Segregation and linkage analyses in families of patients with bipolar,unipolar, and schizoaffective mood disorders.

Hypotheses of single major locus transmission (autosomal and X chromosome) of major affective disorder (i.e., bipolar, unipolar, and schizoaffective) are tested using the Elston-Stewart likelihood method of pedigree segregation analysis. The sample consists of families of varying size ascertained through patients treated at the National Institute of Mental Health in Bethesda, Maryland. We test hypotheses on subsamples of families according to: (1) diagnosis of proband (75 bipolar I, 22 bipolar II, 18 unipolar, and six schizoaffective); (2) extreme value of a biological trait in the proband ("low" monoamine oxidase, "low" cerebrospinal fluid serotonin metabolite 5-HIAA); and (3) positive response to lithium in the proband. We cannot find evidence for single major locus transmission of major affective disorder from segregation analysis in any subsample of family even when the diagnostic classification of ill phenotypes is widened to include possible affective "spectrum" diagnoses. In addition, linkage studies of 21 autosomal markers do not provide evidence for single major locus transmission of illness. The maximum lod score, found for 30 families at the MNS locus, was 1.39 at 20% recombination.     

Interrelationships of Heterozygosity, Growth Rate and Heterozygote Deficiencies in the Coot Clam, Mulinia Lateralis

Allozyme surveys of marine invertebrates commonly report heterozygote deficiencies, a correlation between multiple locus heterozygosity and size, or both. Hypotheses advanced to account for these phenomena include inbreeding, null alleles, selection, spatial or temporal Wahlund effects, aneuploidy and molecular imprinting. Previous studies have been unable to clearly distinguish among these alternative hypotheses. This report analyzes a large data set (1906 individuals, 15 allozyme loci) from a single field collection of the coot clam Mulinia lateralis and demonstrates (1) significant heterozygote deficiencies at 13 of 15 loci, (2) a correlation between the magnitude of heterozygote deficiency at a locus and the effect of heterozygosity at that locus on shell length, and (3) a distribution of multilocus heterozygosity which deviates from that predicted by observed single-locus heterozygosities. A critical examination of the abovementioned hypotheses as sources of these findings rules out inbreeding, null alleles, aneuploidy, population mixing and imprinting as sole causes. The pooling of larval subpopulations subjected to varying degrees of selection, aneuploidy or imprinting could account for the patterns observed in this study.     

The evolutionary dynamics of self-incompatibility systems

Self-incompatible flowering plants reject pollen that expresses the same mating specificity as the pistil (female reproductive tract). In most plant families, pollen and pistil mating specificities segregate as a single locus, the S locus. In at least two self-incompatibility systems, distinct pollen and pistil specificity genes are embedded in an extensive nonrecombining tract. To facilitate consideration of how new S locus specificities arise in systems with distinct pollen and pistil genes, we present a graphical model for the generation of hypotheses. It incorporates the evolutionary principle that nonreciprocal siring success (cross-pollinations between two plants produce seeds in only one direction) tends to favor the rejecting partner. This model suggests that selection within S-allele specificity classes could accelerate the rate of nonsynonymous (amino acid-changing) substitutions, with periodic selective sweeps removing segregating variation within classes. Accelerated substitution within specificity classes could also promote the origin of new S-allele specificities.     

Is the Notch Locus of DROSOPHILA MELANOGASTER a Tandem Repeat? Correlation of the Genetic Map and Complementation Pattern of Selected Mutations

Correlation of the complementation relationships between the Notch locus alleles fa(g), fa(no), Ax(59d) and nd, with their genetic map order, suggests a tandem repetition within the locus of functionally related sites. This observation is discussed in relation to two hypotheses: (1) that the Notch locus contains a tandem repeat of genetic material; and (2) that the tertiary structure of the Notch locus product has a spiral configuration.     

Segregation and linkage studies of plasma dopamine-beta-hydroxylase (DBH), erythrocyte catechol-O-methyltransferase (COMT), and platelet monoamine oxidase (MAO): possible linkage between the ABO locus and a gene controlling DBH activity.

Measurements of dopamine-beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), and monoamine oxidase (MAO) along with 27 polymorphic marker phenotypes were available for 162 patients with major affective disorders and 1,125 of their relatives. Levels of enzymes were previously found not to be associated with illness. Pedigree analysis methods for quantitative traits are used to test single-gene hypotheses for segregation of DBH in 32 families with 411 individuals. COMT in 30 families with 351 individuals, and MAO in 50 families with 309 individuals. The familial distribution of both DBH and COMT are consistent with two codominant alleles at the same locus that account for 56% and 59% of the total variance, respectively. MAO activity cannot be shown to be segregating as a single major gene, but a purely nongenetic hypothesis is also rejected. A possible linkage of a locus for DBH to the ABO locus is indicated by a maximum lod score of 1.82 at 0% and 10% recombination fractions for males and females, respectively. A lod score of 0.61 at 0% recombination for a similar analysis in a single large pedigree was reported by Elston et al., making the combined lod score for the two studies equal to 2.32 at 0% recombination.     

Nonresponsiveness to Mlsd in F1 hybrid mice carrying Mlsa and Mlsc genes

Neither the biological function nor a basic understanding of the enigmatic chromosome 1-encoded Mls locus of the mouse has yet been uncovered despite extensive investigations. The present report is a continuation of our genetic analyses of the Mls locus in an attempt to better define the system. Data presented here indicate that in contrast to cells of mice expressing either the Mlsa or Mlsc allele which respond in mixed leukocyte reactions to cells expressing the Mlsd allelic products, cells from (Mlsa X Mlsc)F1-hybrid mice do not. In addition, the nonresponder phenotype appears to segregate as a single autosomal genetic system in backcross animals. These findings fail to support two recently advanced hypotheses: first, that the Mls locus is nonpolymorphic, or second, that the Mls locus controls differential expression of Ia antigenic determinants. Although the mechanism by which a (responder X responder) converts to a nonresponder remains unknown, three models involving gene complementation are discussed.     

Estimation of allele numbers at the sex-determining locus in a field population of the turnip sawfly (Athalia rosae)

Hymenopteran insects (sawflies, ants, bees, and wasps) have an unusual genetic system called haplodiploidy, where parthenogenetically produced haploid eggs become males, and fertilized, diploid eggs become females. Several hypotheses have been proposed to explain the mechanism of such sex determination, including control at a single polymorphic locus. From experiments of mother-son mating and using a genetic marker, we show that a single multiallele locus controls sex determination in the turnip sawfly (Athalia rosae). We estimated the number of alleles at this single locus in a field population by analyzing the rate of diploid males in the field and the rate of diploid males by random crossing in the laboratory. Only one diploid male was discovered in 1306 diploid larvae collected in the field. However, the number of alleles calculated by random crossing in the laboratory was 45-50. We suggest that the effective population size may be much larger than that from the areas where we collected larvae, and that there are mechanisms for avoiding inbreeding, including protogyny, dispersion, and sperm displacement by second-mated males.     

Platelet monoamine oxidase (MAO) activity: evidence for a single major locus.

Monoamine oxidase (MAO), a mitochondrial enzyme involved in the degradation of biogenic amines, has been associated with psychiatric morbidity. Although twin and family studies have indicated that MAO activity is familial, the exact mode of transmission is unclear. We performed segregation analysis on 154 nuclear families containing 419 individuals using the mixed model, which allows for a single major locus with a polygenic background. We were able to reject a dominant and additive locus with or without a heritable background and a recessive locus without background. The acceptable models were: (1) a codominant model without background where the mean of the heterozygote distribution was 30% of the distance from the low to the high homozygote distributions, and (2) a recessive locus with heritable background. In both cases, the gene frequency for the high-MAO allele is approximately .25--at odds with suggestions that low-MAO represents a genetic marker for a disorder such as schizophrenia with a lifetime risk of only 0.85%. To ensure that results were not artifacts from a familial, skewed distribution, the data were also analyzed after power transformation. In addition, hypotheses were tested using both the joint and conditional likelihoods to examine for possible misspecification of the model with respect to intergenerational differences. Finally, we allowed for non-Mendelian transmission probabilities to provide another class of alternatives against which to test the hypothesis of a major locus. All these approaches provided additional confirmation for the presence of a major locus segregating within these families.     

An exact test for the association between the disease and alleles at highly polymorphic loci with particular interest in the haplotype analysis

The association analysis between the disease and genetic alleles is one of the simple methods for localizing the susceptibility locus in the genes. For revealing the association, several statistical tests have been proposed without discussing explicitly the alternative hypotheses. We therefore specify two types of alternative hypotheses (i.e., there is only one susceptibility allele in the locus, and there is an extension or shortening of alleles associated with the disease) and derive exact tests for the respective hypotheses. We also propose to combine these two tests when the prior knowledge is not sufficient enough to specify one of these two hypotheses. In particular, these ideas are extended to the haplotype analysis of three-way association between the disease and bivariate allele frequencies at two closely linked loci. As a by-product, a factorization of the probability distribution of the three-way cell frequencies under the null hypothesis of no three-way interaction is obtained.     

Ancestral state reconstruction analysis of hymenopteran sex determination mechanisms

We provide the first phylogenetic evidence supporting complementary sex determination (CSD) as the ancestral mechanism for haplodiploidy in the Hymenoptera. It is currently not possible, however, to distinguish the evolutionary polarity of single locus (sl) CSD and multiple‐locus (ml) CSD given the available data. In this light, we discuss the seemingly maladaptive hypothesis of ml‐CSD ancestry, suggesting that collapse from ml‐CSD to sl‐CSD should remain a viable evolutionary hypothesis based on (i) likely weakening of frequency‐dependent selection on sex alleles under ml‐CSD and (ii) recent findings with respect to the evolutionary novelty of the complementary sex determiner gene in honeybees. Our findings help provide a phylogenetically informed blueprint for future sampling of sex determination mechanisms in the Hymenoptera, as they yield hypotheses for many unsampled or ambiguous taxa and highlight taxa whose further sampling will influence reconstruction of the evolutionary polarity of sex determination mechanisms in major clades.     

Estimation of Allele Frequencies at Isoloci

In some polyploid animals and plants, pairs of duplicated loci occur that share alleles encoding proteins with identical electrophoretic mobilities. Except in cases where these ``isoloci' are known to be inherited tetrasomically, individual genotypes cannot be determined unambiguously, and there is no direct way to assign observed variation to a particular locus of the pair. For a pair of diallelic isoloci, nine genotypes are possible but only five phenotypes can be identified, corresponding to individuals with 0-4 doses of the variant allele. A maximum likelihood (ML) approach is used here to identify the set of allele frequencies (p, q) at the individual gene loci with the highest probability of producing the observed phenotypic distribution. A likelihood ratio test is used to generate the asymmetrical confidence intervals around ML estimates. Simulations indicate that the standard error of p is typically about twice the binomial sampling error associated with single locus allele frequency estimates. ML estimates can be used in standard indices of genetic diversity and differentiation and in goodness-of-fit tests of genetic hypotheses. The noncentral χ(2) distribution is used to evaluate the power of a test of apparent heterozygote deficiency that results from attributing all variation to one locus when both loci are polymorphic.     

Phenotypic reversion in some early blocked sporulation mutants of Bacillus subtilis. Genetic study of polymyxin resistant partial revertants

Summary A class of suppressor mutations restores, in pleiotropic sporulation mutants of B. subtilis (SPO mutants), the wild type level of resistance to Polymyxin, and, most often, other properties of the wild strain as well, but never the ability to sporulate. These suppressors, extracistronic, are active on mutations occurring in any one of the 5 genes in which SPO mutations have been found. The phenotype of the suppressed strains is dependent on both the suppressed (SPO) and the suppressive mutations. All these suppressors are located in a single locus and some of them are thermosensitive. The evidence suggests that a physiological compensation is at work in the partial revertants, so that the locus at which the suppressors are located was called cps X. Two hypotheses are discussed that might account for these observations.     

Heterozygote excess in a self-incompatible and partially clonal forest tree species -- Prunus avium L

Wild cherry (Prunus avium L.), a partially asexual self-incompatible forest tree, shows heterozygote excess, which is a poorly studied phenomenon. In three natural populations, we found significant heterozygote excess at almost all investigated loci (eight microsatellites and markers for the self-incompatibility locus). We examined four hypotheses to account for this observed heterozygote excess. First, negative F(IS) can result from a lack of selfed progeny in small populations of outcrossing species. A second explanation for negative F(IS) is selection during the life cycle of the most heterozygous individuals. A third explanation is negative assortative mating when reproduction occurs between individuals bearing phenotypes more dissimilar than by chance. The last explanation for negative F(IS) relies on asexual reproduction. Expectations for each hypothesis were tested using empirical data. Patterns of F(IS) differed among loci. Nevertheless, our experimental results did not confirm the small sample size hypothesis. Although one locus is probably under a hitch-hiking effect from the SI locus, we rejected the effect of the self-incompatibility locus for the genome as a whole. Similarly, although one locus showed a clear pattern consistent with the selection of heterozygous individuals, the heterosis effect over the whole genome was rejected. Finally, our results revealed that clonality probably explains significant negative F(IS) in wild cherry populations when considering all individuals. More theoretical effort is needed to develop expectations and hypotheses, and test them in the case of species combining self-incompatibility and partially asexual reproduction.     

The Sampling Distribution of Disease-Associated Alleles

A theory is developed that provides the sampling distribution of low frequency alleles at a single locus under the assumption that each allele is the result of a unique mutation. The numbers of copies of each allele is assumed to follow a linear birth-death process with sampling. If the population is of constant size, standard results from theory of birth-death processes show that the distribution of numbers of copies of each allele is logarithmic and that the joint distribution of numbers of copies of k alleles found in a sample of size n follows the Ewens sampling distribution. If the population from which the sample was obtained was increasing in size, if there are different selective classes of alleles, or if there are differences in penetrance among alleles, the Ewens distribution no longer applies. Likelihood functions for a given set of observations are obtained under different alternative hypotheses. These results are applied to published data from the BRCA1 locus (associated with early onset breast cancer) and the factor VIII locus (associated with hemophilia A) in humans. In both cases, the sampling distribution of alleles allows rejection of the null hypothesis, but relatively small deviations from the null model can account for the data. In particular, roughly the same population growth rate appears consistent with both data sets.     

Evidence for multigene control of cryptorchidism in swine

The mode of inheritance of cryptorchidism was investigated in Duroc swine. Matings of cryptorchid males with females whose full-sib brothers were cryptorchids were done. Sixteen of these litters were farrowed, and 54 males were born, of which 8 were cryptorchid. Two hypotheses were examined: first, that this trait is controlled by homozygosity of a recessive gene at a single locus; second, that it is controlled by homozygosity of recessive genes at two loci. The single-locus recessive hypothesis was rejected (P less than .01), but the two-locus model was not. Culling to reduce the incidence of cryptorchidism is discussed.     

Molecular phylogeny of the brachyuran crab superfamily Majoidea indicates close congruence with trees based on larval morphology

In this study, we constructed the first molecular phylogeny of the diverse crab superfamily Majoidea (Decapoda: Pleocyemata: Brachyura), using three loci (16S, COI, and 28S) from 37 majoid species. We used this molecular phylogeny to evaluate evidence for phylogenetic hypotheses based on larval and adult morphology. Our study supports several relationships predicted from larval morphology. These include a monophyletic Oregoniidae family branching close to the base of the tree; a close phylogenetic association among the Epialtidae, Pisidae, Tychidae, and Mithracidae families; and some support for the monophyly of the Inachidae and Majidae families. However, not all majoid families were monophyletic in our molecular tree, providing weaker support for phylogenetic hypotheses inferred strictly from adult morphology (i.e., monophyly of individual families). This suggests the adult morphological characters traditionally used to classify majoids into different families may be subject to convergence. Furthermore, trees constructed with data from any single locus were more poorly resolved than trees constructed from the combined dataset, suggesting that utilization of multiple loci are necessary to reconstruct relationships in this group.     

Segregation analysis reveals a major gene effect in compact and cancellous bone mineral density in 2 populations

Involvement of genetic factors in determining bone mineral density (BMD) is doubtless. However, the exact nature of the genes governing BMD variation and sources for genetic determination of BMD of different parts of bone (compact and cancellous) have not been completely studied. The results of the complex segregation analyses performed in our previous study (Livshits et al. 1996) on a Turkmenian sample strongly support the hypothesis that a single Mendelian locus has a large effect on BMD. The parameter estimates for both types of bone tissue were so similar that we could assume a common gene effect for BMD variation of cancellous and compact bone. The objectives of the present study are to test again the possibility of major gene control of BMD in a different ethnic sample of pedigrees, namely, the Chuvasha. In addition, we report here the results of a bivariate segregation analysis of compact and cancellous BMD performed in both the Turkemenian and the Chuvasha samples of pedigrees. The results of the present study closely resemble the results obtained on the Turkmenian pedigrees. Likewise, the major finding of the present study is that there is a significant major gene effect on both compact and cancellous BMD; polygenic hypotheses were clearly rejected. Moreover, the results of the bivariate segregation analysis in both the Chuvasha and Turkmenian samples were similar. They lead to acceptance of the hypothesis that there is a single major locus with pleiotropy to both compact and cancellous bone.     

Different Sources of Allelic Variation Drove Repeated Color Pattern Divergence in Cichlid Fishes

The adaptive radiations of East African cichlid fish in the Great Lakes Victoria, Malawi, and Tanganyika are well known for their diversity and repeatedly evolved phenotypes. Convergent evolution of melanic horizontal stripes has been linked to a single locus harboring the gene agouti-related peptide 2 (agrp2). However, where and when the causal variants underlying this trait evolved and how they drove phenotypic divergence remained unknown. To test the alternative hypotheses of standing genetic variation versus de novo mutations (independently originating in each radiation), we searched for shared signals of genomic divergence at the agrp2 locus. Although we discovered similar signatures of differentiation at the locus level, the haplotypes associated with stripe patterns are surprisingly different. In Lake Malawi, the highest associated alleles are located within and close to the 5′ untranslated region of agrp2 and likely evolved through recent de novo mutations. In the younger Lake Victoria radiation, stripes are associated with two intronic regions overlapping with a previously reported cis-regulatory interval. The origin of these segregating haplotypes predates the Lake Victoria radiation because they are also found in more basal riverine and Lake Kivu species. This suggests that both segregating haplotypes were present as standing genetic variation at the onset of the Lake Victoria adaptive radiation with its more than 500 species and drove phenotypic divergence within the species flock. Therefore, both new (Lake Malawi) and ancient (Lake Victoria) allelic variation at the same locus fueled rapid and convergent phenotypic evolution.