Linkage analysis of two murine polycystic kidney disease genes, pcy and cpk.

Two murine models of polycystic kidney disease (PKD) in humans are currently available: the infant-type cpk in mice and the adult-type pcy mutation in mice. Our linkage analysis was to determine whether these genes are allelic forms of the same gene, or infant-type and adult-type PKD resulting from homozygous and heterozygous mutation, as in the rat Cy gene. We found that the pcy gene in the mice was linked with the d gene on chromosome 9, but the cpk gene was not. A segregation test indicated that the two genes are inherited independently. This indicates that the cpk and pcy genes are not alleles and that the genetic mechanism of PKD pathogenesis in the mouse is different from that in the Cy rat.     

Closely Linked Polymorphic Markers for Determining the Autosomal Dominant Allele (Cy) in Rat Polycystic Kidney Disease

The Han:SPRD strain is an SD-background strainknown to be a model of polycystic kidney disease (PKD)expressed through an autosomal dominant gene (Cy).However, different genotypes of this strain cannot be identified in the neonatal period. First, toestablish an accurate method of determining thegenotypes (Cy/Cy, Cy/+, +/+) which cause differentdisease progressions, we used polymorphic markers on rat chromosome 5. PCR products of tissue DNAtemplated with D5Rat9 showed distinct patterns onelectrophoresis indicating three genotypes. Second, todetermine whether the same locus plays a major role inexpressing PKD, we performed linkage analyses in a [BN X(BN X Han:SPRD)F₁] backcross. Cy/Cy and Cy/+also caused PKD in a BN background. In this backcross,we discovered that D5Rat11 is located closer to the Cy locus than D5Mgh10, which is regardedas one of the closest loci. We conclude that D5Rat9 andD5Rat11 are useful markers for determining the presenceof the Cy allele, which is regarded as the gene responsible for PKD.     

Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD)

Cyst expansion in polycystic kidney disease (PKD) results in localized hypoxia in the kidney that may activate hypoxia-inducible factor-1α (HIF-1α). HIF-1α and autophagy, a form of programmed cell repair, are induced by hypoxia. The purposes were to determine HIF-1α expression and autophagy in rat and mouse models of PKD. HIF-1α was detected by electrochemiluminescence. Autophagy was visualized by electron microscopy (EM). LC3 and beclin-1, markers of autophagy, were detected by immunoblotting. Eight-week-old male heterozygous (Cy/+) and 4-wk-old homozygous (Cy/Cy) Han:SPRD rats, 4-wk-old cpk mice, and 112-day-old Pkd2WS25/- mice with a mutation in the Pkd2 gene were studied. HIF-1α was significantly increased in massive Cy/Cy and cpk kidneys and not smaller Cy/+ and Pkd2WS25/- kidneys. On EM, features of autophagy were seen in wild-type (+/+), Cy/+, and cpk kidneys: autophagosomes, mitophagy, and autolysosomes. Specifically, autophagosomes were found on EM in the tubular cells lining the cysts in cpk mice. The increase in LC3-II, a marker of autophagosome production and beclin, a regulator of autophagy, in Cy/Cy and cpk kidneys, followed the same pattern of increase as HIF-1α. To determine the role of HIF-1α in cyst formation and/or growth, Cy/+ rats, Cy/Cy rats, and cpk mice were treated with the HIF-1α inhibitor 2-methoxyestradiol (2ME2). 2ME2 had no significant effect on kidney volume or cyst volume density. In summary, HIF-1α is highly expressed in the late stages of PKD and is associated with an increase in LC3-II and beclin-1. The first demonstration of autophagosomes in PKD kidneys is reported. Inhibition of HIF-1α did not have a therapeutic effect.     

Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease

The kidney has both afferent (sensory) and efferent (sympathetic) nerves that can influence renal function. Renal innervation has been shown to play a role in the pathogenesis of many forms of hypertension. Hypertension and flank pain are common clinical manifestations of autosomal dominant (AD) polycystic kidney disease (PKD). We hypothesize that renal innervation contributes to the hypertension and progression of cystic change in rodent PKD. In the present study, the contribution of renal innervation to hypertension and progression of renal histopathology and dysfunction was assessed in male Han:SPRD-Cy/+ rats with ADPKD. At 4 weeks of age, male offspring from crosses of heterozygotes (Cy/+) were randomized into either 1) bilateral surgical renal denervation, 2) surgical sham denervation control, or 3) nonoperated control groups. A midline laparotomy was performed to allow the renal denervation (i.e., physical stripping of the nerves and painting the artery with phenol/alcohol). Blood pressure (tail cuff method), renal function (BUN) and histology were assessed at 8 weeks of age. Bilateral renal denervation reduced the cystic kidney size, cyst volume density, systolic blood pressure, and improved renal function (BUN) as compared with nonoperated controls. Operated control cystic rats had kidney weights, cyst volume densities, systolic blood pressures, and plasma BUN levels that were intermediate between those in the denervated animals and the nonoperated controls. The denervated group had a reduced systolic blood pressure compared with the operated control animals, indicating that the renal innervations was a major contributor to the hypertension in this model of ADPKD. Renal denervation was efficacious in reducing some pathology, including hypertension, renal enlargement, and cystic pathology. However, sham operation also affected the cystic disease but to a lesser extent. We hypothesize that the amelioration of hypertension in Cy/+ rats was due to the effects of renal denervation on the renin angiotensin system.     

Different Allelic Distribution of a Single SNP Between Sexes in Humans

We searched for a difference in allele distribution between males and females of a single nucleotide polymorphism located in the human beta T-cell receptor, in 500 subjects (200 males and 300 females). Genotype analysis gave the following results: among the males, 114 (57%) were heterozygous for the T/C polymorphism, 52 (26%) were homozygous (T/T), and 34 (17%) were homozygous (C/C). Among the females, 142 (47.3%) were heterozygous, 73 (24.3%) were homozygous (T/T), and 85 (28.3%) were homozygous (C/C). The allele frequency was significantly different between sexes (chi2 = 8.799, P = 0.012).     

Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease

Dysregulated signaling cascades alter energy metabolism and promote cell proliferation and cyst expansion in polycystic kidney disease (PKD). Here we tested whether metabolic reprogramming towards aerobic glycolysis (“Warburg effect”) plays a pathogenic role in male heterozygous Han:SPRD rats (Cy/+), a chronic progressive model of PKD. Using microarray analysis and qPCR, we found an upregulation of genes involved in glycolysis (Hk1, Hk2, Ldha) and a downregulation of genes involved in gluconeogenesis (G6pc, Lbp1) in cystic kidneys of Cy/+ rats compared with wild-type (+/+) rats. We then tested the effect of inhibiting glycolysis with 2-deoxyglucose (2DG) on renal functional loss and cyst progression in 5-week-old male Cy/+ rats. Treatment with 2DG (500 mg/kg/day) for 5 weeks resulted in significantly lower kidney weights (-27%) and 2-kidney/total-body-weight ratios (-20%) and decreased renal cyst index (-48%) compared with vehicle treatment. Cy/+ rats treated with 2DG also showed higher clearances of creatinine (1.98±0.67 vs 1.41±0.37 ml/min), BUN (0.69±0.26 vs 0.40±0.10 ml/min) and uric acid (0.38±0.20 vs 0.21±0.10 ml/min), and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-α, a negative regulator of mTOR, and restoration of ERK signaling. Assessment of Ki-67 staining indicated that 2DG limits cyst progression through inhibition of epithelial cell proliferation. Taken together, our results show that targeting the glycolytic pathway may represent a promising therapeutic strategy to control cyst growth in PKD.     

Polycystic nephropathy in slender lorises (Loris lydekkerianus)

In a colony of slender lorises, 20 deaths that occurred over a period of 11 years were investigated postmortem. Juvenile/adult polycystic nephropathy was observed in one newborn and 13 adult slender lorises. Although polycystic kidney disease (PKD) in humans and other animals is known to be inherited, it is not clear whether kidney alterations in slender lorises are genetically transmitted, stress related, or induced by microbiological influences.     

Invited review: Bioinformatic methods to discover the likely causal variant of a new autosomal recessive genetic condition using genome-wide data

In animals, new autosomal recessive genetic diseases (ARGD) arise all the time due to the regular, random mutations that occur during meiosis. In order to reduce the effect of any damaging new variant, it is necessary to find its cause. To evaluate the best way of doing this, 34 papers which found the exact location of a new genetic disease in livestock were reviewed and found to require at least two stages. In the initial stage the commonly used χ² method, applied in a case-control association analysis with single nucleotide polymorphism (SNP)-chip data, was found to have limitations and was almost always used in conjunction with a second method to locate the target region on the genome containing the variant. The commonly used methods had their drawbacks; so a new method was devised based on long runs of homozygosity, a common feature of new ARGD. This ‘autozygosity by difference’ method was found to be as good as, or better than, all the reviewed methods tested based on its ability to unambiguously find the shortest known target region in an already analysed data set. Mean target region length was found to be 4.6 megabases in the published reports. Success did not depend on the size of commercial SNP-chip used, and studies with as few as three cases and four controls were large enough to find the target region. The final stage relied on either sequencing the candidate genes found in the target region or using whole genome sequencing (WGS) on a small number of cases. Sometimes this latter method was used in conjunction with WGS on a number of control animals or resources such as the 1000 bull genomes data. Calculations showed that, in cattle, less than 15 animals would be needed in order to locate the new variant when using WGS data. This could be any combination of cases plus parents or other unrelated animals in the breed. Using WGS data, it would be necessary to search the three billion bases of the cattle genome for base positions which were homozygous for the same allele in all cases and heterozygous for that allele in parents, or not containing that homozygote in unrelated controls. This site could be confirmed on other healthy animals using much cheaper methods, and then a genetic test could be devised for that variant in order to screen the whole population and to devise a breeding programme to eliminate the disorder from the population.     

New C-band polymorphism in the White Park cattle of Great Britain

A chromosome analysis, using G- and sequential Q- and C-banding, of 133 cattle distributed among seven rare breeds of cattle in Great Britain, showed a new C-band polymorphism of chromosome 27. The polymorphism was demonstrated by the absence of a centromeric block of heterochromatin and was only seen in the White Park breed. The polymorphic chromosome had a frequency of 0.446 and was present in either a heterozygous or homozygous state in 75 percent of the White Park cattle studied. The animals carrying the polymorphic chromosome have been traced back to three bulls, two of which have been widely used throughout the breed. It seems likely that the polymorphism arose in one common ancestor before 1949.     

A Novel CCR5 Mutation Common in Sooty Mangabeys Reveals SIVsmm Infection of CCR5-Null Natural Hosts and Efficient Alternative Coreceptor Use In Vivo

In contrast to HIV infection in humans and SIV in macaques, SIV infection of natural hosts including sooty mangabeys (SM) is non-pathogenic despite robust virus replication. We identified a novel SM CCR5 allele containing a two base pair deletion (Δ2) encoding a truncated molecule that is not expressed on the cell surface and does not support SIV entry in vitro. The allele was present at a 26% frequency in a large SM colony, along with 3% for a CCR5Δ24 deletion allele that also abrogates surface expression. Overall, 8% of animals were homozygous for defective CCR5 alleles and 41% were heterozygous. The mutant allele was also present in wild SM in West Africa. CD8+ and CD4+ T cells displayed a gradient of CCR5 expression across genotype groups, which was highly significant for CD8+ cells. Remarkably, the prevalence of natural SIVsmm infection was not significantly different in animals lacking functional CCR5 compared to heterozygous and homozygous wild-type animals. Furthermore, animals lacking functional CCR5 had robust plasma viral loads, which were only modestly lower than wild-type animals. SIVsmm primary isolates infected both homozygous mutant and wild-type PBMC in a CCR5-independent manner in vitro, and Envs from both CCR5-null and wild-type infected animals used CXCR6, GPR15 and GPR1 in addition to CCR5 in transfected cells. These data clearly indicate that SIVsmm relies on CCR5-independent entry pathways in SM that are homozygous for defective CCR5 alleles and, while the extent of alternative coreceptor use in SM with CCR5 wild type alleles is uncertain, strongly suggest that SIVsmm tropism and host cell targeting in vivo is defined by the distribution and use of alternative entry pathways in addition to CCR5. SIVsmm entry through alternative pathways in vivo raises the possibility of novel CCR5-negative target cells that may be more expendable than CCR5+ cells and enable the virus to replicate efficiently without causing disease in the face of extremely restricted CCR5 expression seen in SM and several other natural host species.     

Dietary betaine modifies hepatic metabolism but not renal injury in rat polycystic kidney disease

We undertook a morphometric and proton nuclear magnetic resonance ((1)H-NMR) study to test the hypothesis that 1% dietary betaine supplementation would ameliorate renal disease in the heterozygous Han:SPRD-cy rat, a model of polycystic kidney disease (PKD) and progressive chronic renal failure. After 8 wk of pair feeding, betaine had no effect on renal cystic change, renal interstitial fibrosis, serum creatinine, serum cholesterol, or serum triglycerides. (1)H-NMR spectroscopy of renal tissue revealed no change in renal osmolytes, including betaine, or renal content of other organic anions in response to diet. (1)H-NMR spectroscopy of hepatic tissue performed to explore the metabolic fate of ingested betaine revealed that heterozygous animals fed the control diet had elevated hepatic levels of gluconeogenic amino acids, increased beta-hydroxybutyrate, and increased levels of some citric acid cycle metabolites compared with animals without renal disease. Betaine supplementation eliminated these changes. Chronic renal failure in the Han:SPRD-cy rat is associated with disturbances of hepatic metabolism that can be corrected with betaine therapy, suggesting the presence of a reversible methylation defect in this form of chronic renal failure.     

Association between population structure and allele frequencies of the glycogen synthase 1 mutation in the Austrian Noriker draft horse

The aim of this study was to determine the allele frequency of the glycogen synthase 1 (GYS1) mutation associated with polysaccharide storage myopathy type 1 in the Austrian Noriker horse. Furthermore, we examined the influence of population substructures on the allele distribution. The study was based upon a comprehensive population sample (208 breeding stallions and 309 mares) and a complete cohort of unselected offspring from the year 2014 (1553 foals). The mean proportion of GYS1 carrier animals in the foal cohort was 33%, ranging from 15% to 50% according to population substructures based on coat colours. In 517 mature breeding horses the mutation carrier frequency reached 34%, ranging on a wider scale from 4% to 62% within genetic substructures. We could show that the occurrence of the mutated GYS1 allele is influenced by coat colour; genetic bottlenecks; and assortative, rotating and random mating strategies. Highest GYS1 carrier frequencies were observed in the chestnut sample comprising 50% in foals, 54% in mares and 62% in breeding stallions. The mean inbreeding of homozygous carrier animals reached 4.10%, whereas non‐carrier horses were characterized by an inbreeding coefficient of 3.48%. Lowest GYS1 carrier frequencies were observed in the leopard spotted Noriker subpopulation. Here the mean carrier frequency reached 15% in foals, 17% in mares and 4% in stallions and inbreeding decreased from 3.28% in homozygous non‐carrier horses to 2.70% in heterozygous horses and 0.94% in homozygous carriers. This study illustrates that lineage breeding and specified mating strategies result in genetic substructures, which affect the frequencies of the GYS1 gene mutation.     

Human neutral alpha-glucosidase C: genetic polymorphism including a "null" allele.

We describe a genetic polymorphism of human neutral alpha-glucosidase C, detected in lymphoid cells by a combination of starch gel electrophoresis and isoelectric focusing. The seven phenotypes observed appear to result from the expression of four different alleles. The distribution of the observed phenotypes fits the expected distribution predicted from calculated gene frequencies in Hardy-Weinberg equilibrium. Family studies are consistent with autosomal inheritance of the gene. The product of one of the alleles is unusual in that it is "silent," with an estimated gene frequency of .174 in an outbred white population. Approximately one-third of the population is heterozygous "null." Homozygosity for the allele has not been associated with any obvious disease state. This is the third example of a "null" allele which has a substantial gene frequency in an outbred population but does not appear to result in disease in the homozygous state.     

Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling

Han:SPRD Cy is a spontaneous rat model of polycystic kidney disease (PKD) caused by a missense mutation in Pkdr1. Cystogenesis in this model is not clearly understood. In the current study, we performed global gene expression profiling in early-stage PKD cyst development in Cy/Cy kidneys and normal (+/+) kidneys at 3 and 7 days of postnatal age. Expression profiles were determined by microarray analysis, followed by validation with real-time RT-PCR. Genes were selected with over 1.5-fold expression changes compared with age-matched +/+ kidneys for canonical pathway analysis. We found nine pathways in common between 3- and 7-day Cy/Cy kidneys. Three significantly changed pathways were designated "Vitamin D Receptor (VDR)/Retinoid X Receptor (RXR) Activation," "LPS/IL-1-Mediated Inhibition of RXR Function," and "Liver X Receptor (LXR)/RXR Activation." These results suggest that RXR-mediated signaling is significantly altered in developing kidneys with mutated Pkdr1. In gene ontology analysis, the functions of these RXR-related genes were found to be involved in regulating cell proliferation and organ morphogenesis. With real-time RT-PCR analysis, the upregulation of Ptx2, Alox15b, OSP, and PCNA, major markers of cell proliferation associated with the RXR pathway, were confirmed in 3- and 7-day Cy/Cy kidneys compared with 3-day +/+ kidneys. The increased RXR protein was observed in both the nucleus and cytoplasm of cystic epithelial cells in early-stage Cy/Cy kidneys, and the RXR-positive cells were strongly positive for PCNA staining. Taken together, cell proliferation and organ morphogenesis signals transduced by RXR-mediated pathways may have important roles for cystogenesis in early-stage PKD in this Pkdr1-mutated Cy rat.     

DNA repair genetic polymorphisms and risk of colorectal cancer in the Czech Republic

Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case-control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01-2.22; p=0.05). The data stratification showed increased risk of colorectal cancer in the age group 64-86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04-3.07; p=0.04) and homozygous (OR: 2.57; 95% CI: 1.30-5.06; p=0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism showed increased risk of colorectal cancer (OR: 4.17; 95% CI: 1.17-15.54; p=0.03). The analysis of binary genotype combinations showed increased colorectal cancer risk in individuals simultaneously homozygous for the variant alleles of APE1 Asn148Glu and hOGG1 Ser326Cys (OR: 6.37; 95% CI: 1.40-29.02; p=0.02). Considering the subtle effect of the DNA repair polymorphisms on the risk of colorectal cancer, exploration of gene-gene and gene-environmental interactions with a large sample size with sufficient statistical power are recommended.     

基于磁性颗粒“在位”PCR和通用标签技术的新型高通量SNP分型方法

单核苷酸多态性(single nucleotide polymorphism,SNP)在对复杂疾病遗传易感性以及基于群体基因识别等方面的研究中起着非常重要的作用,尤其是对复杂疾病遗传易感性的研究,需要对大量样本进行分型.为了满足这种要求,亟待需要发展一种操作简单、成本较低、适于自动化和高通量的分型技术.利用磁性颗粒"在位"固相PCR(insituMPs-PCR)扩增的靶序列,通过与野生、突变标签探针以及双色荧光(Cy3,Cy5)通用检测子杂交实现对样本的分型.应用该方法,对96个样本的亚甲基四氢叶酸还原酶(MTHFR)基因C677T位点的多态性进行了检测,其野生型和突变型样本的正错配信号比大于4.5,杂合型正错配信号比接近1,分型结果与测序结果一致.     

Not too much and not too little

We tend to think in black and white terms of good versus bad alleles and their meaning for disease. However, in doing so, we ignore the potential importance of heterozygous alleles.The structure and function of any protein is determined by its amino acid sequence. Thus, the substitution of one amino acid for another can alter the activity of a protein or its function. Mutations—or rather, polymorphism, once they become fixed in the population—can be deleterious, such that the altered protein is no longer able to fulfil its role with potentially devastating effects on the cell. Rarely, they can improve protein function and cell performance. In either case, any changes in the amino acid sequence, whether they affect only one amino acid or larger parts of the protein, are encoded by polymorphisms in the nucleotide sequence of that protein''s gene. For any given polymorphism, diploid organisms with two sets of chromosomes can therefore exist in either a heterozygous state or one of two homozygous states. When the polymorphism is rare, most individuals are homozygous for the ‘wild-type'' state, some individuals are heterozygous and a few are homozygous for the rare polymorphic variant. Conversely, if the polymorphism occurs in 50% of the alleles, the heterozygous state is common.At first glance, the deleterious homozygous state seems to be something that organisms try to avoid: close relatives usually do not breed, probably to prevent the homozygous accumulation of deleterious alleles. Thus, human cultural norms, founded in our biology, actively select for heterozygosity as many civilizations and societies regard incest as a social taboo. The fields of animal husbandry and conservation biology are littered with information about the significant positive correlation between genetic diversity, evolutionary advantage and fitness [1]. In sexually reproducing organisms, heterozygosity is generally regarded as ‘better'' in terms of adaptability and evolutionary advantage.Why then do we seldom, if ever, regard allelic heterozygosity as an advantage when it comes to genes linked with health and disease? Perhaps it is because we tend to distinguish between the ‘good'' allele, the ‘bad'' allele and the ‘ugly'' heterozygote—since it is burdened with one ‘bad'' allele. Maybe this attitude is a remnant of the outdated ‘one gene, one disease'' model, or of the early studies on inheritable diseases that focused on monogenic or autosomal-dominant genetic disorders. Even modern genetics almost always assigns ‘risk'' to an allele that is associated with a health condition or disadvantaged phenotype; clearly, then, the one homozygous state must have an advantage—sometimes referred to as wild-type—but the heterozygote is often ignored altogether.Maybe we also shun heterozygosity because it is hard to prove, beyond a few examples, that it might offer advantage. A 2010 paper published in Cell claimed that heterozygosity of the lth4A locus conveys protection against tuberculosis [2]. There is a mechanistic basis for the claim: lth4A encodes leukotriene A4 hydrolase, which is the final catalyst to synthesize leukotriene B4, an efficient pro-inflammatory eicosanoid. However, an extensive case–control study could not confirm the association between heterozygosity and protection against tuberculosis [3]. Therefore, many in the field dismiss the prior claim to protection conferred by the heterozygous state.Yet, we know that most biochemical and physiological processes are highly complex systems that involve multiple, interlinked steps with extensive control and feedback mechanisms. Heterozygosity might be one strategy by which an organism maintains flexibility, as it provides more than one allele to fall back on, should conditions change. We may therefore hypothesize that heterozygosity can be either a risk or an advantage, depending on the penetrance or dominance of the alleles. Indeed, there are a few cases in which heterozygosity confers some advantage. For example, individuals who are homozygous for the CCR5 deletion polymorphism (D32/D32) are protected against HIV1 infection, whereas CCR5/D32 heterozygotes have a slower progression to acquired immunodeficiency syndrome (AIDS). In sickle-cell anaemia, heterozygotes have a protective advantage against malaria, whereas the homozygotes either lack protection or suffer health consequences. Thus, although heterozygosity might not create a general fitness advantage, it is advantageous under certain specific conditions, namely the presence of the malaria parasite.In most aspects of life, there are few absolutes and many shades of grey. The ‘normal'' range of parameters in medicine is a clear example of this: optimal functioning of the relevant physiological processes depends on levels that are ‘just right''. As molecular and genetic research tackles the causes and risk factors of complex diseases, we may perhaps find more examples of how heterozygosity at the genetic level conveys health advantages in humans. As the above example regarding tuberculosis indicates, it is difficult to demonstrate any advantage of the heterozygous state. We simply need to be receptive to such possibilities, and improve and reconcile our understanding of allelic diversity and heterozygosity. Researchers working on human disease could benefit from the insights of evolutionary biologists and breeders, who are more appreciative of the heterozygous state.     

Distribution of the HIV resistance CCR5-Delta32 allele among Egyptians and Syrians

A mutant allele of the beta-chemokine receptor gene CCR5 bearing a 32-basepair (bp) deletion that prevents cell invasion by the primary transmitting strain of HIV-1 has recently been characterized. Individuals homozygous for the mutation are resistant to infection, even after repeated high-risk exposure, but this resistance appears not absolute, as isolated cases of HIV-positive deletion homozygotes are emerging. The consequence of the heterozygous state is not clear, but it may delay the progression to AIDS in infected individuals. In order to evaluate the frequency distribution of CCR5-Delta32 polymorphism among Egyptians, a total of 200 individuals (154 from Ismailia and 46 from Sinai) were tested. Only two heterozygous individuals from Ismailia carried the CCR5-Delta32 allele (0.6%), and no homozygous (Delta32/Delta32) individuals were detected among the tested samples. The presence of the CCR5-Delta32 allele among Egyptians may be attributed to the admixture with people of European descent. Thus we conclude that the protective deletion CCR5-Delta32 is largely absent in the Egyptian population.     

Bodily heat resistance and polymorphism of liver esterases of grass frogs]

The determination of organismal heat resistance and qualitative composition of polymorphous liver esterases during heat acclimation (25 degrees) has been made on frogs Rana temporaria. During hybernation the most heat resistant frogs possess the homozygous allele of A2 esterase. Heat acclimation and the summer rise in temperature in nature lead to an increase in heat resistance of frogs and to the disappearance of selective advantage of animals possessing the isoenzyme of the A2A2 esterase. The functional homeostasis of populations can maintain biochemical polymorphism regardless of the selective advantage of individuals possessing one of the homozygous alleles of the isoenzyme.     

Socialization strategies and disease transmission in captive colonies of nonhuman primates

In captive research environments for nonhuman primates (NHP), social housing strategies are often in conflict with protocols designed to minimize disease transmission. This is particularly true in breeding colonies, and is especially relevant when attempting to eliminate specific pathogens from a population of primates. Numerous strategies have been used to establish such specific pathogen free (SPF) breeding colonies (primarily of macaques), ranging from nursery rearing of neonates to single housing of socially reared yearlings to the rearing of infants in large social groups. All these strategies attempt to balance the effects of the chosen socialization strategy on parameters related to disease transmission, including the ultimate elimination of the target pathogens. Such strategies may affect the overall disease states of NHP breeding colonies through selective breeding processes. This can occur either by creating subpopulations of animals that do not have target diseases (SPF colonies), but may have other issues; or by creating situations in which the "best" animals are sold and the breeding colony is stocked with animals that may be more disease susceptible than those that were sold. The disease states of NHP research colonies also may be affected by selective utilization programs, in which animals removed from the breeding colony for health/behavior reasons, are preferentially chosen for use in scientific investigations. Such utilization criteria raise the question of whether ideal subjects are being chosen for use in research. Finally, captive primate colonies, where both socialization and disease states are intensely managed, may provide opportunities for those testing predictions from models of the interactions of socialization and disease transmission in the evolution of wild populations of NHP. This would be especially true for some extreme conditions of these disease ecology models, given the exceedingly high social densities and levels of pathogen control that exist in many captive nonhuman primate colonies.