healthy Swedish women, aged 20-39 were randomly selected from the population registry and included in the study. Body mass measurements (lean mass, fat mass, body weight and BMI) and muscle strength (quadriceps, hamstring and grip strength) were evaluated. The TA-repeat in the ERalpha gene was amplified by polymerase chain reaction. RESULTS: Alleles with a TA-repeat length of 16 repeats or shorter were denoted short (e), and repeat length of 17 repeats or longer were denoted long (E). Women homozygous for the short and long genotype were denoted ee (31%) and EE (21%), respectively, while heterozygous individuals were denoted Ee (48%). The frequencies were in Hardy-Weinberg equilibrium. No associations were found between ERalpha genotypes and muscle strength or body composition. CONCLUSION: The TA-repeat in the human ERalpha gene does not correlate with muscle strength or body mass measurements, indicating that body composition is not as sensitive to genetic variation in this receptor as other target organs for estrogen.
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| 16. |
- Grundberg, Elin, 1979-
(author)
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Genetic Variability in Human Bone Phenotypes : The Vitamin D Receptor Gene and the Estrogen Receptor-α Cofactor RIZ Gene
- 2006
-
Doctoral thesis (other academic/artistic)abstract
- Important candidate genes to human bone phenotypes are those involved in the regulation of hormonal action, such as the vitamin D receptor (VDR) and the estrogen receptor-α (ERα) genes and their cofactors. RIZ1 is a specific ERα cofactor proved to strongly enhance the function of the ERα. The main focus of this thesis has been to study genetic variants in the VDR and RIZ genes and their associations to human bone phenotypes using candidate gene and functional approaches. Specifically, polymorphisms in the VDR 3’ untranslated region (UTR) and a deletion/insertion polymorphism of a proline in the RIZ gene were investigated.The candidate gene approach was applied to large-scale population-based cohorts of pre-and post-menopausal women from Sweden and of elderly men from Sweden and Hong Kong. VDR 3’ UTR polymorphisms were associated with peak bone mass and body composition in young women. Further analysis of common VDR 3’ UTR haplotypes confirmed the association with BMD and risk of fractures in elderly men from Sweden and Hong Kong. The VDR polymorphisms were investigated for cis-acting effects, affecting allelic expression in the normal chromosomal context of human bone cells. The VDR allelic transcripts in the bone samples were unequally expressed, suggesting presence of regulatory variants in the 3’ UTR. The polymorphism in the RIZ gene was strongly associated to BMD in pre- and postmenopausal women and in elderly men. The functional analyses included reporter constructs containing the RIZ polymorphic variants transfected in a cell line and its abilities in coactivating the ERα were examined. The variants were functionally different in coactivating the ERα-receptor complex. To summarize, the results of this thesis show novel evidence for functional relevant polymorphisms in candidate genes to human bone phenotypes. These polymorphisms may contribute to the variation seen in BMD and risk of fractures in the population.
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| 17. |
- Grundberg, Elin, et al.
(author)
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Genetic variation in the human vitamin D receptor is associated with muscle strength, fat mass and body weight in Swedish women
- 2004
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In: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 150:3, s. 323-328
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Journal article (peer-reviewed)abstract
- Objective: Bone mineral density (BMD) is under strong genetic control and a number of candidategenes have been associated with BMD. Both muscle strength and body weight are considered to beimportant predictors of BMD but far less is known about the genes affecting muscle strength andfat mass. The purpose of this study was to investigate the poly adenosine (A) repeat and the BsmISNP in the vitamin D receptor (VDR) in relation to muscle strength and body composition in healthywomen. Design: A population-based study of 175 healthy women aged 20–39 years was used. Methods: The polymorphic regions in the VDR gene (the poly A repeat and the BsmI SNP) were amplifiedby PCR. Body mass measurements (fat mass, lean mass, body weight and body mass index) andmuscle strength (quadriceps, hamstring and grip strength) were evaluated. Results: Individuals with shorter poly A repeat, ss and/or absence of the linked BsmI restriction site(BB) have higher hamstring strength (ss vs LL, P ¼ 0.02), body weight (ss vs LL, P ¼ 0.049) andfat mass (ss vs LL, P ¼ 0.04) compared with women with a longer poly A repeat (LL) and/or thepresence of the linked BsmI restriction site (bb). Conclusions: Genetic variation in the VDR is correlated with muscle strength, fat mass and bodyweight in premenopausal women. Further functional studies on the poly A microsatellite areneeded to elucidate whether this is the functionally relevant locus or if the polymorphism is in linkagedisequilibrium with a functional variant in a closely situated gene further downstream of the VDR30UTR.
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| 18. |
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| 19. |
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| 20. |
- Grundberg, Elin, et al.
(author)
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Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells
- 2008
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 33:3, s. 301-11
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Journal article (peer-reviewed)abstract
- Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor (P < 10(-8)). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.
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| 21. |
- Grundberg, Elin, et al.
(author)
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The impact of estradiol on bone mineral density is modulated by the specific estrogen receptor-alpha cofactor retinoblastoma-interacting zinc finger protein-1 insertion/deletion polymorphism.
- 2007
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:6, s. 2300-6
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Journal article (peer-reviewed)abstract
- CONTEXT: Estrogens regulate bone mass by binding to the estrogen receptor (ER)-alpha as well as ER-beta. The specific ERalpha cofactor retinoblastoma-interacting zinc finger protein (RIZ)-1 enhances ERalpha function in the presence of estrogen. OBJECTIVE: The objective of the study was to determine whether a RIZ P704 insertion (+)/deletion (-) (indel) polymorphism modulates the impact of estradiol on bone mineral density (BMD) and study the association between the polymorphism and BMD in elderly subjects. DESIGN: This was a population-based, prospective, and cross-sectional study, the Swedish MrOS Study, and the Malmö OPRA Study, respectively. SETTING: The study was conducted at three academic medical centers: Sahlgrenska Academy in Gothenburg, Malmö University Hospital, and Uppsala University Hospital. PARTICIPANTS: In total, 4058 men and women, aged 69-81 yr, were randomly selected from population registries. MAIN OUTCOME MEASURES: BMD (grams per square centimeter) was measured at femoral neck, trochanter, lumbar spine, and total body. RESULTS: The RIZ P704(+/+) genotype was associated with low BMD in both women (femoral neck, P < 0.001; trochanter, P < 0.01; lumbar spine, P < 0.05; total body, P < 0.01) and men (lumbar spine, P < 0.05). However, the association between the polymorphism and BMD was dependent on estradiol status. The positive correlation between serum estradiol and BMD was significantly modulated by the genotype with a stronger correlation in the P704(+/+) group than the P704(-/-) group (r = 0.19 vs. r = 0.08, P < 0.05). CONCLUSIONS: These large-scale studies of elderly men and women indicate that the ERalpha cofactor RIZ gene has a prominent effect on BMD, and the P704 genotype modulates the impact of estradiol on BMD. Further studies are required to determine whether this polymorphism modulates the estrogenic response to estradiol treatment.
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| 22. |
- Grundberg, Elin, et al.
(author)
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Vitamin D receptor 3' haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: the MrOS Study in Sweden and Hong Kong.
- 2007
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In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 0884-0431. ; 22:6, s. 832-40
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Journal article (peer-reviewed)abstract
- The VDR is a prime candidate gene for osteoporosis. Here, we studied three common VDR haplotypes in relation to bone phenotypes in 5014 participants of the global MrOS Study. We also studied the relative expression of the haplotypes in human bone cells. One haplotype was associated with increased fracture risk and differently expressed in primary human bone cells. INTRODUCTION: Vitamin D plays an essential role in skeletal metabolism by binding to its nuclear steroid receptor, the vitamin D receptor (VDR). The heritability of BMD is well established, and the VDR gene is considered a prime candidate suggested to partially account for genetically controlled BMD variance in the population. MATERIALS AND METHODS: Here, we reconstructed common haplotypes in the VDR 3' untranslated region (UTR) and studied the association to BMD and risk of vertebral fractures in elderly men from Sweden (n = 3014) and Hong Kong (n = 2000), all participants of the global MrOS Study. To assess any functional implications of the VDR polymorphisms, we studied allele-specific expressions of the different VDR 3' UTR haplotypes in the normal chromosomal context of 70 unrelated human trabecular bone samples. This was performed by quantitative genotyping of coding polymorphisms in RNA samples and in corresponding DNA samples isolated from the bone samples. RESULTS: Three major haplotypes were reconstructed and in agreement with the previously well-defined baT, BAt, and bAT haplotypes, herein denoted Hap1, Hap2, and Hap3. The Hap1 haplotype was independently associated with increased risk of vertebral fractures in Swedish men (OR, 1.655; 95% CI, 1.146-2.391; p < 0.01) and with lower lumbar spine BMD in elderly men from Sweden (p < 0.01) and Hong Kong (p < 0.05). The VDR gene was also shown to exhibit a 3' UTR haplotype dependent allelic imbalance, indicating that the VDR Hap1 allele was overexpressed in human trabecular bone samples. CONCLUSIONS: The results indicate that the relatively overexpressed VDR Hap1 haplotype could be considered a risk allele for osteoporosis regardless of ethnicity.
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| 23. |
- Grundberg, Elin, et al.
(author)
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Vitamin D receptor 3 ' haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: The MrOS study in Sweden and Hong kong
- 2007
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In: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 22:6, s. 832-840
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Journal article (peer-reviewed)abstract
- The VDR is a prime candidate gene for osteoporosis. Here, we studied three common VDR haplotypes in relation to bone phenotypes in 5014 participants of the global MrOS Study. We also studied the relative expression of the haplotypes in human bone cells. One haplotype was associated with increased fracture risk and differently expressed in primary human bone cells. Introduction: Vitamin D plays an essential role in skeletal metabolism by binding to its nuclear steroid receptor, the vitamin D receptor (VDR). The heritability of BMD is well established, and the VDR gene is considered a prime candidate suggested to partially account for genetically controlled BMD variance in the population. Materials and Methods: Here, we reconstructed common haplotypes in the VDR 3 ' untranslated region (UTR) and studied the association to BMD and risk of vertebral fractures in elderly men from Sweden (n = 3014) and Hong Kong (n = 2000), all participants of the global MrOS Study. To assess any functional implications of the VDR polymorphisms, we studied allele-specific expressions of the different VDR 3 ' UTR haplotypes in the normal chromosomal context of 70 unrelated human trabecular bone samples. This was performed by quantitative genotyping of coding polymorphisms in RNA samples and in corresponding DNA samples isolated from the bone samples. Results: Three major haplotypes were reconstructed and in agreement with the previously well-defined baT, BAt, and bAT haplotypes, herein denoted Hap1, Hap2, and Hap3. The Hap1 haplotype was independently associated with increased risk of vertebral fractures in Swedish men (OR, 1.655; 95% Cl, 1.146-2.391;p < 0.01) and with lower lumbar spine BMD in elderly men from Sweden (p < 0.01) and Hong Kong (P < 0.05). The VDR gene was also shown to exhibit a 3 ' UTR haplotype dependent allelic imbalance, indicating that the VDR Hap1 allele was overexpressed in human trabecular bone samples. Conclusions: The results indicate that the relatively overexpressed VDR Hap1 haplotype could be considered a risk allele for osteoporosis regardless of ethnicity.
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| 24. |
- Jensen, Per, 1956-, et al.
(author)
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Feather pecking in chickens is genetically related to behavioural and developmental traits.
- 2005
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In: Physiology & behavior. - : Elsevier BV. - 0031-9384 .- 1873-507X. ; 86:1-2, s. 52-60
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Journal article (peer-reviewed)abstract
- Feather pecking (FP) is a detrimental behaviour in chickens, which is performed by only some individuals in a flock. FP was studied in 54 red junglefowl (ancestor of domestic chickens), 36 White Leghorn laying hens, and 762 birds from an F(2)-intercross between these two lines. From all F(2)-birds, growth and feed consumption were measured. Age at sexual maturity and egg production in females, and corticosterone levels in males were also measured. From 333 F(2)-birds of both sexes, and 20 parental birds, body composition with respect to bone mineral content, muscle and fat was obtained by post-mortem examinations using Dual X-Ray Absorptiometry (DXA). In femurs of the same birds, the bone density and structure were analysed using DXA and Peripheral Quantitative Computerized Tomography (pQCT), and a biomechanical analysis of bone strength was performed. Furthermore, plumage condition was determined in all birds as a measure of being exposed to feather pecking. Using 105 DNA-markers in all F(2)-birds, a genome-wide scan for Quantitative Trait Loci (QTL), associated with the behaviour in the F(2)-generation was performed. FP was at least as frequent in the red junglefowl as in the White Leghorn strain studied here, and significantly more common among females both in the parental strains and in the F(2)-generation. In the F(2)-birds, FP was phenotypically linked to early sexual maturation, fast growth, weak bones, and, in males, also high fat accumulation, indicating that feather peckers have a different resource allocation pattern. Behaviourally, F(2) feather peckers were more active in an open field test, in a novel food/novel object test, and in a restraint test, indicating that feather pecking might be genetically linked to a proactive coping strategy. Only one suggestive QTL with a low explanatory value was found on chromosome 3, showing that many genes, each with a small effect, are probably involved in the causation of feather pecking. There were significant effects of sire and dam on the risk of being a victim of feather pecking, and victims grew faster pre- and post-hatching, had lower corticosterone levels and were less active in a restraint test. Hence, a wide array of behavioural and developmental traits were genetically linked to FP.
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| 25. |
- Lindahl, Katarina, et al.
(author)
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Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk.
- 2009
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In: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 384:4, s. 501-5
-
Journal article (peer-reviewed)abstract
- Genetic variation plays an important role in osteoporosis and a prime candidate gene is Collagen alpha2(I) (COL1A2). A coding polymorphism (rs42524) in COL1A2 has previously been associated with intracranial aneurysms. Here the effects of this polymorphism have been studied in relation to bone mineral density (BMD) and prevalences of stroke and myocardial infarction (MI). rs42524 was genotyped in elderly men (n = 2004) from the Swedish MrOS cohort. Genotypes were analysed for association to BMD and certain health parameters. Significant associations (overall P < 0.05), were observed between rs42524 genotype and BMD at several skeletal sites. Surprisingly, the heterozygote genotype class exhibited lower BMD than either homozygote group. When subjects were classified as heterozygotes or homozygotes, the heterozygous genotype was found to confer a lower BMD at total hip, femoral neck and trochanter Furthermore, the heterozygote genotype had an increased risk of stroke and MI, with population Attributable Risks being 0.12 and 0.08, respectively.
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| 26. |
- Nilbert, Mef, et al.
(author)
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The power of empirical data; lessons from the clinical registry initiatives in Scandinavian cancer care
- 2020
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In: Acta Oncologica. - 0284-186X. ; 59:11, s. 1343-1356
-
Research review (peer-reviewed)abstract
- Background: In Scandinavia, there is a strong tradition for research and quality monitoring based on registry data. In Denmark, Norway and Sweden, 63 clinical registries collect data on disease characteristics, treatment and outcome of various cancer diagnoses and groups based on process-related and outcome-related variables. Aim: We describe the cancer-related clinical registries, compare organizational structures and quality indicators and provide examples of how these registries have been used to monitor clinical performance, develop prediction models, assess outcome and provide quality benchmarks. Further, we define unmet needs such as inclusion of patient-reported outcome variables, harmonization of variables and barriers for data sharing. Results and conclusions: The clinical registry framework provides an empirical basis for evidence-based development of high-quality and equitable cancer care. The registries can be used to follow implementation of new treatment principles and monitor patterns of care across geographical areas and patient groups. At the same time, the lessons learnt suggest that further developments and coordination are needed to utilize the full potential of the registry initiative in cancer care.
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| 27. |
- Nordström, Anna, 1973-, et al.
(author)
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Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women.
- 2004
-
In: Osteoporosis international. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 15:10, s. 820-6
-
Journal article (peer-reviewed)abstract
- Interleukin 6 (IL-6) is a multifunctional cytokine and a potent stimulator of bone resorption and has been implicated in the pathogenesis of osteoporosis in postmenopausal women. The aim of this study was to investigate if a functional IL-6 promoter polymorphism (-174) was related to bone mass and fractures in a cohort consisting of 964 postmenopausal Caucasian women aged 75 years. Bone mineral density (BMD; g/cm2) of the femoral neck, lumbar spine and total body was measured using dual energy X-ray absorptiometry (DXA). Quantitative ultrasound (QUS) was also measured in the calcaneus and quantified as speed of sound (SOS; m/s), broadband ultrasound attenuation (BUA; dB/MHz), and stiffness index (SI). IL-6 genotypes was determined by restriction fragment length polymorphism (RFLP) using the restriction enzyme NlaIII. The frequencies of the different IL-6 genotypes were 27.5% (GG), 47.9% (GC), 24.6% (CC). The IL-6 polymorphism (presence of G) was independently related to a lower stiffness (beta=-0.07; P=0.03) and BUA (beta=-0.08; P=0.02), but not to BMD at any site measured by DXA. In the cohort, 420 subjects (44%) reported at least one fracture during their lifetime, and 349 (36%) reported at least one fracture after the age of 50. Using binary logistic regression, the IL-6 polymorphism (presence of G) was significantly related to an increased risk of a previous fracture during life (odds ratio 1.46, 95% CI 1.08-1.97) and to an increased risk of a fracture occurring after 50 years of age (odds ratio 1.37, 95% CI 1.004-1.88). The risk was further increased for fractures grouped as osteoporotic fractures (odds ratio 1.67, 95% CI 1.14-2.45), including forearm fractures (odds ratio 1.59, 95% CI 1.05-2.40). In conclusion, presence of G allele in the IL-6 promoter polymorphism at position -174 is independently related to previous fractures in postmenopausal women. This association may be related primarily to an altered bone quality identified by QUS and not a lower bone mass. This is also the first demonstration of association of IL-6 gene polymorphism to calcaneal QUS.
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| 28. |
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| 29. |
- Penno, Hendrik, et al.
(author)
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Expression of RANK-ligand in prostate cancer cell lines
- 2009
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In: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 69:1, s. 151-155
-
Journal article (peer-reviewed)abstract
- The molecular mediators of bone remodelling, receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK) and osteoprotegerine (OPG), are believed to be involved in the cellular mechanisms by which tumours metastasize to bone. RANKL is a potent stimulator of osteoclastic bone resorption and is expressed in a variety of tumour cells. We have investigated if the membrane bound form of RANKL is expressed in prostate cancer cell lines, and whether this expression might be regulated by the presence of human osteoblasts. Three prostate cancer cell lines were co-cultured with human osteoblast-like cells (hOB) and RANKL expression on cell surface was measured by FACS. We found basal expression of RANKL on the cell surface, and in co-culture with hOBs the number of cells expressing RANKL was increased between 2.5 and 4 times. These data suggest a signalling mechanism between bone cells and prostate cancer cells that might increase bone resorption and thereby promote bone metastases.
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| 30. |
- Rubin, Carl-Johan, et al.
(author)
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Quantitative trait loci for BMD and bone strength in an intercross between domestic and wildtype chickens.
- 2007
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In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 0884-0431. ; 22:3, s. 375-84
-
Journal article (peer-reviewed)abstract
- With chicken used as a model species, we used QTL analysis to examine the genetic contribution to bone traits. We report the identification of four QTLs for femoral traits: one for bone strength, one for endosteal circumference, and two affecting mineral density of noncortical bone. INTRODUCTION: BMD is a highly heritable phenotype, governed by elements at numerous loci. In studies examining the genetic contribution to bone traits, many loci have been identified in humans and in other species. The goal of this study was to identify quantitative trait loci (QTLs) controlling BMD and bone strength in an intercross between wildtype and domestic chickens. MATERIALS AND METHODS: A set of 164 markers, covering 30 chromosomes (chr.), were used to genotype 337 F2-individuals from an intercross of domesticated white Leghorn and wildtype red junglefowl chicken. DXA and pQCT were used to measure BMD and bone structure. Three-point bending tests and torsional strength tests were performed to determine the biomechanical strength of the bone. QTLs were mapped using forward selection for loci with significant marginal effects. RESULTS: Four QTLs for femoral bone traits were identified in QTL analysis with body weight included as a covariate. A QTL on chr. 1 affected female noncortical BMD (LOD 4.6) and is syntenic to human 12q21-12q23. Also located on chr. 1, a locus with synteny to human 12q13-14 affected endosteal circumference (LOD 4.6). On chr. 2, a QTL corresponding to human 5p13-p15, 7p12, 18q12, 18q21, and 9q22-9q31 affected BMD in females; noncortical (LOD 4.0) and metaphyseal (LOD 7.0) BMD by pQCT and BMD by DXA (LOD 5.9). A QTL located on chr. 20 (LOD 5.2) affected bone biomechanical strength and had sex-dependent effects. In addition to the significant QTLs, 10 further loci with suggestive linkage to bone traits were identified. CONCLUSIONS: Four QTLs were identified: two for noncortical BMD, one for endosteal circumference, and one affecting bone biomechanical strength. The future identification of genes responsible for these QTLs will increase the understanding of vertebrate skeletal biology.
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| 31. |
- Rubin, Carl-Johan, et al.
(author)
-
Quantitative Trait Loci for BMD and Bone Strength in an Intercross Between Domestic and Wildtype Chickens
- 2007
-
In: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 22:3, s. 375-384
-
Journal article (peer-reviewed)abstract
- With chicken used as a model species, we used QTL analysis to examine the genetic contribution to bone traits. We report the identification of four QTLs for femoral traits: one for bone strength, one for endosteal circumference, and two affecting mineral density of noncortical bone. Introduction: BMD is a highly heritable phenotype, governed by elements at numerous loci. In studies examining the genetic contribution to bone traits, many loci have been identified in humans and in other species. The goal of this study was to identify quantitative trait loci (QTLs) controlling BMD and bone strength in an intercross between wildtype and domestic chickens. Materials and Methods: A set of 164 markers, covering 30 chromosomes (chr.), were used to genotype 337 F 2-individuals from an intercross of domesticated white Leghorn and wildtype red junglefowl chicken. DXA and pQCT were used to measure BMD and bone structure. Three-point bending tests and torsional strength tests were performed to determine the biomechanical strength of the bone. QTLs were mapped using forward selection for loci with significant marginal effects. Results: Four QTLs for femoral bone traits were identified in QTL analysis with body weight included as a covariate. A QTL on chr. 1 affected female noncortical BMD (LOD 4.6) and is syntenic to human 12q21-12q23. Also located on chr. 1, a locus with synteny to human 12q 13-1.4 affected endosteal circumference (LOD 4.6). On chr. 2, a QTL corresponding to human 5p13-p15, 7p12, 18q12, 18q21, and 9q22-9q31 affected BMD in females; noncortical (LOD 4.0) and metaphyseal (LOD 7.0) BMD by pQCT and BMD by DXA (LOD 5.9). A QTL located on chr. 20 (LOD 5.2) affected bone biomechanical strength and had sex-dependent effects. In addition to the significant QTLs, 10 further loci with suggestive linkage to bone traits were identified. Conclusions: Four QTLs were identified: two for noncortical BMD, one for endosteal circumference, and one affecting bone biomechanical strength. The future identification of genes responsible for these QTLs will increase the understanding of vertebrate skeletal biology.
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| 32. |
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| 33. |
- Stiger, Fredrik, et al.
(author)
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Association between repeat length of exon 1 CAG microsatellite in the androgen receptor and bone density in men is modulated by sex hormone levels
- 2008
-
In: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 82:6, s. 427-35
-
Journal article (peer-reviewed)abstract
- In this study we examined whether the androgen receptor (AR) gene CAG repeat polymorphism and serum androgen levels are associated with bone mineral density (BMD) and changes in BMD during 2-3 years in 229 healthy men 41-76 years old. Microsatellite analysis was performed on an automated sequencer. Indices of bioavailable testosterone (free testosterone [FT] and free androgen index) were calculated. BMD was measured using both dual-energy Xray absorptiometry and quantitative ultrasound. All participants completed a questionnaire regarding major possible osteoporosis risk factors. In linear regression analysis there was a modest positive association, which was independent of age and body mass index (BMI), between AR repeat length and BMD at all sites. Although this association was significant independent of BMI, analyses in the subgroup of obese men (BMI > 30) did not reach significance, while the effect was enhanced when analyzing only nonobese men (BMI < or = 30). There was no association between the AR gene polymorphism and rate of bone loss, FT, and BMD or testosterone and bone loss. Interestingly, the association between AR and BMD was modified by total testosterone. The lowest age- and BMI-adjusted average femoral neck BMD was found among men in the lowest tertile for both AR repeat length and FT, whereas men within the higher categories of these variables displayed the highest BMD. In conclusion, there is a positive association between the AR CAG repeat polymorphism and BMD, which is modified by androgen levels in healthy men.
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| 34. |
- Wright, Dominic, et al.
(author)
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Onset of Sexual Maturity in Female Chickens is Genetically Linked to Loci Associated with Fecundity and a Sexual Ornament
- 2012
-
In: Reproduction in domestic animals. - : Blackwell Publishing. - 0936-6768 .- 1439-0531. ; 47:SI, s. 31-36
-
Journal article (peer-reviewed)abstract
- Onset of sexual maturation is a trait of extreme importance both evolutionarily and economically. Unsurprisingly therefore, domestication has acted to reduce the time to sexual maturation in a variety of animals, including the chicken. In comparison with wild progenitor chickens [the Red Junglefowl (RJF)], domestic layer hens attain maturity approximately 20% earlier. In addition, domestic layers also possess larger combs (a sexual ornament), produce more eggs and have denser bones. A large quantitative trait loci (QTL) analysis (n = 377) was performed using an F2 intercross between a White Leghorn layer breed and a RJF population, with onset of sexual maturity measured and mapped to three separate loci. This cross has already been analysed for comb mass, egg production and bone allocation. Onset of sexual maturity significantly correlated with comb mass, whilst the genetic architecture for sexual maturity and comb mass overlapped at all three loci. For two of these loci, the QTL for sexual maturity and comb mass were statistically indistinguishable from pleiotropy, suggesting that the alleles that increase comb mass also decrease onset of sexual maturity.
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| 35. |
- Wright, Dominic, et al.
(author)
-
The genetic architecture of a female sexual ornament
- 2008
-
In: Evolution. - Oxford, United Kingdom : Wiley. - 0014-3820 .- 1558-5646. ; 62:1, s. 86-98
-
Journal article (peer-reviewed)abstract
- Understanding the evolution of sexual ornaments, and particularly that of female sexual ornaments, is an enduring challenge in evolutionary biology. Key to this challenge are establishing the relationship between ornament expression and female reproductive investment, and determining the genetic basis underpinning such relationship. Advances in genomics provide unprecedented opportunities to study the genetic architecture of sexual ornaments in model species. Here, we present a quantitative trait locus (QTL) analysis of a female sexual ornament, the comb of the fowl, Gallus gallus, using a large-scale intercross between red junglefowl and a domestic line, selected for egg production. First, we demonstrate that female somatic investment in comb reflects female reproductive investment. Despite a trade-off between reproductive and skeletal investment mediated by the mobilization of skeletal minerals for egg production, females with proportionally large combs also had relatively high skeletal investment. Second, we identify a major QTL for bisexual expression of comb mass and several QTL specific to female comb mass. Importantly, QTL for comb mass were nonrandomly clustered with QTL for female reproductive and skeletal investment on chromosomes one and three. Together, these results shed light onto the physiological and genetic architecture of a female ornament.
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| 36. |
- Wright, Dominic, 1977-, et al.
(author)
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The genetic architecture of domestication in the chicken: effects of pleiotropy and linkage
- 2010
-
In: Molecular Ecology. - Oxford : Blackwell Publishing Ltd. - 0962-1083 .- 1365-294X. ; 19, s. 5140-5156
-
Journal article (peer-reviewed)abstract
- The extent of pleiotropy and epistasis in quantitative traits remains equivocal. In the caseof pleiotropy, multiple quantitative trait loci are often taken to be pleiotropic if theirconfidence intervals overlap, without formal statistical tests being used to ascertain ifthese overlapping loci are statistically significantly pleiotropic. Additionally, the degreeto which the genetic correlations between phenotypic traits are reflected in thesepleiotropic quantitative trait loci is often variable, especially in the case of antagonisticpleiotropy. Similarly, the extent of epistasis in various morphological, behavioural andlife-history traits is also debated, with a general problem being the sample sizes requiredto detect such effects. Domestication involves a large number of trade-offs, which arereflected in numerous behavioural, morphological and life-history traits which haveevolved as a consequence of adaptation to selective pressures exerted by humans andcaptivity. The comparison between wild and domestic animals allows the geneticanalysis of the traits that differ between these population types, as well as being ageneral model of evolution. Using a large F2 intercross between wild and domesticatedchickens, in combination with a dense SNP and microsatellite marker map, bothpleiotropy and epistasis were analysed. The majority of traits were found to segregate in11 tight ‘blocks’ and reflected the trade-offs associated with domestication. These blockswere shown to have a pleiotropic ‘core’ surrounded by more loosely linked loci. Incontrast, epistatic interactions were almost entirely absent, with only six pairs identifiedover all traits analysed. These results give insights both into the extent of such blocks inevolution and the development of domestication itself.
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