Quantitative trait loci for porcine baseline erythroid traits at three growth ages in a White Duroc × Erhualian F<Subscript>2</Subscript> resource population

Baseline erythroid indices are increasingly involved as risk factors for common complex diseases in humans. However, little is known about the genetic architecture of baseline erythroid traits in pigs. In this study, hematocrit (Hct), hemoglobin (Hgb), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red blood cell (RBC), and red cell distribution width (RDW) were measured in 1420 (day 18), 1410 (day 46), and 1033 (day 240) F(2) pigs from a White Duroc x Erhualian intercross resource population. The entire resource population was genotyped for 183 microsatellite loci across the pig genome, and the quantitative trait loci (QTL) analysis was performed for all erythroid-related traits measured with QTL Express based on a least-squares method. A total of 101 QTL, including 46 genome-wide significant QTL and 55 chromosome-wide significant QTL, regulating erythroid traits were found on all pig chromosomes (SSC) except for SSC15 and SSC18. The genome-wide significant QTL were mainly localized on SSC1, 7, 8, 10, and X. These results confirmed most of QTL previously identified in the swine. More importantly, this study detected age-specific QTL for baseline erythroid traits in pigs for the first time. Notably, the QTL for MCV and MCH on day 18 on SSC8 with small intervals of 3 and 4 cM, respectively, provided a good starting point for identifying causal genes underlying MCV and MCH in the future.     

Mature hematology in neonatal walruses supports diving alongside their mothers

An animal's physiology limits the environmental conditions where it can persist; quantifying the physiology of the walrus is timely since they are being impacted by alterations in sea ice. We examined postnatal changes in hematology, an important attribute that supports diving, by analyzing a longitudinal data set from aquaria walruses (five males and nine females) sampled from 0.04 to 12.0 years of age (n = 795 samples). Red blood cell count (RBC), hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean cell hemoglobin (MCH), and mean corpuscular hemoglobin content (MCHC) did not change markedly after birth and appears to have not been influenced by sex. Estimated values at birth were RBC: 3.78 ± 0.12 × 10⁶ mm⁻³, Hb: 17.62 ± 0.82 g dl⁻¹, Hct: 45.21 ± 2.01%, MCV: 118.99 ± 3.99 fl, MCH: 47.10 ± 1.77 pg, and MCHC: 39.60 ± 0.70 g dl⁻¹. Compared to newborns, there were only subtle decreases in RBC, Hb, and MCHC, and a slight increase in MCV in the years following birth; Hct and MCH appear not to have changed. Unlike other pinnipeds, walruses swim within days of birth and have a prolonged 2-year nursing interval. Mature hematology early in life supports breath-holding, as young walruses must transit under sea ice with patchily distributed breathing holes.     

Hematological responses to thermal acclimation in a cold water squaliform (Heterodontus francisci girard)

Summary The hematological modifications occurring as a result of acclimation to increased temperature in the cold water horn shark,Heterodontus francisci, were evaluated. Sharks were maintained under constant conditions except for temperature (15°C and 25°C) in a closed marine system. The total red blood cell (RBC) number decreased in the 25°C sharks. In contrast, hemoglobin concentration, hematocrit, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) significantly increased at 25°C compared to the control animals. RBC size was increased at 25°C, but the surface area/mm³ whole blood was reduced. Folic acid levels were not different between the groups. Vitamin B₁₂ levels decreased and testosterone increased at 25°C. Blood pH, number of erythroblasts, number of white blood cells (WBC) and WBC differential analyses were essentially unchanged at the two temperatures, except that the relative neutrophil number was increased. The major hematological changes occur in the erythrocytes and appear to be sequential in nature with an initial loss of RBC followed by increased hemoglobin synthesis and increased RBC size, but lack of recovery of RBC numbers.Abbreviations Hb hemoglobin - Hct hematocrit - MCH(C) mean corpuscular hemoglobin (concentration) - MCV mean corpuscular volume - RBC red blood cells - WBC white blood cells Contribution Number 359, Department of Biology     

Cadmium induced MTs synthesis via oxidative stress in yeast Saccharomyces cerevisiae

Lignan complex has been isolated from flaxseed. It has been shown to reduce serum lipids and the extent of hypercholesterolemic atherosclerosis. However, it is not known whether the chronic use of lignan complex has any adverse effects on the hemopoietic system. The effects of lignan complex (40 mg/kg body wt orally daily for 2 months) on the red blood cells (RBC) count, mean corpuscular volume (MCV), red cell distribution width (RDW), hematocrit (Hct), hemoglobin (Hb), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and counts of white blood cell (WBC), granulocytes, lymphocytes, monocytes and platelet, and platelet volume were investigated in normo- and hypercholesterolemic rabbits. The results show that lignan complex had no adverse effects of counts of RBC, WBC, granulocytes, lymphocytes, monocytes and platelet in both the normo- and hyper-cholesterolemic rabbits. The values for MCV, RDW, Hct, Hb, MCH, MCHC, and platelet volume were similar in lignan complex-treated or untreated normo- and hypercholesterolemic rabbits. It is concluded that chronic use of lignan complex had no adverse effects on the hemopoietic system. (Mol Cell Biochem 270: 139–145, 2005)     

Quantitative trait loci for baseline white blood cell count, platelet count, and mean platelet volume

A substantial genetic contribution to baseline peripheral blood counts has been established. We performed quantitative trait locus/loci (QTL) analyses to identify chromosome (Chr) regions harboring genes influencing the baseline white blood cell (WBC) count, platelet (Plt) count, and mean platelet volume (MPV) in F₂ intercrosses between NZW/LacJ, SM/J, and C57BLKS/J inbred mice. We identified six significant WBC QTL: Wbcq1 (peak LOD score at 38 cM, Chr 1), Wbcq2 (42 cM, Chr 3), Wbcq3 (0 cM, Chr 15), Wbcq4 (58 cM, Chr 1), Wbcq5 (82 cM, Chr 1), and Wbcq6 (8 cM, Chr 14). Three significant Plt QTL were identified: Pltq1 (24 cM, Chr 2), Pltq2 (36 cM, Chr 7), and Pltq3 (10 cM, Chr 12). Two significant MPV QTL were identified, Mpvq1 (62 cM, Chr 15) and Mpvq2 (44 cM, Chr 8). In total, the WBC QTL accounted for up to 31% of the total variance in baseline WBC count, while the Plt and MPV QTL accounted for up to 30% and 49% of the total variance, respectively. These analyses underscore the genetic complexity underlying these traits in normal populations and provide the basis for future studies to identify novel genes involved in the regulation of mammalian hematopoiesis.     

The effect of different dietary iron levels on growth and hepatic iron concentration in juvenile gibel carp (Carassius auratus gibelio)

An 83-day growth trial was conducted using a flow-through system to examine the effects of different dietary iron levels on growth and hepatic iron concentration in juvenile gibel carp ( Carassius auratus gibelio ). Six purified diets supplemented with different levels of iron (0, 10, 30, 60, 100 and 200 mg kg⁻¹) (as ferrous sulfate) were fed to triplicate groups of fish (initial weight 2.12 ± 0.00 g per fish). The results showed that the addition of iron to the basal diet did not significantly affect the specific growth rate (SGR), feed efficiency (FE), survival, red blood cell amount (RBC), hemoglobin content (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) or mean corpuscular hemoglobin concentration (MCHC). Hepatic iron concentration and hematocrit (Hct) were significantly influenced by dietary iron level (P < 0.05). On the basis of the iron concentration for the maintenance of optimum hepatic iron concentration and Hct, it was concluded that the dietary iron concentration of juvenile gibel carp should be not less than 202 mg Fe kg⁻¹ diet.     

Development of hematological respiratory variables in late chicken embryos: the relative importance of incubation time and embryo mass

Oxygen demand increases during embryonic development, requiring an increase in red blood cells (RBCs) containing hemoglobin (Hb) to transport O(2) between the respiratory organ and systemic tissues. A thorough ontogenetic understanding of the onset and maturation of the complex regulatory processes for RBC concentration ([RBC]), Hb concentration ([Hb]), hematocrit (Hct), mean corpuscular indices (mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration ([MCHb])) is currently lacking. We hypothesize that during the last half of incubation when the respiratory organ (the chorioallantoic membrane) envelops most of the egg contents, mean corpuscular indices will stabilize. Accordingly, Hct, [RBC] and [Hb] must also all change proportionally across development. Further, we hypothesize that the hematological respiratory variables develop and mature as a function of incubation duration, independently of embryonic growth. As predicted, a similar increase in Hct (from 18.7±0.6% on day 10 (d10) to 34.1±0.5% on d19 of incubation), [RBC] (1.13±0.03×10(6)/μL to 2.50±0.03×10(6)/μL) and [Hb] (6.1±0.2 g% to 11.2±0.1 g%) occurred during d10-19. Both [RBC] and [Hb] demonstrated high linear correlation with Hct, resulting in constant [MCHb] (~33 g% from d10 to d19). The decrease in MCV (from ~165 μ(3) on d10 to ~140 μ(3) on d13) and MCH (~55 pg to ~45 pg) during d10-13, may be attributed to a changeover from larger primary to smaller secondary and adult-type erythrocytes with MCV and MCH remaining constant (~140 μ(3) and ~45 pg respectively) for the rest of the incubation period (d13-19). Hematological respiratory values on a given incubation day were identical between embryos of different masses using either natural mass variation or experimental growth acceleration, indicating that the hematological variables develop as a function of incubation time, irrespective of embryo growth.     

猪2、7和8号染色体上影响血常规指标的数量性状基因座(QTL)检测

以3个品种（长白猪、大白猪、松辽黑猪）16个公猪家系共计368头仔猪组成资源群体,在猪2、7和8号染色体上共选取35个微卫星标记,采用基于线性混合模型的方差组分分析方法,对影响与猪白细胞、红细胞和血小板相关的共计18项血常规指标的数量性状基因座（quantitative trait loci,QTL）进行了检测．通过似然比检验,并以自由度为2的卡方分布作为检验统计量的分布,共发现22个在P〈5％水平下显著的QTL,其中在2号染色体上有9个,分别影响白细胞总数、中性粒细胞数、平均红细胞体积、血红蛋白含量、平均红细胞血红蛋白浓度、血小板总数、平均血小板体积、血小板分布宽度和血小板压积,在7号染色体有7个,分别影响白细胞总数、中性粒细胞数、平均红细胞血红蛋白浓度、血红蛋白含量、血小板总数、平均红细胞体积和红细胞分布宽度变异,在8号染色体上有6个,分别影响中性粒细胞百分比、淋巴细胞百分比、平均红细胞血红蛋白浓度、血小板总数、血小板压积和平均红细胞体积．为尽可能地避免由于多重检验所造成的假阳性率的升高,我们采用了控制假检出率（false discovery rate,FDR）的方法来对这22个QTL进行进一步检验,发现有14个达到FDR〈5％显著水平,其中又有9个达到FDR〈1％显著水平．     

Lack of prominent compensatory polycythemia in traditional native Andeans living at 4,200 meters

Red blood cell count (RBC), hemoglobin concentration ([Hb]) and hematocrit (Hct) were measured in 303 male Quechua children and adults, aged 6 to 57 years, living a lifestyle as traditional pastoralists and horticulturalists at a mean altitude of 4,200 m in the Southern Peruvian Andes. Values for RBC, [Hb], and Hct increased with age from middle childhood to young adulthood. However, among adults there was no significant association between age and any of these three parameters. Overall, there was approximately a 10-12% increase in the RBC, [Hb], and Hct above sea-level norms for all age groups. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) showed a slight but significant increase with age in children and adolescents, but the mean corpuscular hemoglobin concentration (MCHC) did not. We conclude that the study of highland Quechua Indians, living a traditional lifestyle as pastoralists and horticulturalists, does not support the long-held belief that altitude hypoxia provokes a dramatic compensatory polycythemia in healthy Andeans.     

Quantitative trait loci associated with blood pressure of metabolic syndrome in the progeny of NZO/HILtJ × C3H/HeJ intercrosses

In a previous study in 15 inbred mouse strains, we found highest and lowest systolic blood pressures in NZO/HILtJ mice (metabolic syndrome) and C3H/HeJ mice (common lean strain), respectively. To identify the loci involved in hypertension in metabolic syndrome, we performed quantitative trait locus (QTL) analysis for blood pressure with direction of cross as a covariate in segregating F₂ males derived from NZO/HILtJ and C3H/HeJ mice. We detected three suggestive main-effect QTLs affecting systolic and diastolic blood pressures (SBP and DBP). We analyzed the first principle component (PC1) generated from SBP and DBP to investigate blood pressure. In addition to all the suggestive QTLs (Chrs 1, 3, and 8) in SBP and DBP, one suggestive QTL on Chr 4 was found in PC1 in the main scan. Simultaneous search identified two significant epistatic locus pairs (Chrs 1 and 4, Chrs 4 and 8) for PC1. Multiple regression analysis revealed three blood pressure QTLs (Bpq10, 100 cM on Chr 1; Bpq11, 6 cM on Chr 4; Bpq12, 29 cM on Chr 8) accounting for 29.4% of blood pressure variance. These were epistatic interaction QTLs constructing a small network centered on Chr 4, suggesting the importance of genetic interaction for development of hypertension. The blood pressure QTLs on Chrs 1, 4, and 8 were detected repeatedly in multiple studies using common inbred nonobese mouse strains, implying substantial QTL independent of development of obesity and insulin resistance. These results enhance our understanding of complicated genetic factors of hypertension in metabolic diseases. Eri Nishihara, Shirng-Wern Tsaih, Chieko Tsukahara and Sarah Langley contributed equally to this work.     

Single and interacting QTLs for cholesterol gallstones revealed in an intercross between mouse strains NZB and SM

Quantitative trait locus (QTL) mapping was employed to investigate the genetic determinants of cholesterol gallstone formation in a large intercross between mouse strains SM/J (resistant) and NZB/B1NJ (susceptible). Animals consumed a gallstonepromoting diet for 18 weeks. QTL analyses were performed using gallstone weight and gallstone absence/presence as phenotypes; various models were explored for genome scans. We detected seven single QTLs: three new, significant QTLs were named Lith17 [chromosome (Chr) 5, peak=60 cM, LOD=5.4], Lith18 (Chr 5, 76 cM, LOD=4.3), and Lith19 (Chr 8, 0 cM, LOD=5.3); two confirmed QTLs identified previously and were named Lith20 (Chr 9, 44 cM, LOD=2.7) and Lith21 (Chr 10, 24 cM, LOD=2.9); one new, suggestive QTL (Chr 17) remains unnamed. Upon searching for epistatic interactions that contributed to gallstone susceptibility, the final suggestive QTL on Chr 7 was determined to interact significantly with Lith18 and, therefore, was named Lith22 (65 cM). A second interaction was identified between Lith19 and a locus on Chr 11; this QTL was named Lith23 (13 cM). mRNA expression analyses and amino acid haplotype analyses likely eliminated Slc10a2 as a candidate gene for Lith19. The QTLs identified herein largely contributed to gallstone formation rather than gallstone severity. Cloning the genes underlying these murine QTLs should facilitate prediction and cloning of the orthologous human genes.Abbreviations: CI, confidence interval; F₁,first filial generation; F₂, second filial (intercross) generation; LOD, logarithm of the odds ratio; NZB, NZB/B1NJ; QTL, quantitative trait locus; SM, SM/J. The nucleotide sequence data for Slc10a2 were submitted to GenBank and were assigned the accession numbers AY529655 (strain SM) and AY529656 (strain NZB).     

甘肃鼢鼠血象及其与低氧适应的关系

甘肃鼢鼠(Myospalax cansus)是一种严格营地下生活的鼠类,其形态、行为及生理特征均与地面鼠不同。为探讨甘肃鼢鼠适应低氧环境的机理,本研究采用血象指标测定方法,对甘肃鼢鼠低氧适应前后的红细胞数、血红蛋白浓度、红细胞压积等各血象指标进行测定。结果显示,甘肃鼢鼠低氧适应后红细胞数、血红蛋白浓度和红细胞压积均显著升高,而平均红细胞体积、平均红细胞血红蛋白及平均红细胞血红蛋白浓度明显下降。与地面生活的啮齿动物低氧适应后血象相比,甘肃鼢鼠红细胞数量多,红细胞压积大,血红蛋白浓度高,红细胞膜表面积大,血红蛋白的利用率较高,可能是对低氧环境适应的一种途径。     

Effect of storage time on haematological parameters in mullet,Mugil cephalus

The aim of the present study was to assess the effect of storage time at +4 °C on red blood cell count (RBC), haematocrit (Hct), haemoglobin (Hb), white blood cell count (WBC), thrombocyte count (TC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) in mullet (Mugil cephalus) using an automatic method. After blood collection (T₀), all samples were analyzed using both the manual and automatic method. To test the validation of the automatic method, a paired t‐test was applied, and no statistical difference was observed. The samples were successively divided into four different aliquots and stored at +4 °C to assess the haematological parameters using the automatic method. The first aliquot was refrigerated for 6 h, the second one for 24 h, the third one for 48 h and the last one at for 72 h. One‐way repeated‐measures ANOVA showed a significant effect of storage time (P < 0.05) on Hb, WBC, TC, MCH and MCHC. These results suggest that haematological parameters can be assessed within 6 h from blood collection when samples are stored at +4 °C because long‐term storage modifies the results of the analyses. Further studies on these parameters could be still needed in various fish species to validate an appropriate method for haematological analysis useful not only for the evaluation of the health status of animal living in captivity and in aquaculture but also to have reliability environmental haematological biomarkers. Copyright © 2012 John Wiley & Sons, Ltd.     

Generation of N-ethyl-N-nitrosourea-induced mouse mutants with deviations in hematological parameters

Research on hematological disorders relies on suitable animal models. We retrospectively evaluated the use of the hematological parameters hematocrit (HCT), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red blood cell count (RBC), white blood cell count (WBC), and platelet count (PLT) in the phenotype-driven Munich N-ethyl-N-nitrosourea (ENU) mouse mutagenesis project as parameters for the generation of novel animal models for human diseases. The analysis was carried out on more than 16,000 G1 and G3 offspring of chemically mutagenized inbred C3H mice to detect dominant and recessive mutations leading to deviations in the levels of the chosen parameters. Identification of animals exhibiting altered values and transmission of the phenotypic deviations to the subsequent generations led to the successful establishment of mutant lines for the parameters MCV, RBC, and PLT. Analysis of the causative mutation was started in selected lines, thereby revealing a novel mutation in the transferrin receptor gene (Tfrc) in one line. Thus, novel phenotype-driven mouse models were established to analyze the genetic components of hematological disorders.     

Hematology and recovery response in jacundá, Crenicichla saxatilis (Linnaeus, 1758) after short‐term handling stress

The objective of this study was to evaluate the hematological response of ringtail pike cichlid ornamental fish (Crenicichla saxatilis) during the recovery period after short‐term stress. The fish were previously submitted to the stress of chasing, capture and air exposure. Assayed were 24 C. saxatilis (85.2 ± 61.6 g) in three groups of eight fish; after 0.5, 6 and 24 h recovery, blood samples were collected. The total erythrocyte, relative thrombocyte and differential leukocyte counts as well as total hemoglobin, hematocrit, glucose, total plasma protein and the red blood cells (RBC) indices of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and MCH concentration (MCHC) were determined. Stress responses were observed after 0.5 h, although hyperglycemia remained constant during the experiment. Total lymphocyte and hemoglobin values decreased after 0.5 h in the recovery period. An increase of neutrophils and monocytosis was observed after 0.5 and 6 h, respectively. The MCHC remained stable until after 0.5 h, then varied from this time forward. MCV, MCH and erythrocyte numbers oscillated throughout the experiment. Intense stress was observed in the studied C. saxatilis, with most hematological variables not returning to their initial levels after 24 h.     

Effect of irradiation and/or leucocyte filtration on RBC storage lesions

Red blood cell (RBC) storage lesions have been shown to be associated with some adverse reactions; numerous studies have focused on the lesions caused by storage, and few data on the RBC storage lesions caused by prestorage treatments of leucocyte filtration and irradiation. In this study, we examined the changes related with the RBC storage lesions, including 2,3-diphosphatidylglyceric acid (2,3-DPG), pH, free hemoglobin (Hb), supernatant free K+ and Na+ concentration, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH). Along with the increasing storage time, decreases in 2, 3-DPG levels, pH and Na+ concentration, increases in K+ and free Hb concentrations, and significant morphological changes in RBC in all groups were found. The changes in the groups of irradiation, leucocyte filtration and the combined irradiation and leucocyte filtration were more significant than those in the untreated group. Meanwhile, the MCV levels of the three treated groups were significantly lower than those in the untreated group, while the MCH variations were significantly higher. Our results suggest that irradiation and leucocyte filtration before storage may aggravate blood storage lesions.     

Effect of triploidy on turbot haematology

This study was carried out to compare key haematological features of diploid (2n) and triploid (3n) turbot as a first step towards the assessment of the ability of 3n turbot to withstand sub-optimal culture conditions. Morphometric indices of erythrocytes were determined on blood smears by light microscopy. Triploidy significantly (P<0.001) increased all morphometric indices measured in the erythrocytes, including size, surface, and volume, except for the size of minor nuclear axis. The increase in cell size was larger for the major (31.0%) than for the minor (8.3%) axis, thus rendering erythrocytes of 3n turbot more ellipsoidal. The increase in erythrocyte volume (45.9%) was close to the theoretical expected 50% increase as a result of one extra chromosome set. Haematological indices were measured automatically by a haematological Coulter Counter. Triploid turbot had lower numbers of red blood cells (RBC: 1.84 cells pL(-1) in 2n vs. 1.27 cells pL(-1) in 3n; P<0.001) but they were of a larger size (Mean corpuscular volume [MCV]: 145.51 fL in 2n vs. 181.78 fL in 3n; P<0.001). However, the decrease in RBC was not compensated by the increase in MCV, and thus, triploidy decreased the haematocrit (Hct: 26.80% in 2n vs. 23.11% in 3n; P<0.001) and total blood haemoglobin concentration (Hb: 73.74 g l(-1) in 2n vs. 67.54 g l(-1) in 3n; P<0.05). In contrast, mean corpuscular hemoglobin (MCH: 40.27 pg in 2n vs. 53.28 pg in 3n; P<0.001) was higher for 3n turbot as a result of their larger erythrocytes although MCH concentration (MCHC: 0.28 pg fL(-1) in 2n vs. 0.29 pg fL(-1) in 3n did not significantly differ. RBC, Hct and MCV were also determined manually using light microscopy. In general, discrepancies between the two methods were small (overall approximately 7%) but the Coulter Counter tended to overestimate RBC and Hct (and thus to underestimate MCV). Nevertheless, relative differences between ploidies were very similar, thus verifying triploidy-associated changes in hematological features. These changes, as determined in the present study, are essential when evaluating the feasibility of triploid turbot for intensive aquaculture systems in which unfavorable situations may occur.     

New seizure frequency QTL and the complex genetics of epilepsy in EL mice

EL/Suz (EL) mice experience recurrent seizures that are similar to common partial complex epilepsy in humans. In the mice, seizures occur naturally at 90–100 days of age, but can be induced in younger mice and analyzed as a semi-quantitative trait after gentle rhythmic stimulation. A previous genetic mapping study of EL backcrosses to the strains ABP/LeJ or DBA/2J showed two quantitative trait loci (QTL) with large effects on seizure frequency (El1, Chr 9; El2, Chr 2) and implied the existence of other QTL with lesser effects. To further the understanding of EL-derived seizure alleles, we examined intercross progeny of EL and the strains ABP/LeJ and DDY/Jcl, and also a backcross of (EL x DDY)F₁ hybrids to DDY. A new large-effect seizure frequency QTL was found (El5, Chr 14), a more minor QTL confirmed (El3, Chr 10), and two additional QTL proposed (El4, Chr 9; El6, Chr 11). The serotonin receptor gene, Htr2a, maps near and is a candidate for El5, and linkages of other serotonin receptor genes to seizure frequency QTL are noted. In addition, a strong gender effect was revealed, and epistasis was found between Chr 9 and Chr 14 markers. Despite this progress, however, our results revealed a more complex determinism of epilepsy in EL mice than previously described. In particular, no single El locus or pair was essential for frequent seizures, as QTL with large effects, such as El5, El2, and El1, were highly dependent on genetic context. Our studies highlight the importance of gene interaction in some complex mammalian traits defined by natural variation.     

Genetic linkage analysis of X-ray hypersensitivity in the LEC mutant rat

The LEC rat has been reported to exhibit X-ray hypersensitivity and deficiency in DNA double-strand break (DSB) repair. The present study was performed to map the locus responsible for this phenotype, the xhs (X-ray hypersensitivity), as the first step in identifying the responsible gene. Analysis of the progeny of (BN × LEC)F₁× LEC backcrosses indicated that the X-ray hypersensitive phenotype was controlled by multiple genetic loci in contrast to the results reported previously. Quantitative trait loci (QTL) linkage analysis revealed two responsible loci located on Chromosomes (Chr) 4 and 1. QTL on Chr 4 exhibited very strong linkage to the X-ray hypersensitive phenotype, while QTL on Chr 1 showed weak linkage. The Rad52 locus, mutation of which results in hypersensitivity to ionizing radiation and impairment of DNA DSB repair in yeast, was reported to be located on the synteneic regions of mouse Chr 6 and human Chr 12. However, mapping of the rat Rad52 locus indicated that it was located 23 cM distal to the QTL on Chr 4. Furthermore, none of the radio-sensitivity-related loci mapped previously in the rat chromosome were identical to the QTL on Chrs 4 and 1 in the LEC rat. Thus, it seems that X-ray hypersensitivity in the LEC rat is caused by mutation(s) in as-yet-undefined genes. Received: 14 February 2000 / Accepted: 17 May 2000     

Identification of genetic determinants of IGF‐1 levels and longevity among mouse inbred strains

The IGF‐1 signaling pathway plays an important role in regulating longevity. To identify the genetic loci and genes that regulate plasma IGF‐1 levels, we intercrossed MRL/MpJ and SM/J, inbred mouse strains that differ in IGF‐1 levels. Quantitative trait loci (QTL) analysis of IGF‐1 levels of these F2 mice detected four QTL on chromosomes (Chrs) 9 (48 Mb), 10 (86 Mb), 15 (18 Mb), and 17 (85 Mb). Haplotype association mapping of IGF‐1 levels in 28 domesticated inbred strains identified three suggestive loci in females on Chrs 2 (13 Mb), 10 (88 Mb), and 17 (28 Mb) and in four males on Chrs 1 (159 Mb), 3 (52 and 58 Mb), and 16 (74 Mb). Except for the QTL on Chr 9 and 16, all loci co‐localized with IGF‐1 QTL previously identified in other mouse crosses. The most significant locus was the QTL on Chr 10, which contains the Igf1 gene and which had a LOD score of 31.8. Haplotype analysis among 28 domesticated inbred strains revealed a major QTL on Chr 10 overlapping with the QTL identified in the F2 mice. This locus showed three major haplotypes; strains with haplotype 1 had significantly lower plasma IGF‐1 and extended longevity (P < 0.05) than strains with haplotype 2 or 3. Bioinformatic analysis, combined with sequencing and expression studies, showed that Igf1 is the most likely QTL gene, but that other genes may also play a role in this strong QTL.