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Extending preimplantation genetic diagnosis: the ethical debate. Ethical issues in new uses of preimplantation genetic diagnosis.

The use of preimplantation genetic diagnosis (PGD) to screen embryos for aneuploidy and genetic disease is growing. New uses of PGD have been reported in the past year for screening embryos for susceptibility to cancer, for late-onset diseases, for HLA-matching for existing children, and for gender. These extensions have raised questions about their ethical acceptability and the adequacy of regulatory structures to review new uses. This article describes current and likely future uses of PGD, and then analyses the ethical issues posed by new uses of PGD to screen embryos for susceptibility and late-onset conditions, for HLA-matching for tissue donation to an existing child, and for gender selection. It also addresses ethical issues that would arise in more speculative scenarios of selecting embryos for hearing ability or sexual orientation. The article concludes that except for sex selection of the first child, most current extensions of PGD are ethically acceptable, and provides a framework for evaluating future extensions for nonmedical purposes that are still speculative.

Genetic Predisposition to Disease↗

Genetic selection strategies--population genetics.

This paper provides an overview of the association between population genetics and selection strategies in poultry. Relationships between artificial and natural selection and among causes contributing to limits to artificial selection are discussed. Homeostasis and resource allocations at the individual and at the population level are reviewed. Examples from poultry demonstrate where human intervention has circumvented biological limits. Lastly, this paper considers the role of population genetics in future breeding strategies for poultry.

Animal Husbandry↗

Epistasis between new mutations and genetic background and a test of genetic canalization.

The importance for fitness of epistatic interactions among mutations is poorly known, yet epistasis can exert important effects on the dynamics of evolving populations. We showed previously that epistatic interactions are common between pairs of random insertion mutations in the bacterium Escherichia coli. In this paper, we examine interactions between these mutations and other mutations by transducing each of twelve insertion mutations into two genetic backgrounds, one ancestral and the other having evolved in, and adapted to, a defined laboratory environment for 10,000 generations. To assess the effect of the mutation on fitness, we allowed each mutant to compete against its unmutated counterpart in that same environment. Overall, there was a strong positive correlation between the mutational effects on the two genetic backgrounds. Nonetheless, three of the twelve mutations had significantly different effects on the two backgrounds, indicating epistasis. There was no significant tendency for the mutations to be less harmful on the derived background. Thus, there is no evidence supporting the hypothesis that the derived bacteria had adapted, in part, by becoming buffered against the harmful effects of mutations.

Epistasis, Genetic↗

Plasmids of lactococci - genetic accessories or genetic necessities?

Lactococci are one of the most exploited microorganisms used in the manufacture of food. These intensively used cultures are generally characterized by having a rich plasmid complement. It could be argued that it is the plasmid complement of commercially utilized cultures that gives them their technical superiority and individuality. Consequently, it is timely to reflect on the desirable characteristics encoded on lactococcal plasmids. It is argued that plasmids play a key role in the evolution of modern starter strains and are a lot more than just selfish replicosomes but more essential necessities of intensively used commercial starters. Moreover, the study of plasmid biology provides a genetic blueprint that has proved essential for the generation of molecular tools for the genetic improvement of Lactococcus lactis.

Genetic Markers↗

Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies.

Population stratification, secondary effects of illness or treatment, biological heterogeneity of a clinical syndrome, or complex biology underlying a syndrome (where only one component is measured) are conditions which may obscure the association of a genetic risk factor with a clinical syndrome. We consider several investigative strategies under each of these conditions. Only segregation-based paradigms are robust to genetic heterogeneity and population stratification. But secondary effects on the risk factor produced by illness or treatment require other strategies for their detection.

Chromosome Aberrations↗

Genetic analysis of cystic fibrosis in Denmark. Implications for genetic counselling, carrier diagnosis and prenatal diagnosis.

Cystic fibrosis is the most common, severe, inherited disease in the Caucasian population. As a consequence, the demand for genetic counselling of patients with cystic fibrosis and their families is large. In Denmark the incidence of cystic fibrosis is 1:4700, which is quite low compared to other European countries. We have investigated 268 Danish cystic fibrosis patients with respect to DNA markers (haplotypes) and the most common mutation delta F508. The delta F508 mutation is found on 88% of all cystic fibrosis chromosomes, the highest frequency reported so far. This had had an important impact on genetic counselling, prenatal diagnosis and eventually population screening. In the Danish population 78% of all couples at risk will be informative for delta F508 and will be identifiable by simple screening methods.

Cystic Fibrosis↗

A consortium approach to molecular genetic services. Scottish Molecular Genetics Consortium.

The four Scottish university medical genetics centres formed a consortium in 1985 to provide a DNA based service in prenatal diagnosis, carrier detection, and predictive testing for a range of Mendelian disorders. Each centre took sole responsibility for laboratory analyses of an assigned set of disorders, while families continued to be investigated and patients counselled within their own areas. DNA was extracted from relevant tissues in the centre most convenient to the family member and then dispatched to the appropriate laboratory for analysis. Results were interpreted and risks assessed by discussion between laboratory staff and the clinical geneticist in charge of the case. In the first three years of the consortium 92 prenatal diagnoses or exclusion tests were carried out, the majority being for cystic fibrosis (35), Duchenne muscular dystrophy (21), and Huntington's disease (11). Carrier testing was carried out in 271 X linked recessive disorders, the most common indications being Duchenne and Becker muscular dystrophies (198) and haemophilias A and B (48). Predictive testing was attempted in 41 consultants at risk for Huntington's disease, 37 at risk for myotonic dystrophy, and 32 at risk for developing adult polycystic kidney disease. The total of all carrier tests, including those for autosomal recessives, was 543. A consortium or supraregional approach to molecular genetics services has a number of advantages. Constituent laboratories need hold only those probes and enzymes relevant to their assigned disorders and can gain maximum experience with these systems. Scattered families may often be linked into single kinships, thus allowing rapid confirmation of diagnosis when an urgent request is made for a prenatal diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Cystic Fibrosis↗

On the genetics and population genetics of Gm(4).

Investigations on 70 German families with 142 children confirmed the autosomal-dominant inheritance of Gm(4). However, in our material as well as in the materials published so far, Gm(4) X Gm(-4) parental combinations show clear surplusses of Gm(4) and deficits of Gm(-4) children, which might indicate prenatal selection. The world distribution of Gm4 alleles reveals a remarkable racial heterogeneity. Furthermore, marked North-South distribution gradients in Caucasoids and Mongoloids were found. The genetical and population genetical observations are discussed.

Adult↗

Genetic factors in lipoprotein metabolism. Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach.

A genetic cross was constructed from two parental inbred strains of mice, NZB/BINJ and SM/J, which differ markedly in their plasma lipoprotein levels. Plasma lipid and apolipoprotein values were measured in 184 F2 progeny on a normal chow diet and on an atherogenic diet. Genetic markers were typed at 126 loci spanning all chromosomes except the Y. Statistical analysis revealed significant linkage or suggestive linkage of lipoprotein levels with markers on a number of chromosomes. Chromosome 1 markers were linked to levels of total cholesterol (lod 5.9) and high density lipoprotein (HDL) cholesterol (lod 8.1), chromosome 5 markers were linked to levels of total cholesterol (lod 6.7) and HDL cholesterol (lod 5.6), and chromosome 7 markers were linked to levels of total plasma triglycerides (lod 5.1) and free fatty acids (lod 5.6). Plasma apoAII levels were linked to the apoAII gene (lod score 19.6) and were highly correlated with plasma HDL cholesterol levels (r = 0.63, P = 0.0001), indicating that apoAII expression influences HDL cholesterol levels. Molecular studies suggested that structural differences in the apoAII polypeptide of the two strains may contribute to differences in clearance of the protein.

Amino Acid Sequence↗

Genetic epidemiology. Approaches to the genetic analysis of rheumatoid arthritis.

The basis of susceptibility to rheumatoid arthritis (RA) is complex, comprising genetic and environmental susceptibility factors. We have reviewed the available approaches to the investigation of the genetic basis of complex diseases and how these are being applied to RA. Affected-sibling-pair methods for nonparametric linkage analysis, linkage-disequilibrium-based approaches, transmission disequilibrium testing, and disease-association studies are discussed. The pros, cons, and limitations of the approaches are considered and are illustrated by examples from the literature about rheumatoid arthritis.

Arthritis, Rheumatoid↗

Genetic and environmental effects on carcass characteristics of Southdown x Romney lambs: II. Genetic and phenotypic variation.

Approximately 4,400 crossbred lambs from Southdown sires and Romney ewes were slaughtered at approximately 18, 23, and 28 wk of age over a 16-yr period. Live weights, carcass measurements, and chemical percentages were analyzed to estimate genetic and phenotypic parameters. Heritabilities of postweaning weights and gains were about .20. Heritabilities of fat and water percentages were about .35 adjusted for age. Heritability of kidney fat percentage was .53. Heritabilities of fat depth and muscle measurements ranged from .21 to .37. Crutch depth (h2 = .73) and cannon bone length (h2 = .74) were the most highly heritable carcass measurements. The genetic correlation between carcass fat and fat-free weight was .47 when lambs were slaughtered at a constant age. Fat-free weight was nearly uncorrelated with percentages of fat, water, and protein when lambs were slaughtered at the same age. Carcass measurements increased accuracy of selection for fat-free weight at a constant age very little compared with using only carcass weight. However, this does not mean that additional measurements are useless. The addition of carcass measurements to the selection criteria would result in correlated responses in chemical composition that more closely resembled direct selection for fat-free weight. Carcass weight would be of little value when used by itself to reduce fat weight adjusted for carcass weight. Direct measurement of carcass composition resulted in 1.6 to 2.6 times more predicted response for reduced fat weight than any combination of carcass weight and one fat depth measurement.

Adipose Tissue↗

Nonlinear genetic relationships between traits and their implications on the estimation of genetic parameters.

To estimate nonlinear genetic relationships between traits, formulas based on the paternal halfsib analysis theory were derived. To illustrate the usefulness of the formulas, a series of data sets with halfsib structure for some preselected parameters and sample size situations were generated by means of Monte Carlo techniques. When a nonlinear relationship in the form of a polynomial relationship of degree two is present, the linear and quadratic regression coefficients can be estimated from a paternal halfsib analysis without bias. Some of the traditional linear genetic parameters need correction; however, their value is limited if the relationship between two traits is nonlinear. Although regression coefficients may be estimated appropriately in many situations, the application of the described method is restricted to situations in which the causal flow between the traits involved is clear and the heritability of the determining trait is larger than approximately .10. Further work should be directed to investigation of possibilities for including such parameters in selection decisions in a formalized way.

Analysis of Variance↗

Genetic and developmental analysis of irreC, a genetic function required for optic chiasm formation in Drosophila.

Irregular chiasm C (irreC) is an X-linked genetic function necessary for the correct projection of visual fibers in the optic chiasms of Drosophila optic ganglia. In addition to a severe disorganization of the inner optic chiasm irreC mutants display a subtle phenotype in the outer optic chiasm, in which some bundles of axons that leave the posterior equatorial part of the lamina on their way to the anterior medulla take a long detour before eventually finding their specific targets in the medulla neuropile. Deletion and recombination mapping of two irreC alleles (one P-element induced, the other associated with an inversion) have yielded a precise cytogenetic location in 3C4-5. A complex complementation pattern between roughest (rst) and irreC alleles indicates that both genetic functions are structurally and/or functionally closely interrelated. Flies in which the irreC locus is completely deleted by overlapping deficiencies are viable and their defects in the optic chiasms are similar to those seen in the two alleles. The defects in the outer and inner optic chiasms are not epigenetically connected and mosaic analyses have shown them to be independent from the genotype of the compound eye. Although the larval visual nerve looks normal, we have found that in the optic lobes of irreC mutants a group of early differentiating larval neurons is misplaced, suggesting a pioneering function of these cells during organization of the outer optic chiasms.

Animals↗

Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.

OBJECTIVE: To determine the spectrum, frequency, and ethnic-specificity of channel variants in the potassium channel genes implicated in congenital long QT syndrome (LQTS) among healthy subjects. SUBJECTS AND METHODS: Genomic DNA from 744 apparently healthy individuals-305 black, 187 white, 134 Asian, and 118 Hispanic--was subject to a comprehensive mutational analysis of the 4 LQTS-causing potassium channel genes: KCNQ1 (LQT1), KCNH2 (LQT2), KCNE1 (LQT5), and KCNE2 (LQT6). RESULTS: Overall, 49 distinct amino acid-altering variants (36 novel) were identified: KCNQ1 (n = 16), KCNH2 (n = 25),KCNE1 (n = 5), and KCNE2 (n = 3). More than half of these variants (26/49) were found exclusively in black subjects. The known K897T-HERG and the G38S-min K common polymorphisms were identified in all 4 ethnic groups. Excluding these 2 common polymorphisms, 25% of black subjects had at least 1 nonsynonymous potassium channel variant compared with 14% of white subjects (P < .01). CONCLUSIONS: To our knowledge, this study represents the first comprehensive determination of the frequency and spectrum of cardiac channel variants found among healthy subjects from 4 major ethnic groups. Defining the population burden of genetic variants in these critical cardiac ion channels is crucial for proper interpretation of genetic test results of individuals at risk for LQTS. This compendium provides a resource for epidemiological and functional investigation of variant effects on the repolarization properties of cardiac tissues, including susceptibility to lethal cardiac arrhythmias.

Alleles↗

[Genetic counseling and clinical genetics services for cancer prone kindreds].

Gene testing elucidates the identification of heterozygous carrier for hereditary cancer and the needs for genetics services are increasing in cancer hospitals. Genetic services include educational explanation for the disease and Mendelian inheritance, risk assessment, orientation for gene testing, post-test counseling for cancer prevention and psychosocial issues, and support services. This review outlines how they are performed in the clinic of cancer hospital.

Female↗

[Hereditary cancer: identification, genetic heterogeneity, medico-genetic consult].

The paper deals with a role of inherited factors responsible for the occurrence of malignant tumors. Inherited types of cancer are shown to occur virtually at its sites and averaged 5-15%. Formalized criteria for identifying inherited cancer diseases and their etiological and genetic heterogeneity are presented. A role of genes that genetically predispose to particular forms of cancer is shown, which allows for early (preclinical) diagnosis and prevention of cancer diseases.

Genetic Counseling↗

Genetics of suicidal behavior: candidate association genetic approach.

Suicidal behavior runs in families and seemed to be genetically determined in part and independent of the presence of psychiatric disorders. This review presents the current knowledge of candidate gene association studies in the field of suicidology. Concordance for monozygotic twins is about 13% Vs. 0.7% in dizygotics. It seems that there is a relationship to intermediate phenotypes such as impulsivity and aggression. The problem of studying complex traits and of ethnic stratification in heterogeneous population are major concerns in studying genetics of suicide. Family-based methods is one of the strategies to overcome stratification. We found a possible association of tryptophane hydroxylase gene polymorphism with depression and serotonin transporter promoter gene to violence traits by family-based methods. Recent data from the study of COMT. MAO and serotonin receptors genes polymorphisms are controversial at this stage. Future directions for research includes alternative phenotypes, endo-phenotypes and genome scan.

Adolescent↗

[Medico-genetic study of the population of the Samarkand region. II. Population-genetic description of 4 kishlaks of the Urgut district].

This report is a second one in a series of works devoted to the medico-genetical screening of Uzbekistan populations. The paper comprises the results of the analysis of the populational structure of one of the village councils (soviets) of the Urgut District of the Samarkand Region. The main parameters of the population studied were as follows: total number 1529 persons, the average number of inhabitants of one village--328. The proportion of the inhabitants studied--56%, the average number of persons per family--5.22; the average period between subsequent generations--30-35 years, the gametic index--0.8, the inbreeding coefficient inferred from pedigrees--0.018899--0.00781, Fst = 0.03577, the average genetic distanse according to Edwards--0.0231-0.0671. The distribution of Mendelian markers (ABO, Rh, Hp and Ptc) was studied. The observed ratio between a high degree of inbreeding and a relatively low extent of isolation of populations permits to explain satisfactorily the distribution and frequencies of hereditary pathology in the Urgut District of the Samarkand Region pointed out in the previous report.

Adolescent↗