Carter Denniston

Inbreeding and variance effective population numbers

In this paper, a correction and extension of earlier work, we derive expressions for the inbreeding effective number, NeI, and the variance effective number, NeV, with various models. Diploidy, random mating, and discrete generations are assumed and formulas for NeI are given for six situations: isogamous monoecious populations with self‐fertilization permitted or excluded; monoecious populations, male and female gametes distinguished, with self‐fertilization permitted or excluded; and separate sexes with or without male and female progeny distinguished. NeV is given for monoecious and separate‐sexed populations.

X chromosome constitution and the human female phenotype

SummaryThe correlations of abnormal X chromosome constitutions and the resulting phenotypes in the human female are reviewed. The following hypotheses put forward to explain these correlations are discussed in detail: (1) The damage is done before X inactivation; (2) An effect is exerted between reactivation of the X chromosome(s) and meiosis in oocytes; (3) A recessive gene(s) in hemizygous condition might be expressed in the cases in which the same X is active in all cells; (4) A change in the number of presumed active regions on the inactive X chromosomes might have an effect; (5) A position effect, in that the region Xq13-q27 has to be intact in both X chromosomes to allow normal development, may be responsible; (6) An effect during the period when cells with different inactivation patterns compete is a probability; (7) The original X inactivation may be neither regular nor random.The conclusion reached is that the phenotypic effects of a specific X chromosome aberration may be simultaneously exerted through different pathways (Tables 1 and 2). Hypotheses (2), (4), (5), and (6) are considered probable. Hypothesis (3) has been discarded, and there is very little evidence for hypotheses (1) and (7).

Genetic Polymorphism of Human Salivary Proline- Rich Proteins: Further Genetic Analysis

Electrophoresis of concentrated parotid saliva on slab polyacrylamide gels negatively stained with 3,3′-dimethoxybenzidine and hydrogen peroxide (DMB stain) showed nine phenotypes among the proline-rich proteins. These phenotypes are the expression of four autosomal codominant alleles. Gene frequencies are, for Caucasians, Pr1=0.640, Pr1′=0.005, Pr2=0.080, Pr2′=0.275; for Negroes, Pr1=0.700, Pr1′=0.050, Pr2=0.080, Pr2′=0.170; for Chinese, Pr1=0.770, Pr1′=0, Pr2=0, Pr2′=0.230. The presence or absence of another pair of proteins giving the same negative staining is inherited as an autosomal dominant trait (Db). Homozygous Db + + and heterozygous Db + − individuals could not be distinguished. The genetic determinant (Db) for this pair of proteins is either closely linked to or part of the Pr locus. Gene frequencies are, for Caucasians, Db+=0.12, Db−=0.88; for Negroes, Db+=0.56, Db−=0.44; for Chinese, Db+=0.07, Db−=0.93.

Hot spots and functional organization of human chromosomes

SummaryOur working hypothesis is that the Q-darker human chromosome segments have higher gene densities than the bright regions. Especially prominent in this respect are six hot spots, the short Q-dark regions in 3p, 6p, 11q, 12q, 17q, and 19 (p or q), which have been chosen because their density of mitotic chiasmata is above 5. Chromosomes with gene-rich segments would act as trisomy lethals in very early embryos, whose spontaneous abortions would not be recognized. Containing active genes, the regions would be looped out in interphase and thus be more easily available for mitotic pairing and crossing-over.To test this hypothesis, correlations and partial correlations of the following parameters have been determined: the density of mitotic chiasmata, the number and density of localized genes, the incidence of trisomic abortions, the length of chromosomes, and their Q-brightness. Overall, the correlations and partial correlations agree with, but do not prove, the working hypothesis. Far stronger evidence for our hypothesis comes from the highly significant negative effect of hot spots on trisomic abortions which would act as a kind of trisomy lethal. The gene numbers on the hot-spot chromosomes as compared with the controls, on the other hand, are in the right direction, but the difference is not significant.

A possible active segment on the inactive human X chromosome.

An idic(Xp-) in which the two X chromosomes are attached short arm to short arm, and which thus has two b regions (the Q-dark segment next to the centromere on Xp) between the inactivation centers, assumed to be situated on the Q-dark region next to the centromere on Xq, showed 63.8% bipartite Barr bodies as compared with 22.2% formed by idic(Xq-). In addition, the mean distance of the two parts of the Barr bodies in the fibroblasts of a patient with idic(Xp-) is significantly greater than in the cases with one or no b region. Contrary to the other patients with abnormal X chromosomes, the buccal cells of a woman idic(Xp-) showed a number of bipartite Barr bodies. — To explain these observations we have put forward the hypothesis that the b region on the Xp always remains active and thus, when the rest of the chromosome forms a Barr body, this segment is extended, allowing the two parts of the X chromatin to get farther apart and at the same time increasing the percentage of bipartite bodies.

Mutation in Human Populations

Spontaneous mutation in man was reviewed in this series almost a decade ago (Vogel and Rathenberg, 1975). These authors remarked that mutation rates in general, and human rates in particular, had not been the subject of the extensive, systematic study that might be expected from the importance of the subject. That statement is still true. As mentioned by Vogel and Rathenberg, estimates of human mutation rates depend on large epidemiologic studies of a type that were more popular in the 1940s and 1950s than since. As a result, the values given in still earlier reviews (Penrose, 1961; Crow, 1961) do not differ importantly from those of more recent reviews, including the present one.

Polymorphism of Ps (parotid size variant) and detection of a protein (PmS) related to the Pm (parotid middle band) system with genetic linkage of Ps and Pm to Gl, Db, and Pr genetic determinants

Genetic polymorphism of the Ps (parotid size variant) proteins found in saliva is determined by autosomal inheritance of two expressed and one unexpressed allele. This hypothesis is supported by studies in 43 families including 153 children. Gene frequencies determined for 150 randomly collected salivas from whites and 101 randomly collected salivas from blacks are as follows: for whites, Ps1=0.598, Ps2=0.101, Ps0=0.301; for blacks, Ps1=0.185, Ps2=0.126, and Ps0=0.689. The electrophoretic polymorphism is manifested by apparent differences in molecular weights between Ps proteins. The Ps proteins are glycosylated and have an approximate isoelectric point of pI 8.1 as determined by isoelectric focusing in gels. We have also found in saliva the presence of a protein (PmS) which shows strong positive correlations with the presence of the smaller sized Pm (PmF) salivary protein described by Ikemoto et al. (1977). This suggested that PmS is probably part of the Pm protein polymorphic system. For randomly collected salivas from whites, the gene frequencies are PmF+=0.15 (N=140) and PmS+=0.12 (N=150). For randomly collected salivas from blacks, the gene frequency is PmS+=0.24 (N=101). The gene frequency of PmF+ was not determined. Family studies support autosomal inheritance of PmF and PmS proteins. There is strong evidence for linkage of Pm to the proline-rich protein (PPP) “region” (11 families, lod score at ϑ=0.01 is 7.64) and of Ps to the PPP “region” (13 families, lod score at ϑ=0.01 is 11.50). Protein products of six linked loci (Pr, Pa, Db, Ps, Pm, and Gl), when tested against rabbit anti-Gl antiserum, show immunological reactions of partial or complete identity with each other by double diffusion analysis.

Genetic polymorphism of the major parotid salivary glycoprotein (Gl) with linkage to the genes for Pr, Db, and Pa

Genetic polymorphism of the major glycoprotein (Gl) found in parotid saliva is determined by autosomal inheritance of one unexpressed and four expressed alleles. This hypothesis is supported by studies in 41 white families including 146 children. For 143 randomly collected salivas from whites and 82 randomly collected salivas from blacks, maximum likelihood estimates of the gene frequencies are as follows: for whites, Gl1=0.742, Gl2=0.040, Gl3=0.155, Gl4=0.017, Gl0=0.046; for blacks, Gl1=0.459, Gl2=0.050, Gl3=0.337, Gl4=0.044, Gl0=0.110. There is strong evidence for linkage of Gl/Pr (seven families, lod score at θ=0 is 5.24) and Gl/Db (eight families, lod score at θ=0 is 4.45). The allelic products of Gl show evidence for linkage disequilibrium with the products of the Pr, Db, and Pa loci (P<0.0005). On the basis of varying degrees of linkage disequilibrium, Gl may be closer to Db than to Pr or Pa and on the “outside” of Db with respect to Pr or Pa. Amino acid analyses of Gl 1 and Gl 4 proteins show strong resemblances in composition to the major basic glycoprotein and the acidic proline-rich proteins of parotid saliva described by other workers. The polymorphic forms of the Gl proteins show microheterogeneity due to variability in charge and molecular weight. The electrophoretic polymorphism appears to be determined by apparent differences in molecular weights between the Gl proteins.

Genetic polymorphism of PIF (parotid isoelectric focusing variant) proteins with linkage to the PPP (parotid proline-rich protein) gene complex

Genetic polymorphism is found among the PIF (parotid isoelectric focusing variant) salivary proteins after separation by prolonged isoelectric focusing in pH 3.5–5.2 urea polyacrylamide slab gels subsequently stained for protein. Two PIF proteins are either present (PIF +) or absent (PIF −) from all salivas. The phenotypes are determined by autosomal inheritance of two alleles, PIF+ and PIF−. Gene frequencies in randomly collected samples show marked racial differences: among 148 whites, PIF+ is 0.66 and PIF− is 0.34; among 90 blacks, PIF+ is 0.35 and PIF− is 0.65; among 78 Chinese, PIF+ is 0.56 and PIF− is 0.44. Studies in 41 families including 129 children support the interpretation of control of PIF by a single autosomal locus. In 8 PIF+ × PIF− matings, there were 8 PIF− (6.34 expected) children. In 33 PIF+ × PIF+ matings, there were 7 PIF− (6.70 expected) children. Linkage studies indicate that PIF is closely linked to the proline-rich protein (PPP) gene complex (e.g., for six families, lod score at ϑ=0.00 of PIF/G1 is 3.58). In 107 randomly collected samples from whites, PIF is strongly associated with Db (x12=20.02; P<0.0001) and Gl (x12=12.58; P=0.0005) but not with Pr, Ps, Pm, and Pa proteins. These data (probably reflecting genetic disequilibrium) suggest that PIF may be closer to Db and G1 than to other identified loci of the PPP gene complex. The PPP gene complex includes at least seven genes (and probably more) that produce many acidic and basic proline-rich proteins, constituting about two-thirds of parotid salivary proteins that are thought to have important functions at the tooth surfaces.

Mitotic chiasmata, gene density, and oncogenes

SummaryChromosomes with regions rich in mitotic chiasmata in Bloom syndrome (1, 3, 6, 11, 12, 17, 19, and 22) have been compared for various parameters to similar-sized chromosomes 2, 4, 7, 10, 9, 18, 20, and 21 with the following results: (1) The number of genes localized on the test chromosomes is significantly higher (248) than that in the control chromosomes (133). (2) The number of trisomic abortions is significantly lower (45) for the test chromosomes than for the control chromosomes (140). (3) Homogeneously stained regions in neuroblastoma lie at chiasma-containing regions on chromosome arms 1p, 6p, 17q, and 19p or q. (4) The average chiasma density of regions with at least one oncogene is 2.414, whereas that of regions containing no known oncogene is 1.137; however, the difference is not statistically significant. The association of constant cancer chromosome breaks is also in the positive direction, but is not statistically significant.Our tentative conclusion is that the chiasma-rich regions which are Q-dark and early-replicating, and therefore assumed to contain active “housekeeping” genes are extended in interphase. Thus they are available for mitotic crossing-over. In the trisomic state they act as trisomy lethals, leading to early abortions. Being gene-rich they are more likely to contain oncogenes which is reflected also in their agreement with cancer breakpoints. The very high incidence of cancer in Bloom syndrome is a further indication of the possible association of cancer-related phenomena and mitotic crossingover.