Biomedical subjects
D L Hartl
Publications and source records attributed to D L Hartl.
Allele multiplicity in simple Mendelian disorders.
A model of selection involving two selectively equivalent classes of alleles at a locus is considered. One class consists of normal alleles A1, A2, A3,. . .; the other class consists of detrimental alleles a1, a2, a3, . . . . Mutation within and between allelic classes can occur without restriction, but selection operates in such a way as to maintain an approximately constant overall frequency of A-type and a-type alleles is derived, and it is shown that the distribution of allele frequencies in a sample of detrimental alleles depends on the forward (A to a) mutation rate but not on the selection coefficient, degree of dominance, or mutation rate among a-type alleles. Recurrent mutation therefore generates allelic multiplicity among detrimental alleles, and this is discussed in the context of clinical heterogeneity in simple Mendelian disorders.
Potential for selection among nearly neutral allozymes of 6-phosphogluconate dehydrogenase in Escherichia coli.
Six gnd alleles coding for naturally occurring allozymes of 6-phosphogluconate dehydrogenase [6-phospho-D-gluconate:NAD(P)+ 2-oxidoreductase, EC 1.1.1.43] have been transferred by transduction into the genetic background of Escherichia coli K-12 and examined for their selective effects in chemostats in which gluconate was limiting. Four of the alleles are evidently neutral or nearly neutral, inasmuch as their selective effects, if any, fall below the limit of resolution of the procedure--0.5%/hr or about 1% per generation. One allele is detrimental in limiting gluconate but not in limiting glucose or fructose. Another allele has a detrimental, density-dependent, epistatic interaction with tonA. We suggest that all six alleles are neutral or nearly neutral in natural populations but that they are not functionally equivalent; their functional differences are potentially important because they can become expressed as differences in fitness under the appropriate conditions of environment or genetic background. Under these conditions, otherwise neutral alleles can become subject to selection.
Ultrastructural analysis of spermiogenesis in segregation distorter males of Drosophila melanogaster: the homozygotes.
We have studied spermiogenesis at the ultrastructural level in males of genotype SD(NH)-2/SD-72, which are nearly sterile owing to the dysfunction of virtually all of their sperm. Ultrastructural aspects of spermiogenesis in these homozygous SD males are qualitatively similar to those found among dysfunctional sperm produced by heterozygous SD males. In particular, chromatin condensation and/or compaction has been found to be abnormal. However, major quantitative differences have been noted. Most of the dysfunctional sperm in SD(NH)-2/SD-72 males are individualized and coiled. Then, the sperm evidently undergo degeneration, as few mature sperm can be found in the seminal vesicle. The relevance of these findings to the mechanism leading to near sterility in homozygous SD males is discussed.
Genetic dissection of segregation distortion. III. Unequal recovery of reciprocal recombinants.
The genetic structure of a segregation distorter chromosome (a derivative of SD-36) has been analyzed in a system in which recombination in the second chromosome is blocked by inversions except for the critical region around the centromeric heterochromatin. The results confirm the map order and characteristics of four loci known to be involved in segregation distortion, namely Sd, E(SD), Rspins, M(SD). However, SD-36 carries a fifth major locus involved in distortion. This locus is near pr in 2L and has the effect of enhancing the degree of distortion. In addition, reciprocal recombinant products from SD-36 are recovered unequally. All recombinants carrying the pr region from SD-36 seem also to carry Sd, although Sd has previously been mapped 1.6 units to the left of pr. Both the enhancement of distortion and the unequal recovery of reciprocal products can be explained if it is assumed that the new locus near pr in SD-36 is actually a duplication of Sd.
Selective neutrality of 6PGD allozymes in E. coli and the effects of genetic background.
We have used gluconate-limited chemostats to study selective differences between isogenic strains of Escherichia coli K12 into which four naturally occurring alleles coding for allozymes of 6-phosphogluconate dehydrogenase (6PGD) had been transferred. The limit of detectability of selection with our procedures is a selection coefficient of 0.5%. In the normal E. coli K12 genetic background, all alleles are selectively neutral or nearly neutral. The absence of detectable selection does, however, depend on genetic background and on such environmental factors as cell density. In a genetic background containing a mutation that cuts off the alternative metabolic route for 6-phosphogluconate, selection between allozymes can be detected, and the selection is in the direction expected from the measured apparent Km values of the allozymes. Even when the alternative metabolic route is not blocked by mutation, one of the 6PGD allozymes has a detrimental, but density-dependent, interaction with a mutation conferring resistance to bacteriophage T5. In all cases, the observed selection is due to the allozymes themselves (or to associated regulatory elements), as the selection disappears when the chemostats are limited by a different carbon source (ribose plus succinate). Nevertheless, the four alleles do seem to be selectively neutral or nearly neutral in the normal E. coli K12 genetic background. Moreover, the distribution of allele frequencies in natural populations of E. coli is in accord with the expectations of selective neutrality.
Mechanism of a case of genetic coadaptation in populations of Drosophila melanogaster.
A cryptic polymorphism found in natrual populations of Drosophila melanogaster has been examined in an artificial population maintained for over 200 generations. The polymorphism is selected because it is insensitive to the segregation distorter phenomenon, and it thereby largely preserves the Mendelian rules of segregation. Segregation distorter chromosomes and the cryptic polymorphism form part of a coadapted complex which is associated with linkage disequilibrium in natrual populations.
Mutation-selection balance with stochastic selection.
Diffusion theory has been used to analyze a model of mutation-selection balance in which the selection process is assumed to be stochastic in time. The limiting outcome of the mutation-stochastic selection process is determined qualitatively by the geometric mean fitnesses of the genotypes, and the conditions for fixation or polymorphism are similar to those that determine the outcome of the mutation-selection process when selection is constant. However, in the case of a completely recessive allele, detailed numerical study of the polymorphism associated with stochastic selection has shown that the average allele frequency maintained is greater than the equilibrium frequency expected when selection is constant, even when the geometric mean fitness of the recessive homozygotes is identical in the stochastic and deterministic models. Thus, allele frequencies in natural populations that are too high to be plausibly explained by a balance between mutation and constant selection can be accounted for if selection is stochastic.
Stochastic selection in both haplophase and diplophase.
A population genetic model incorporating the evolutionary forces of zygotic selection, gametic selection and non-Mendelian segregation has been analyzed for the case in which all selection coefficients and the segregation parameter are assumed to be random variables that are uncorrelated from generation to generation. The diffusion approximation of the model is developed, and the subsequent analysis shows that one of four limiting outcomes of the stochastic process may obtain--an allele may be fixed or lost almost surely and irrespective of the initial gene frequency, the gene frequency may converge to a unique stationary distribution, or an allele may be fixed or lost with probabilities depending on the initial gene frequency. These outcomes correspond rather closely with the possible outcomes of the deterministic model--fixation or loss of an allele, convergence to a stable equilibrium, or the existence of an unstable equilibrium.
Histone transition during spermiogenesis is absent in segregation distorter males of Drosophila melanogaster.
Males homozygous for the segregation distorter chromosome are often sterile or nearly sterile as a result of the dysfunction of virtually all their sperm. Spermatid bundles from such males do not exhibit the normal transition from lysine-rich to arginine-rich histones.
Cytogenetic analysis of homozygous segregation distorter males of Drosophila melanogaster.
Certain homozygous SD males are nearly sterile. Sterility is not due to aneuploid gametes--no significant second chromosome nondisjunction was found in matings to attached-2 and mei-S332 females. Some fourth chromosome aneuploidy was observed here, and in the cytological work. Otherwise, cytology of the meiotic divisions was essentially normal. Early spermatid bundles are normal, sperm head counts approximating the normal 64. In the later, coiled bundle stage, one observes less than 30 heads many of which are grossly abnormal: twisted, club-like, or globular. In double mating experiments, SD/SD sperm did not displace normal sperm introduced first. In the reverse experiment, sperm (or fluid) from SD/SD males markedly reduced capacity of the females to store and utilize sperm from normal males, as scored from progeny and by counts of stored sperm. No sperm were seen in the storage organs of females imseminated first by SD/SD then by normal males. Many females refuse such a second mating. Our observations are quantitatively different from those with heterozygous SD males, but qualitatively similar, supporting the view that the near sterility of homozygous SD males arises from a mechanism of sperm dysfunction like that in SD/+ males.
Modifier theory and meiotic drive.
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Genetic dissection of segregation distortion II. Mechanism of suppression of distortion by certain inversions.
In(2L+2R)Cgamma and In(2LR)Pm2 are inversion-bearing chromosomes, the former carrying a paracentric inversion in each arm and the latter carrying a long pericentric. Both chromosomes produce normal segregation ratios when present in heterozygous males with certain segregation distorter chromosomes. The apparent suppression of distortion by these chromosomes was long attributed to a failure of synapsis, but this hypothesis has fallen out of favor recently because a large number of chromosome aberrations, particularly translocations and inversions, suppress distortion even though their breakpoints fall into no recognizable pattern. Although failure of synapsis does not appear to be the mechanism of suppression of distortion, what is responsible for the suppression remains unknown. In this paper it is shown that In(2L+2R)Cgamma and In(2LR)Pm2 suppress segregation distortion because they carry Rsp, a component of the segregation distorter system that renders a chromosome insensitive to distortion. Both chromosomes induce "suicide" of chromosomes carrying Sd Rsp+.
Regulation of newly evolved enzymes. II. The ebg repressor.
The ebg (evolved beta-galactosidase) regulatory locus has been mapped. The map order is argG-ebgA-ebgR-tolC-metC, and there is 1.6% recombination between ebgR and ebgA. Studies with ebgR-/ebgR+ merdiploids have shown that ebgR- is recessive, and it is concluded that the synthesis of ebg enzyme is under negative control.
Adaptive significance of vegetative incompatibility in Neurospora crassa.
Certain features reminiscent of sexuality occur in the vegetative life cycle of some filamentous fungi such as Neurospora crassa. Hyphal fusions can occur between genetically different individuals, thereby endowing the new composite mycelium, a heterokaryon, with some of the advantages of heterozygosity usually associated with diploid organisms. In N. crassa, however, there are a number of incompatibility loci which prevent formation of heterokaryons unless the alleles at the incompatibility loci are identical in the two mycelia. The selection pressures that maintain incompatibility polymorphisms are not known. We suggest here that they are maintained because they prevent a kind of exploitation of heterokaryons by nuclei that are nonadaptive in homokaryons but that enjoy a proliferative advantage over other nuclei in heterokaryons. A mathematical model that abstracts the major features of the vegetative life cycle of Neurosopra crassa has been developed, and the action of selection in this model and various extensions of it is such as to maintain polymorphisms of vegetative incompatibility factors.
Second naturally occurring beta-galactosidase in E. coli.
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Regulation of newly evolved enzymes. I. Selection of a novel lactase regulated by lactose in Escherichia coli.
Thirty-four lactose-utilizing strains of E. coli were selected from a lac Z deletion strain. In 31 of these, the synthesis of the newly evolved lactase is regulated by lactose. The lactase activity in all the strains is indistinguishable from the ebg(+) activity identified by Campbell, Lengyel and Langridge (1973).
Genetic dissection of segregation distortion. I. Suicide combinations of SD genes.
Two major loci in the Tft-cn region of an SD chromosome have been separated by recombination and identified. The allele at the left-hand locus on an SD chromosome is called Sd; the allele at the right-hand locus is called Rsp. Both Sd and Rsp are necessary to bring about a distortion of the segregation ratio in heterozygous SD males, although the particular degree of distortion exhibited by an SD chromosome is influenced by the constellation of polygenic modifiers of SD in the genome. The coupling phase of the alleles, Sd Rsp/Sd(+)Rsp(+), produces about 89-90% of Sd Resp-bearing progeny. The repulsion phase, Sd Rsp(+)/Sd(+)Rsp, produces 10-20% of Sd Rsp(+)-bearing progeny. No coupling-repulsion effects between Sd and Rsp are apparent.