Human Gene Pool Research Articles

Evolution of the nucleoprotein gene of influenza A virus

Nucleotide sequences of 24 nucleoprotein (NP) genes isolated from a wide range of hosts, geographic regions, and influenza A virus serotypes and 18 published NP gene sequences were analyzed to determine evolutionary relationships. The phylogeny of NP genes was determined by a maximum-parsimony analysis of nucleotide sequences. Phylogenetic analysis showed that NP genes have evolved into five host-specific lineages, including (i) Equine/Prague/56 (EQPR56), (ii) recent equine strains, (iii) classic swine (H1N1 swine, e.g., A/Swine/Iowa/15/30) and human strains, (iv) gull H13 viruses, and (v) avian strains (including North American, Australian, and Old World subgroups). These NP lineages match the five RNA hybridization groups identified by W. J. Bean (Virology 133:438-442, 1984). Maximum nucleotide differences among the NPs was 18.5%, but maximum amino acid differences reached only 10.8%, reflecting the conservative nature of the NP protein. Evolutionary rates varied among lineages; the human lineage showed the highest rate (2.54 nucleotide changes per year), followed by the Old World avian lineage (2.17 changes per year) and the recent equine lineage (1.22 changes per year). The per-nucleotide rates of human and avian NP gene evolution (1.62 x 10(-3) to 1.39 x 10(-3) changes per year) are lower than that reported for human NS genes (2.0 x 10(-3) changes per year; D. A. Buonagurio, S. Nakada, J. D. Parvin, M. Krystal, P. Palese, and W. M. Fitch, Science 232:980-982, 1986). Of the five NP lineages, the human lineage showed the greatest evolution at the amino acid level; over a period of 50 years, human NPs have accumulated 39 amino acid changes. In contrast, the avian lineage showed remarkable conservatism; over the same period, avian NP proteins changed by 0 to 10 amino acids. The specificity of the H13 NP in gulls and its distinct evolutionary separation from the classic avian lineage suggests that H13 NPs may have a large degree of adaptation to gulls. The presence of avian and human NPs in some swine isolates demonstrates the susceptibility of swine to different virus strains and supports the hypothesis that swine may serve as intermediates for the introduction of avian influenza virus genes into the human virus gene pool. EQPR56 is relatively distantly related to all other NP lineages, which suggests that this NP is rooted closest to the ancestor of all contemporary NPs. On the basis of estimation of evolutionary rates from nucleotide branch distances, current NP lineages are at least 100 years old, and the EQPR56 NP is much older.(ABSTRACT TRUNCATED AT 400 WORDS)

New notes from underground∗

An American underground man examines arguments to evidence his thesis that Huxley's ‘really revolutionary revolution in the souls and flesh of human beings’ is being fomented by respected scientific rationalists. Believing that Homo sapiens is an evolutionary error, these benevolent intellectuals wish to alter the human gene pool in order to circumvent genosuicide. Mindful of the veridical knowledge of man issuing from current research in the biological and neurosciences, the underground man contends that these precursors of mankind's second genesis are gradually undermining resistance to the transition from natural to artificial selection of the human genotype by disinheriting the collective mind of the superannuated mythologems controlling it: the practitioners of normal science being latter‐day governors or puppeteers exhibiting radically new empirical models of cosmos and man in the shadows of a contemporary Platonic cave. Seeking to awaken the educated public to ominous events of evolutionary enormit...

A genetically controlled pairing anomaly between HLA-DQ alpha and HLA-DQ beta chains.

The HLA-DQ region contains highly polymorphic alpha and beta loci, so that a diverse set of cis- and trans-associated class II alpha/beta dimers are potentially generated in heterozygous individuals. To evaluate the extent of this predicted diversity, DQ2 beta or DQ3.2 beta cDNA were introduced into a panel of homozygous B cell lines that expressed different DQ alpha alleles. Restricted patterns of alpha/beta pairing were observed in which DQ2 beta and DQ3 beta molecules were unable to pair efficiently with DQ1 alpha chains. This pairing anomaly may contribute to altered class II phenotypes in heterozygous individuals, and is reflected in the absence of either DQ1 alpha, DQ2 beta or DQ1 alpha, DQ3 beta haplotypes in the known human gene pool.

Common genetic pools between human populations.

A further inquiry on modern human origins, based on common genetic pool surveys of rigorously selected population samples and highly informative immunological polymorphisms, provides new evidence of an Occidental-Oriental population split as the origin of human gene pool divergences. The most likely ancestral genetic profile is discussed in the context of the debate raised by preliminary DNA restriction fragment length polymorphism studies, which contradict the conclusions drawn from classical blood group analyses.

A genetic model of dental reduction through the probable mutation effect.

A simulation approach is used in order to elucidate the nature of the hypothesized "probable mutation effect" as it applies to dental reduction in man. Computer-generated simulations of the accumulation of mutations in a human gene pool show the results of the proposed model under the influence of various parameters, as well as illustrating the nature of such genetic change through time. This approach supports a polygenic model of the probable mutation effect as a viable hypothesis for an explanation of the dental reduction which has occurred in some human populations over the last 40,000 years.

Human genetic engineering

The author addresses the new ethical and conceptual uncertainties posed by the application of gene-splicing techniques to human beings, an application of technology that raises complex ethical and social public policy issues. The author reviews the advances in the medical uses of gene-splicing, and addresses their consequences on (1) human genetic makeup; (2) intergenerational responsibilities; (3) the distribution of social benefits; and (4) the conception of what a person is. He describes the first two effects as posing new ethical uncertainties by being able to change the human gene pool, and with that change affect people's links to-and responsibilities for-their progeny. The latter two raise new questions of conceptual uncertainty concerning how these technologies will be distributed and to whom, and the resulting social and public consequences that arise from the potentially profound genetic changes possible to the individual. The author concludes by noting the need for circumspection to avoid the unfavorable effects of successes with this technology, which can be done, he notes, by using those goals and values that constitute the ethics and practice of medicine, namely, the application of science and art to human needs.

A new orthomolecular protocol for treating multiple sclerosis and related diseases

Because of a defective gene in the human gene pool and the poor and inadequate correction of the resulting potentially-fatal birth defect, Hypoascorbemia, all multiple sclerosis (MS) patients, as well as victims of other ailments, are a scorbutic population suffering from two diseases, the second disease being chronic subclinical scurvy (the CSS Syndrome). Recent work has added support to the hypothesis that MS is a viral infection of the central nervous system (CNS). It is known that the elimination of the chronic subclinical scurvy in patients afflicted with a wide spectrum of serious viral infections, using daily megadoses of ascorbate in the range of about 100 to 300 grams, provides rapid relief of the viral disease. It is proposed that double-blind clinical studies be conducted on a non-scorbutic population of MS victims, using a protocol which eliminates their chronic subclinical scurvy with the proper daily “mega” intakes of ascorbate.

Careers in Medical Genetics

M EDICAL GENETICS PROVIDES challenge and opportunity for the deeper understanding of the place of humans in the world of living things and for improving the quality of life. Rich and varied careers exist in basic scientific research, in population studies, in genetic medicine, or in the newly allied interdisciplinary approaches to other life sciences, law, social sciences, and engineering. Genetic research has established the physical basis of heredity and has demonstrated that the fundamental rules of inheritance are the same in all living organisms. The close association between genetics and evolution led to the development of population genetics. Many genetic problems require study of large groups rather thaii the laboratory study of selectively bred individuals. Population geneticists observe gene frequency distributions, selection for natural fitness measured by production of offspring, and the occurrence of present and past mutations. Biomedical achievements have had dramatic and profound effects. They range from basic research leading to the discovery of the structure and function of DNA, considered by some to be the major achievement of the century, to the development of new modes of diagnosis and treatment for a large number of heritable disorders and defects, only recently identified, which have become the new clinical specialty known as genetic medicine. Genetic screening and counseling are integral to the work of practitioners in this field. The social implications of medical genetics have spread beyond conventional boundaries and into other fields, notably those of law and ethics (Shaw 1973). We must improve our understanding of how the rapid advances or this science will affect society as a whole, to formulate answers to the questions raised that will have an impact on the lives and values of us all. The human gene pool is the primary resource of humankind. It is the culmination of 3 billion years of evolution and natural selection during which 99% of all species have become extinct, despite the abundant diversity we see around us. A word of caution is in order, however. The engineering of human development to permit survival of the genetically handicapped, called euphenics, has resulted in keeping deleterious genes in the pool. Having thwarted the process of natural selection in human biological history, we must plan carefully to deal with the consequences of unwise choices in the past and to make new choices in the future that provide alternatives for improving the quality of life. Applications of genetics, abundant in medicine, are also found in many other disciplines. Geneticists can be found among biochemists, botanists, agronomists, zoologists, animal husbandry specialists, veterinarians, microbiologists, embryologists, ecologists, nutritionists, immunologists, pharmacologists, toxicologists, exobiologists, paleobiologists, molecular biologists, cell biologists, demographers, anthropologists, dental and medical specialists. Medical geneticists can be found experimenting in the research laboratory, gathering data in the field for analysis in the computer laboratory, and seeing patients in the hospital or outpatient clinic. A review of current and future areas of investigation should be of interest to those contemplating a career in medical genetics. Dolores A. Lamb is assistant to the director, Medical Genetics Center, The University of Texas Health Science Center at Houston Graduate School r of Biomedical Sciences, Post Office Box 20334, Astrodome Station, Houston, Texas 77025. She received her B.A. degree from the University of Texas Institute of Latin American Studies in 1956, and did graduate work at the South Texas College of Law in 1971-72. Prior to joining the staff of the Medical Genetics Center, Lamb was associated with the M.D. Anderson Hospital and Tumor Institute. Margery W. Shaw is director of the Medical Genetics Center, at the Houston Graduate School of Biomedical Sciences. She received her A.B. degree from the University of Alabama in 1945; her M.A. degree from Columbia University in 1946; her M.D. degree from the University of Michigan in 1957; her J.D. degree from the University of Houston in 1973; and an honorary D.Sc. degree from the University of Evansville in 1977. She is active in a number of professional and public organizations. Shaw has given over 75 invited lectures and published over 150 articles. The research for this article was supported by the Medical Genetics Center Grant GM 19513.

The case against abortion.

THE CASE AGAINST ABORTION T HIS ESSAY has but one purpose, namely, to attempt to defend the view that abortion is morally wrong. In seeking this end, the discussion will proceed as follows: First, the main argument against abortion will be critically analyzed and its weaknesses noted. This done, the argument will be modified and, it is hoped, strengthened. Second , the traditional defenses of abortion will be considered and the following two contentions supported: (I) No argument for abortion has succeeded in establishing that such an act is morally justifiable/ and (2) the reason this is so is that the abortion advocates' moral judgment is based, not on fact but rather on subjectively distorted "fact." Finally, my thesis having been fully developed, one possible counter to my arguments will be anticipated. Here, the abortion advocates' position will be re-cast in such a way that it would appear to avoid the thrust of my criticisms. It will be shown, however, that no atempt to defend abortion along the lines thus specified can hope for success. I To begin, how to do those unalterably opposed to abortion usually defend their views? The argument takes various forms, but in its strongest presentation it runs as follows: From conception on, it is claimed, the organism is a human being; and as human it possesses human rights. One of these rights is, as we all recognize, the right to life. Now, when an abortion is effected, the zygote's right to life has been knowingly and 1 This statement may have one exception; viz., it may be legitimate to permit abortion in cases wherein the expectant mother will die unless her pregnancy is terminated. Incidents such as this occur so rarely, however, that they hardly seem worth mentioning. 65 66 JAMES M. HUMBER purposefully violated. Clearly, such action must be considered immoraP If the above fairly represents the conservative position, how may those arguing for an opposing view hope to avoid its conclusion ? The first line of attack is simply to doubt that the conceptus is human. What, it is asked, is the basis for this belief? In reply to questions of this sort the conservative usually answers as follows: ... humanity is an attribute which anyone conceived by a man and a woman has. . . . A being with the human genetic code is Homo sapiens in potency; and his potential capacity to reason makes him share in the universal characteristic of man.8 Or, put another way: Indeed, microgenetics seems to have demonstrated what religion never could; and biological science, to have resolved an ancient theological dispute. The human individual comes into existence first as a minute information speck, drawn at random from many other minute informational specks his parents possessed out of the common human gene pool. This took place at the moment of impregnation . . . . Thus it can be said that the individual is whoever he is going to become from the moment of impregnation.4 That is, microgenetics is said to demonstrate that it is at conception that a being with a human genetic code begins its existence . Since it is the possession of this " code " which makes something human, it is that point (conception) which must be taken as the start of human life. And if this is so, abortion must be seen as halting a human's development by terminating his or her existence. In short, abortion must be murder. As thus stated, the conservatives' argument must surely fail. • I shall refer to this as the conservative position or hardline view. Counted among its proponents are: John T. Noonan Jr. "Abortion and the Catholic Church: A Summary History," Natural Law Forum, Vol. 1!'l (1967); Paul Ramsey, "The Morality of Abortion," in Life or Death: Ethics and Options (Seattle: University of Washington Press, 1968); David Granfield, The Abortion Decision (New York: Doubleday, 1969); and Germain Grisez, Abortion: the Myths, the Realities, and the Arguments (New York: Corpus Publications, 1970). 8 Noonan, "Abortion and Catholic Church," pp. 128-1!'l9. • Ramsey, "Morality of Abortion," pp. 61-62. THE CASE AGAINST ABORTION 67 Simply put, it neglects to consider all the relevant evidence and may therefore be attacked in at least two ways...

Some Medical and Social Aspects of the Treatment for Genetic-Metabolic Diseases

By enhancing the survival of certain patients with inheritable disorders, advances in medical therapy have pro duced an apparent conflict between medical ethics and the natural laws governing the viability of humans. There has arisen considerable concern that the quality of the human gene pool will deteriorate if medicine succeeds in significantly alter ing the survival and reproductive fitness of individuals with deleterious genetic disorders which were heretofore selected against by nature. A review of the successful treatment cur rently used for phenylketonuria (PKU) is given as an example of therapy for a genetic disorder which will not significantly increase the gene frequency in the population. However, the disastrous and unexpected results of reproduction by phenyl ketonuric women dramatically illustrate the unforeseen prob lems that may arise from new therapeutic approaches. Ther apy that confers normal reproductive fitness on a previously incapacitating disorder inherited in a dominant manner will increase the future frequency of the disorder. Medicine is now in the early stages of implementing methods of efficient genetic counseling and prenatal diagnosis which will not only benefit the affected family but will hopefully lessen the impact of deleterious genetic diseases on future generations.

The place of genetics in medicine.

This convocation oration surveys a number of areas in human genetics that are relevant to medical practice. Among the topics dealt with are premendelian empirical findings on transmission of disease states and their later rational interpretation in terms of mendelian genes, genetic counseling, treatments of inborn errors of metabolism, amniocentesis and pregnancy termination, pharmacogenetics, and linkage studies of the genes in human chromosomes as tools in genetic prognosis. Ethical problems are dealt with, such as problems related to secrecy concerning genetic defects, therapeutic abortions, increases in the load of mutations in the human gene pool because of therapeutic successes, deliberate manipulation of genes at the biochemical level, and differential reproduction of genetically different population samples, as well as experimental embryological methods applied to humans, such as cloning.

On the effects of genetic counselling on gene frequencies.

It has been suggested that genetic counselling and therapeutic abortion can lead to increases in the frequencies of autosomal genes determining recessive diseases. Algebra for calculating the consequences of such practices is presented, together with numerical results for one generation where the effects are seen to be very slight. It is concluded that genetic counselling poses no real threat to the human gene-pool in the short term.

The mutagenic properties of the nucleosides of pyrimidine analogues in Drosophila melanogaster

The mutagenic activity of the 5-halogen derivatives of deoxyuridine (FUdR, BUdR and IUdR), cytosine arabinoside (CA), 6-azauridine (AzUR) and 6-azacytidine (AzCR) were tested on the male germ line of Drosophila. All compounds were inactive as regards the induction of point mutations (sex-linked recessive lethals and visibles). They were also virtually ineffective in the induction of viable chromosome rearrangements; the highest yield of X-chromosome fragments occurred with IUdR, but only reached a rate of 1 per 10 4 treated gametes. The only mutations induced at an appreciable rate by the tested nucleosides were the small chromosome deletions resulting in the Minute phenotype. Maximal activity in this respect was of the order of 5 mutations per 10 3 treated sperm and was obtained at an injected concentration of 2·0 × 10 −2 M; further increase in dose did not raise the mutation rate. Mutagenic activity was roughly the same for compounds that could enter DNA (BUdR, IUdR and CA) as with those which were not expected to do so (FUdR, AzUR and AzCR). Activity was higher on cells that could undergo nucleoprotein synthesis and chromosome replication (spermatocytes and spermatogonia) than on stages that were inert in this respect (spermatids and sperm). The damage induced consisted of chromosome deletions involving more than one band of the salivary gland chromosome, suggesting the elimination of several DNA molecules. The chromosome breaks leading to the deletions extended across both chromatids, since the resulting Minutes were almost exclusively complete (non-mosaic). The distribution of the Minutes among the chromosomes was somewhat more preferential for the IVth chromosome with the tested compounds, except CA. Consideration was given to the possible genetic hazards to man involved in the chemotherapeutic use of IUdR, AzUR and AzCR. Attention was drawn to the fact that long term genetic hazards were mainly caused by the rise in point-mutations, which persisted for many generations in the human gene pool. Such hazards would not occur with the nucleosides since they were virtually inactive as regards the induction of intragenic changes. Nevertheless, the small chromosome deletions which these agents produced, were expected to result in short term genetic damage in the treated patients and their offspring.